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1.
Expert Rev Med Devices ; 20(9): 729-739, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37537898

RESUMO

INTRODUCTION: A key determinant of prosthesis use is the quality of fit of the prosthetic socket. The socket surrounds the residual limb and applies the appropriate force distribution to the soft tissues to maintain suspension, support, and stabilization as well as translate limb movement to prosthesis movement. The challenge in socket fabrication lays in achieving geometry that provides the appropriate force distribution at physiologically appropriate locations; a task dependent on the understanding of interface tissue-mechanics. AREAS COVERED: In the last 20 years substantial advancements in sensor innovation and computational power have allowed researchers to quantify the socket-residual limb interface; this paper reviews prominent measurement and sensing techniques described in literature over this time frame. Advantages and short comings of each technique are discussed with a focus on translation to clinical environments. EXPERT OPINION: Prosthetic sockets directly influence comfort, device use, user satisfaction, and tissue health. Advancements in instrumentation technology have unlocked the possibility of sophisticated measurement systems providing quantitative data that may work in tandem with a clinician's heuristic expertise during socket fabrication. If validated, many of the emerging sensing technologies could be implemented into a clinical setting to better characterize how patients interact with their device and help inform prosthesis fabrication and assessment techniques.


Assuntos
Membros Artificiais , Implantação de Prótese , Humanos , Desenho de Prótese , Fenômenos Mecânicos , Extremidades , Cotos de Amputação
2.
Orthod Craniofac Res ; 26(4): 531-538, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36807468

RESUMO

INTRODUCTION: The presented study investigates differences in the biomechanics of straight and mushroom fixed lingual appliances when implementing coil springs and stops for anterior arch expansion. MATERIALS AND METHODS: An in vitro orthodontic simulator was used to measure three-dimensional forces and moments on each tooth of a simulated maxillary arch. Mushroom and straight archwire forms of 0.016″ NiTi round archwire were considered, using 0.010″ × 0.030″ NiTi open coils and 0.016″-0.018″ archwire stops (n = 44 per group). Teeth in the anterior dental arch were moved from a neutral to crowded position to replicate anterior crowding of central and lateral incisors. Forces and moments of interest for lateral incisors and first premolars were compared using repeated measures mixed multivariate analysis of variance (α = 0.05). RESULTS: Three comparisons between straight versus mushroom archwires and two comparisons of coil springs vs. stops were not statistically significant. Overall, it was found that the use of a straight lingual archwire produced larger differences in forces and moments between using stops and coil springs than when using a mushroom archwire. Using stops produced larger forces and moments for both types of archwires as compared to using coil springs. The largest expansion forces were produced using straight archwires with stops, exceeding 3.0 N of force. Straight archwires with coil springs produced the lowest expansion forces on lateral incisors, just exceeding 1.5 N. CONCLUSIONS: The findings of this study have elucidated significant differences in the biomechanics of transverse arch expansion using straight or mushroom fixed lingual appliances with coil springs or stops.


Assuntos
Má Oclusão , Braquetes Ortodônticos , Humanos , Fenômenos Biomecânicos , Desenho de Aparelho Ortodôntico , Fios Ortodônticos , Aparelhos Ortodônticos Fixos , Titânio , Técnicas de Movimentação Dentária/métodos
3.
Sci Rep ; 12(1): 22280, 2022 12 24.
Artigo em Inglês | MEDLINE | ID: mdl-36566292

RESUMO

Ice hockey is a dynamic and competitive sport that requires a high level of neuromuscular and cardiovascular function. An objective assessment of skating helps coaches monitor athletes' performance during training sessions and matches. This study aimed to estimate the temporal and spatial parameters of skating by proposing an optimized configuration of wearable inertial measurement units (IMUs) and validating the system compared to in-lab reference systems. Ten participants were recruited to skate on a 14 m synthetic ice surface built in a motion-capture lab. Eight original event detection methods and three more adopted from gait analysis studies were implemented to detect blades-off and skate-strikes. These temporal events were detected with high accuracy and precision using skate-mounted IMUs. Also, four novel stride length estimation methods were developed to correct the estimated skaters' position using IMUs' readouts. The stride time, contact time, stride length, and stride velocity were obtained with relative errors of 3 ± 3%, 4 ± 3%, 2 ± 6%, and 2 ± 8%, respectively. This study showed that the wearable IMUs placed on skates and pelvis enables the estimation of temporal and spatial parameters of skating with high accuracy and precision, which could help coaches monitor skaters' performance in training.


