RESUMEN
BACKGROUND: Adolescents and young adults (AYAs) represent a small proportion of patients with cancer. The genomic profiles of AYA patients with cancer are not well-studied, and outcomes of genome-matched therapies remain largely unknown. PATIENTS AND METHODS: We investigated differences between Japanese AYA and older adult (OA) patients in genomic alterations, therapeutic evidence levels, and genome-matched therapy usage by cancer type. We also assessed treatment outcomes. RESULTS: AYA patients accounted for 8.3% of 876 cases. Microsatellite instability-high and/or tumor mutation burden was less common in AYA patients (1.4% versus 7.7% in OA; P = 0.05). However, BRCA1 alterations were more common in AYA patients with breast cancer (27.3% versus 1.7% in OA; P = 0.01), as were MYC alterations in AYA patients with colorectal cancer (23.5% versus 5.8% in OA; P = 0.02) and sarcoma (31.3% versus 3.4% in OA; P = 0.01). Genome-matched therapy use was similar between groups, with overall survival tending to improve in both. However, in AYA patients, the small number of patients prevented statistical significance. Comprehensive genomic profiling-guided genome-matched therapy yielded encouraging results, with progression-free survival of 9.0 months in AYA versus 3.7 months in OA patients (P = 0.59). CONCLUSION: Our study suggests that tailored therapeutic approaches can benefit cancer patients regardless of age.
RESUMEN
OBJECTIVE: Mammalian somatic cells can be reprogrammed into induced pluripotent stem cells (iPSCs) via the forced expression of Yamanaka reprogramming factors. However, only a limited population of the cells that pass through a particular pathway can metamorphose into iPSCs, while the others do not. This study aimed to clarify the pathways that chondrocytes follow during the reprogramming process. DESIGN: The fate of human articular chondrocytes under reprogramming was investigated through a time-coursed single-cell transcriptomic analysis, which we termed an inverse genetic approach. The iPS interference technique was also employed to verify that chondrocytes inversely return to pluripotency following the proper differentiation pathway. RESULTS: We confirmed that human chondrocytes could be converted into cells with an iPSC phenotype. Moreover, it was clarified that a limited population that underwent the silencing of SOX9, a master gene for chondrogenesis, at a specific point during the proper transcriptome transition pathway, could eventually become iPSCs. Interestingly, the other cells, which failed to be reprogrammed, followed a distinct pathway toward cells with a surface zone chondrocyte phenotype. The critical involvement of cellular communication network factors (CCNs) in this process was indicated. The idea that chondrocytes, when reprogrammed into iPSCs, follow the differentiation pathway backward was supported by the successful iPS interference using SOX9. CONCLUSIONS: This inverse genetic strategy may be useful for seeking candidates for the master genes for the differentiation of various somatic cells. The utility of CCNs in articular cartilage regeneration is also supported.
RESUMEN
Ice worlds are at the forefront of astrobiological interest because of the evidence of subsurface oceans. Enceladus in particular is unique among the icy moons because there are known vent systems that are likely connected to a subsurface ocean, through which the ocean water is ejected to space. An existing study has shown that sending small robots into the vents and directly sampling the ocean water is likely possible. To enable such a mission, NASA's Jet Propulsion Laboratory is developing a snake-like robot called Exobiology Extant Life Surveyor (EELS) that can navigate Enceladus' extreme surface and descend an erupting vent to capture unaltered liquid samples and potentially reach the ocean. However, navigating to and through Enceladus' environment is challenging: Because of the limitations of existing orbital reconnaissance, there is substantial uncertainty with respect to its geometry and the physical properties of the surface/vents; communication is limited, which requires highly autonomous robots to execute the mission with limited human supervision. Here, we provide an overview of the EELS project and its development effort to create a risk-aware autonomous robot to navigate these extreme ice terrains/environments. We describe the robot's architecture and the technical challenges to navigate and sense the icy environment safely and effectively. We focus on the challenges related to surface mobility, task and motion planning under uncertainty, and risk quantification. We provide initial results on mobility and risk-aware task and motion planning from field tests and simulated scenarios.
RESUMEN
Cosmic rays are energetic charged particles from extraterrestrial sources, with the highest-energy events thought to come from extragalactic sources. Their arrival is infrequent, so detection requires instruments with large collecting areas. In this work, we report the detection of an extremely energetic particle recorded by the surface detector array of the Telescope Array experiment. We calculate the particle's energy as [Formula: see text] (~40 joules). Its arrival direction points back to a void in the large-scale structure of the Universe. Possible explanations include a large deflection by the foreground magnetic field, an unidentified source in the local extragalactic neighborhood, or an incomplete knowledge of particle physics.
RESUMEN
An accessibility enhanced efficient fundamental X-mode electron cyclotron heating (ECH) current start-up regime was identified for a reactorlike toroidal magnetic field range which has more than 100 times higher current drive efficiency compared to more conventional ECH methods for the relevant start-up temperature range. Very high current drive efficiency is possible due to the strong cyclotron interaction only with unidirectional passing electrons constrained by the wave accessibility conditions. This efficient electron cyclotron current drive regime may help facilitate the design of innovative economical solenoid-free tokamak fusion reactor systems.
RESUMEN
OBJECTIVES: Defining an adequate protein intake in older adults remains unresolved. We examined the association between calibrated protein intake and comprehensive frailty by sex in the Kyoto-Kameoka study. DESIGN: Cross-sectional study of baseline data. SETTING AND PARTICIPANTS: The study included 5679 Japanese participants aged 65 years or older. METHODS: Calibration coefficients were estimated from food frequency questionnaires and 7-day dietary records as a reference. Comprehensive frailty was evaluated using the 25-item Kihon Checklist (KCL) and defined as a total KCL score of ≥7points. Sex-specific calibrated protein intakes were presented as % of energy, per kg of actual body weight (BW), and per kg of ideal BW. RESULTS: Multiple logistic regression analysis showed that calibrated protein intake is inversely associated with comprehensive frailty. The association between protein intake and comprehensive frailty was also evaluated using curve fitting with non-linear regression, a weak U-shaped association was found in males and an L-shaped association in females. Men had a low prevalence of frailty at a calibrated protein intake of 15-17% energy from protein, 1.2 g/kg actual BW/day, or 1.4 g/kg ideal BW/day, and women had a low prevalence of frailty at 17-21% energy from protein or 1.6 g/kg ideal BW/day, with the prevalence of frailty remaining unchanged