Assuntos
Desempenho Atlético , Hóquei , Patinação , Dispositivos Eletrônicos Vestíveis , Humanos
4.
Sensors (Basel) ; 22(10)2022 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-35632311

RESUMO

A commonly cited reason for the high abandonment rate of myoelectric prostheses is a lack of grip force sensory feedback. Researchers have attempted to restore grip force sensory feedback by stimulating the residual limb's skin surface in response to the prosthetic hand's measured grip force. Recent work has focused on restoring natural feedback to the missing digits directly through invasive surgical procedures. However, the functional benefit of utilizing somatotopically matching feedback has not been evaluated. In this paper, we propose an experimental protocol centered on a fragile object grasp and lift task using a sensorized myoelectric prosthesis to evaluate sensory feedback techniques. We formalized a suite of outcome measures related to task success, timing, and strategy. A pilot study (n = 3) evaluating the effect of utilizing a somatotopically accurate feedback stimulation location in able-bodied participants was conducted to evaluate the feasibility of the standardized platform, and to inform future studies on the role of feedback stimulation location in prosthesis use. Large between-participant effect sizes were observed in all outcome measures, indicating that the feedback location likely plays a role in myoelectric prosthesis performance. The success rate decreased, and task timing and task focus metrics increased, when using somatotopically-matched feedback compared to non-somatotopically-matched feedback. These results were used to conduct a power analysis, revealing that a sample size of n = 8 would be sufficient to achieve significance in all outcome measures.


Assuntos
Membros Artificiais , Retroalimentação , Mãos , Humanos , Projetos Piloto , Desenho de Prótese
5.
Sensors (Basel) ; 23(1)2022 Dec 28.
Artigo em Inglês | MEDLINE | ID: mdl-36616932

RESUMO

Hockey skating objective assessment can help coaches detect players' performance drop early and avoid fatigue-induced injuries. This study aimed to calculate and experimentally validate the 3D angles of lower limb joints of hockey skaters obtained by inertial measurement units and explore the effectiveness of the on-ice distinctive features measured using these wearable sensors in differentiating low- and high-calibre skaters. Twelve able-bodied individuals, six high-calibre and six low-calibre skaters, were recruited to skate forward on a synthetic ice surface. Five IMUs were placed on their dominant leg and pelvis. The 3D lower-limb joint angles were obtained by IMUs and experimentally validated against those obtained by a motion capture system with a maximum root mean square error of 5 deg. Additionally, among twelve joint angle-based distinctive features identified in other on-ice studies, only three were significantly different (p-value < 0.05) between high- and low-calibre skaters in this synthetic ice experiment. This study thus indicated that skating on synthetic ice alters the skating patterns such that the on-ice distinctive features can no longer differentiate between low- and high-calibre skating joint angles. This wearable technology has the potential to help skating coaches keep track of the players' progress by assessing the skaters' performance, wheresoever.


Assuntos
Hóquei , Dispositivos Eletrônicos Vestíveis , Humanos , Fenômenos Biomecânicos , Gelo , Hóquei/lesões , Extremidade Inferior
6.
Ann Biomed Eng ; 49(10): 2957-2972, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33999296

RESUMO

In helmet impact testing, parameters including acceleration and velocity are measured using instrumented head-neck models that are meant to be mechanically realistic (i.e. biofidelic) stand-ins, or surrogates, for humans. Currently available models of the human neck are designed primarily for application in automotive crash testing, and their applicability in assessment of helmets is often questioned. The object of the present work is to document the mechanical design, repeatability, and biofidelity in low speed impact of a new neck model that we apply with a Hybrid III head. Focusing on Hybrid III head kinematics measured during impacts at 2 to 6 m/s, the co-efficient of variance of repeated measures of kinematics was generally less than 10%. Differences in kinematics between identical copies of the neck was less than 20% when tested with helmets, and less than 7% when the head was not helmeted. In parallel testing using a Hybrid III head-neck, the co-efficient of variance in repeated measures was less than 4% and the kinematics significantly differed from those measured using the new neck. CORAplus scores for the new neck were approximately 0.70 when compared against data for human subjects with passive neck muscles experiencing impact at 2 m/s.


Assuntos
Cabeça , Modelos Anatômicos , Modelos Biológicos , Músculos do Pescoço/fisiologia , Pescoço/fisiologia , Aceleração , Fenômenos Biomecânicos , Futebol Americano , Dispositivos de Proteção da Cabeça , Hóquei , Humanos , Masculino , Reprodutibilidade dos Testes , Equipamentos Esportivos
7.
Cancers (Basel) ; 13(7)2021 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-33916118

RESUMO

The identification of biomarker-driven targeted therapies for patients with triple negative breast cancer (TNBC) remains a major clinical challenge, due to a lack of specific targets. Here, we show that cyclin E, a major regulator of G1 to S transition, is deregulated in TNBC and is associated with mutations in DNA repair genes (e.g., BRCA1/2). Breast cancers with high levels of cyclin E not only have a higher prevalence of BRCA1/2 mutations, but also are associated with the worst outcomes. Using several in vitro and in vivo model systems, we show that TNBCs that harbor either mutations in BRCA1/2 or overexpression of cyclin E are very sensitive to the growth inhibitory effects of AZD-1775 (Wee 1 kinase inhibitor) when used in combination with MK-4837 (PARP inhibitor). Combination treatment of TNBC cell lines with these two agents results in synergistic cell killing due to induction of replicative stress, downregulation of DNA repair and cytokinesis failure that results in increased apoptosis. These findings highlight the potential clinical application of using cyclin E and BRCA mutations as biomarkers to select only those patients with the highest replicative stress properties that may benefit from combination treatment with Wee 1 kinase and PARP inhibitors.

8.
J Mech Behav Biomed Mater ; 114: 104196, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33221162

RESUMO

Orthodontic archwire rotation around its long axis, known as third-order torque, is utilised to correct tooth rotational misalignments moving the tooth root closer to or away from the cheek through engagement with an orthodontic bracket. Studying the behaviour of archwire and brackets during an applied rotation can aid in better understanding and appreciating the mechanics of third-order torque, potentially allowing for more effective orthodontic treatment protocols. Mechanically characterising archwire behaviour during third-order torque application is a complex task due to their physical scale and geometries. An advanced measurement technique was needed to address these constraints. A three-dimensional (3D) non-contact optical method using a digital image correlation (DIC) system was developed. An orthodontic torque simulator (OTS) was used to apply and measure third-order torque with 0.483 × 0.635 mm (0.019″ x 0.025″) rectangular archwires in tandem with a 3D DIC system, whereby surface deformations and strains could be computed using correlation algorithms. The 3D DIC system was implemented to enable third-order torque experimentation with the OTS while imaging the archwire and bracket surfaces. The 3D DIC system's ability to measure 3D archwire deformations and strains was verified using a finite element model, where comparisons between 3D DIC measurements and calculated results from the model were made to ensure the measurement capabilities of 3D DIC in the context of third-order torque. The 3D DIC system was then used to compare archwire behaviour between stainless steel (SS) and titanium molybdenum alloy (TMA) archwires to study potential clinical differences in archwire behaviour, in which the archwires were rotated with a custom SS rigid dowel (RD) as well as commercial Damon Q orthodontic brackets. The quantification of third-order torque and archwire deformations and strains led to the conclusion that SS archwires led to larger torque magnitudes compared to TMA archwires. The RD resulted in larger archwire strains compared to Damon Q brackets. The 3D DIC system provides a non-contact measurement technique that can further be used with third-order torque experimentation with the OTS.


Assuntos
Braquetes Ortodônticos , Fios Ortodônticos , Ligas Dentárias , Análise do Estresse Dentário , Teste de Materiais , Desenho de Aparelho Ortodôntico , Aço Inoxidável , Propriedades de Superfície , Titânio , Torque
9.
Angle Orthod ; 90(5): 688-694, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-33378485

RESUMO

OBJECTIVE: To compare the biomechanics of straight labial, straight lingual, and mushroom lingual archwire systems when used in posterior arch expansion. MATERIALS AND METHODS: An electro-mechanical orthodontic simulator allowing for buccal-lingual and vertical displacements of individual teeth and three-dimensional force/moment measurements was instrumented with anatomically shaped teeth for the maxillary arch. In-Ovation L brackets were bonded to lingual surfaces, and Carriere SLX brackets were bonded to labial surfaces to ensure consistency of slot dimensions. Titanium molybdenum archwires were bent to an ideal arch form, and the teeth on the orthodontic simulator were set to a passive position. Posterior teeth from the canine to second molar were moved lingually to replicate a constricted arch. From the constricted position, the posterior teeth were simultaneously moved until the expansive force decreased below 0.2 N. Initial force/moment systems and the amount of predicted expansion were compared for posterior teeth at a significance level of α = 0.05. RESULTS: Archwire type affected both the expected expansion and initial force/moment systems produced in the constricted position. In general, the lingual systems produced the most expansion. The archwire systems were not able to return the teeth to their ideal position, with the closest system reaching 41% of the intended expansion. CONCLUSIONS: In general, lingual systems were able to produce greater expansion in the posterior regions when compared with labial systems. However, less than half of the intended arch expansion was achieved with all systems tested.


Assuntos
Braquetes Ortodônticos , Fios Ortodônticos , Fenômenos Biomecânicos , Incisivo , Desenho de Aparelho Ortodôntico , Técnicas de Movimentação Dentária
10.
J Theor Biol ; 495: 110251, 2020 06 21.
Artigo em Inglês | MEDLINE | ID: mdl-32199857

RESUMO

Muscle is typically modelled using a lump sum idealization, scaling a single fascicle to represent the entire muscle. However, fascicles within a muscle have unique orientations, which could result in forces exerted not only in the axis running along the tendon, but also the two perpendicular axes, describing the muscle's width and depth. The purpose of this research was to develop a geometric-based model of the soleus, medial gastrocnemius, and lateral gastrocnemius as distributed force systems which can predict three-dimensional forces. Measurements were taken from the triceps surae in two human cadavers (80 and 85 years old). These models predicted muscle volumes and ankle plantar flexor moments that were realistic considering the age of the cadavers. Small differences were observed in calcaneal tendon force and moment for the distributed force models compared to modelling muscle force using a lump sum idealization. The major finding of the distributed force models was that forces were present in the axes corresponding to the muscle's length, width, and depth. The forces in the width and depth axes may be relevant for evaluating how muscle shape changes during contraction, as well as to investigate stress-strain patterns along the muscle's proximal and distal aponeuroses.


Assuntos
Tendão do Calcâneo , Modelos Biológicos , Contração Muscular , Músculo Esquelético , Idoso de 80 Anos ou mais , Tornozelo/fisiologia , Fenômenos Biomecânicos , Humanos , Perna (Membro) , Músculo Esquelético/fisiologia , Placa Plantar/fisiologia
11.
Int Orthod ; 18(2): 308-316, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32057733

RESUMO

OBJECTIVE: The main aim of this randomized clinical trial was to determine 3 dimensional skeletal and dental changes six months after the use of bone-anchored versus tooth-anchored rapid maxillary expanders in adolescents. The secondary aim was to determine the symmetrical or asymmetrical expansion pattern between both appliances. MATERIALS AND METHODS: Fifty adolescents with skeletally constricted maxilla (mean age 13-14 years) were randomly assigned into: Dresden B-RME, Hyrax T-RME, or untreated control groups. CBCT scans were taken at initial and expander removal (6 months). Three-dimensional references and treatment landmarks were identified. Orthogonal distances were calculated from those landmarks. The main outcome was to compare skeletal and dental changes in each group and the secondary outcome was to verify if these changes were symmetric or not. Data was analysed using descriptive statistics and repeated measure MANCOVA and MANOVA. RESULTS: Both treatment groups showed significant skeletal and dental expansion compared to controls. T-RME group had greater mean inter-molar crown expansion (5.66mm) than the B-RME group (4.17mm). Both T-RME and B-RME groups showed significant skeletal maxillary expansion compared to controls (mean 1.27mm and 1.31mm respectively, both p<0.01), although no significant difference was found between both appliances. B-RME group showed a lower ratio of dental to skeletal expansion than T-RME group. T-RME showed a symmetrical expansion pattern, whereas the B-RME showed an asymmetrical pattern relative to mid-sagittal plane. The extent of molar crown expansion was 1.84mm greater on the TAD-side compared to the Implant-side. T-RME group showed significant anterior movement of the maxillary first premolar and molar (1.5mm, p<0.05), and vertical dental extrusion (1.8mm). No significant dental vertical or anterior-posterior changes were noted in the B-RME group. CONCLUSIONS: T-RME and B-RME produced similar amounts of skeletal expansion. B-RME group produced a lower component of dental expansion. Due to the Dresden B-RME configuration, asymmetrical expansion was noted.


Assuntos
Tomografia Computadorizada de Feixe Cônico , Maxila/anatomia & histologia , Procedimentos de Ancoragem Ortodôntica/métodos , Técnica de Expansão Palatina/instrumentação , Adolescente , Análise de Variância , Cefalometria , Criança , Arco Dental/anatomia & histologia , Arco Dental/diagnóstico por imagem , Feminino , Humanos , Masculino , Maxila/diagnóstico por imagem , Procedimentos de Ancoragem Ortodôntica/instrumentação , Desenho de Aparelho Ortodôntico , Dente/diagnóstico por imagem
12.
Head Face Med ; 16(1): 1, 2020 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-31987041

RESUMO

INTRODUCTION: Cone-Beam Computed Tomography (CBCT) images can be superimposed, allowing three-dimensional (3D) evaluation of craniofacial growth/treatment effects. Limitations of 3D superimposition techniques are related to imaging quality, software/hardware performance, reference areas chosen, and landmark points/volumes identification errors. The aims of this research are to determine/compare the intra-rater reliability generated by three 3D superimposition methods using CBCT images, and compare the changes observed in treated cases by these methods. METHODS: Thirty-six growing individuals (11-14 years old) were selected from patients that received orthodontic treatment. Before and after treatment (average 24 months apart) CBCTs were analyzed using three superimposition methods. The superimposed scans with the two voxel-based methods were used to construct surface models and quantify differences using SlicerCMF software, while distances in the landmark-derived method were calculated using Excel. 3D linear measurements of the models superimposed with each method were then compared. RESULTS: Repeated measurements with each method separately presented good to excellent intraclass correlation coefficient (ICC ≥ 0.825). ICC values were the lowest when comparing the landmark-based method and both voxel-based methods. Moderate to excellent agreement was observed when comparing the voxel-based methods against each other. The landmark-based method generated the highest measurement error. CONCLUSIONS: Findings indicate good to excellent intra-examiner reliability of the three 3D superimposition methods when assessed individually. However, when assessing reliability among the three methods, ICC demonstrated less powerful agreement. The measurements with two of the three methods (CMFreg/Slicer and Dolphin) showed similar mean differences; however, the accuracy of the results could not be determined.


Assuntos
Tomografia Computadorizada de Feixe Cônico , Imageamento Tridimensional , Dente , Adolescente , Cefalometria , Criança , Assistência Odontológica , Humanos , Ortodontia , Reprodutibilidade dos Testes , Dente/diagnóstico por imagem
13.
IEEE Int Conf Rehabil Robot ; 2019: 816-823, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31374731

RESUMO

Upper limb loss is a devastating injury for which current prosthetic replacement inadequately compensates. A lack of wrist movement in prostheses due to mechanical design and control system considerations compels prosthetic users to employ compensatory movements using their upper back and shoulder that can eventually result in strain and overuse injuries. One possible means of easing this control burden is to allow a prosthetic wrist to self-regulate, keeping the terminal device of the prosthesis level relative to the ground when appropriate, such as when raising a cup of liquid. This study aims to outline such a wrist control scheme, and evaluate its function in terms of the effect on compensatory movements, objective system performance, and subjective perception of system performance based on user feedback. To that end, twelve able-bodied participants were recruited to control a body-mounted robotic arm using three different control schemes: fixed-wrist (FW), sequential switching (SS), and automatic levelling (AL). The resulting movement strategies were recorded for two different tasks using 3D motion-capture. SS and AL control schemes induced similar movement strategies and less compensation than FW for horizontal movements, while AL reduced shoulder flexion compared to FW and SS for vertical movements. However, AL was ranked less intuitive and less reliable than the FW. AL and SS both seemed to involve more conscious thought to operate than FW. These results suggest that more complex wrist control schemes may indeed be able to eliminate harmful compensatory movements, but reinforce prior observations that control must be reliable and simple to use or people will opt for an easier system.


Assuntos
Punho/fisiologia , Adulto , Membros Artificiais , Automação , Retroalimentação , Feminino , Humanos , Masculino , Desenho de Prótese , Análise e Desempenho de Tarefas
14.
Clin Cancer Res ; 25(13): 3996-4013, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-30867218

RESUMO

PURPOSE: Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors are currently used in combination with endocrine therapy to treat advanced hormone receptor-positive, HER2-negative breast cancer. Although this treatment doubles time to progression compared with endocrine therapy alone, about 25%-35% of patients do not respond, and almost all patients eventually acquire resistance. Discerning the mechanisms of resistance to CDK4/6 inhibition is crucial in devising alternative treatment strategies. EXPERIMENTAL DESIGN: Palbociclib-resistant cells (MCF-7 and T47D) were generated in a step-wise dose-escalading fashion. Whole-exome sequencing, genome-wide expression analysis, and proteomic analysis were performed in both resistant and parental (sensitive) cells. Pathway alteration was assessed mechanistically and pharmacologically. Biomarkers of altered pathways were examined in tumor samples from patients with palbociclib-treated breast cancer whose disease progressed while on treatment. RESULTS: Palbociclib-resistant cells are cross-resistant to other CDK4/6 inhibitors and are also resistant to endocrine therapy (estrogen receptor downregulation). IL6/STAT3 pathway is induced, whereas DNA repair and estrogen receptor pathways are downregulated in the resistant cells. Combined inhibition of STAT3 and PARP significantly increased cell death in the resistant cells. Matched tumor samples from patients with breast cancer who progressed on palbociclib were examined for deregulation of estrogen receptor, DNA repair, and IL6/STAT3 signaling, and results revealed that these pathways are all altered as compared with the pretreatment tumor samples. CONCLUSIONS: Palbociclib resistance induces endocrine resistance, estrogen receptor downregulation, and alteration of IL6/STAT3 and DNA damage response pathways in cell lines and patient samples. Targeting IL6/STAT3 activity and DNA repair deficiency using a specific STAT3 inhibitor combined with a PARP inhibitor could effectively treat acquired resistance to palbociclib.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Reparo do DNA/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos , Receptores de Estrogênio/metabolismo , Fator de Transcrição STAT3/antagonistas & inibidores , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Biologia Computacional/métodos , Transição Epitelial-Mesenquimal/genética , Feminino , Perfilação da Expressão Gênica , Humanos , Imuno-Histoquímica , Piperazinas/farmacologia , Piperazinas/uso terapêutico , Inibidores de Proteínas Quinases/farmacologia , Piridinas/farmacologia , Piridinas/uso terapêutico , Resultado do Tratamento
15.
Clin Cancer Res ; 24(24): 6594-6610, 2018 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-30181387

RESUMO

PURPOSE: Poor prognosis in triple-negative breast cancer (TNBC) is due to an aggressive phenotype and lack of biomarker-driven targeted therapies. Overexpression of cyclin E and phosphorylated-CDK2 are correlated with poor survival in patients with TNBC, and the absence of CDK2 desensitizes cells to inhibition of Wee1 kinase, a key cell-cycle regulator. We hypothesize that cyclin E expression can predict response to therapies, which include the Wee1 kinase inhibitor, AZD1775. EXPERIMENTAL DESIGN: Mono- and combination therapies with AZD1775 were evaluated in TNBC cell lines and multiple patient-derived xenograft (PDX) models with different cyclin E expression profiles. The mechanism(s) of cyclin E-mediated replicative stress were investigated following cyclin E induction or CRISPR/Cas9 knockout by a number of assays in multiple cell lines. RESULTS: Cyclin E overexpression (i) is enriched in TNBCs with high recurrence rates, (ii) sensitizes TNBC cell lines and PDX models to AZD1775, (iii) leads to CDK2-dependent activation of DNA replication stress pathways, and (iv) increases Wee1 kinase activity. Moreover, treatment of cells with either CDK2 inhibitors or carboplatin leads to transient transcriptional induction of cyclin E (in cyclin E-low tumors) and result in DNA replicative stress. Such drug-mediated cyclin E induction in TNBC cells and PDX models sensitizes them to AZD1775 in a sequential treatment combination strategy.Conclusions: Cyclin E is a potential biomarker of response (i) for AZD1775 as monotherapy in cyclin E-high TNBC tumors and (ii) for sequential combination therapy with CDK2 inhibitor or carboplatin followed by AZD1775 in cyclin E-low TNBC tumors.


Assuntos
Proteínas de Ciclo Celular/antagonistas & inibidores , Ciclina E/genética , Resistencia a Medicamentos Antineoplásicos/genética , Expressão Gênica , Proteínas Nucleares/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Proteínas Tirosina Quinases/antagonistas & inibidores , Neoplasias de Mama Triplo Negativas/genética , Animais , Apoptose , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Linhagem Celular Tumoral , Óxidos N-Cíclicos , Reparo do DNA , Replicação do DNA , Modelos Animais de Doenças , Humanos , Indolizinas , Camundongos , Camundongos Knockout , Modelos Biológicos , Prognóstico , Pirazóis/farmacologia , Compostos de Piridínio/farmacologia , Pirimidinonas/farmacologia , Estresse Fisiológico , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/mortalidade , Neoplasias de Mama Triplo Negativas/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
16.
IEEE J Transl Eng Health Med ; 6: 2100711, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30197843

RESUMO

The aim of this paper was to demonstrate the functionality of an inexpensive mechanotactile sensory feedback system for transhumeral myoelectric prostheses. We summarize the development of a tactile-integrated prosthesis, including 1) evaluation of sensors that were retrofit onto existing commercial terminal devices; 2) design of two custom mechanotactile tactors that were integrated into a socket without compromising suction suspension; 3) design of a modular controller which translated sensor input to tactor output, was wirelessly adjusted, and fit within a prosthetic forearm; and 4) evaluation of the system with a single transhumeral participant. Prosthesis functionality was demonstrated over three test sessions; the participant was able to identify tactor stimulation location and demonstrated a reduction in grasp force with the mechanotactile stimulation. This system offers an inexpensive and modular solution for integration of a mechanotactile sensory feedback system into a prosthetic socket without compromising the suction seal. These principles can be applied in future studies to investigate the direct impact of sensory feedback on tangible outcomes for prosthetic users, thereby reducing barriers to clinical translation.

17.
Cancer Res ; 78(19): 5481-5491, 2018 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-30194068

RESUMO

Cyclin E, a regulatory subunit of cyclin-dependent kinase 2 (CDK2), is central to the initiation of DNA replication at the G1/S checkpoint. Tight temporal control of cyclin E is essential to the coordination of cell-cycle processes and the maintenance of genome integrity. Overexpression of cyclin E in human tumors was first observed in the 1990s and led to the identification of oncogenic roles for deregulated cyclin E in experimental models. A decade later, low-molecular-weight cyclin E (LMW-E) isoforms were observed in aggressive tumor subtypes. Compared with full-length cyclin E, LMW-E hyperactivates CDK2 through increased complex stability and resistance to the endogenous inhibitors p21CIP1 and p27KIP1 LMW-E is predominantly generated by neutrophil elastase-mediated proteolytic cleavage, which eliminates the N-terminal cyclin E nuclear localization signal and promotes cyclin E's accumulation in the cytoplasm. Compared with full-length cyclin E, the aberrant localization and unique stereochemistry of LMW-E dramatically alters the substrate specificity and selectivity of CDK2, increasing tumorigenicity in experimental models. Cytoplasmic LMW-E, which can be assessed by IHC, is prognostic of poor survival and predicts resistance to standard therapies in patients with cancer. These patients may benefit from therapeutic modalities targeting the altered biochemistry of LMW-E or its associated vulnerabilities. Cancer Res; 78(19); 5481-91. ©2018 AACR.


Assuntos
Ciclina E/metabolismo , Regulação Neoplásica da Expressão Gênica , Neoplasias/terapia , Proteínas Oncogênicas/metabolismo , Animais , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Neoplasias da Mama/terapia , Carcinogênese , Ciclo Celular , Divisão Celular , Linhagem Celular Tumoral , Quinase 2 Dependente de Ciclina/metabolismo , Inibidor de Quinase Dependente de Ciclina p27/genética , Citoplasma/metabolismo , Feminino , Humanos , Elastase de Leucócito/metabolismo , Peso Molecular , Metástase Neoplásica , Neoplasias/metabolismo , Neoplasias/patologia , Oncogenes , Prognóstico , Resultado do Tratamento
18.
Oncoscience ; 5(5-6): 137-139, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-30035166
19.
Sci Transl Med ; 10(432)2018 03 14.
Artigo em Inglês | MEDLINE | ID: mdl-29540617

RESUMO

To effortlessly complete an intentional movement, the brain needs feedback from the body regarding the movement's progress. This largely nonconscious kinesthetic sense helps the brain to learn relationships between motor commands and outcomes to correct movement errors. Prosthetic systems for restoring function have predominantly focused on controlling motorized joint movement. Without the kinesthetic sense, however, these devices do not become intuitively controllable. We report a method for endowing human amputees with a kinesthetic perception of dexterous robotic hands. Vibrating the muscles used for prosthetic control via a neural-machine interface produced the illusory perception of complex grip movements. Within minutes, three amputees integrated this kinesthetic feedback and improved movement control. Combining intent, kinesthesia, and vision instilled participants with a sense of agency over the robotic movements. This feedback approach for closed-loop control opens a pathway to seamless integration of minds and machines.


Assuntos
Próteses e Implantes , Amputados , Mãos/fisiologia , Humanos , Cinestesia , Percepção de Movimento/fisiologia , Movimento/fisiologia , Percepção/fisiologia , Robótica
20.
New Phytol ; 218(2): 835-846, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29453936

RESUMO

Rapidly determining root growth patterns is biologically important and technically challenging. Current methods focus on direct observation of roots and require destructive excavations or time-consuming root tracing. We developed a novel methodology based on analyzing soil particle displacement, rather than direct observation of roots. This inferred root growth method uses digital image correlation (DIC) analysis, an established and high-throughput method used in many engineering and science disciplines. By applying DIC analyses to repeated images of plants grown in clear window boxes, we produced visually intuitive and quantifiable strain maps, indicating the magnitude and direction of soil movement. From this, we could infer root growth and rapidly quantify root system metrics. Strain measures were closely associated with the spatial distribution of roots and correlated with root length measured using conventional approaches. The method also allowed for the detection of root proliferation in nutrient-enriched soil patches, indicating its suitability for quantifying biological patterns. This novel application of DIC in root biology is effective, scalable, low cost, flexible and complementary to existing technologies. This method offers a new tool for answering questions in plant biology and will be particularly useful in studies involving temporal dynamics of root processes.


Assuntos
Processamento de Imagem Assistida por Computador/métodos , Raízes de Plantas/anatomia & histologia , Raízes de Plantas/crescimento & desenvolvimento , Helianthus/anatomia & histologia , Helianthus/crescimento & desenvolvimento , Solo
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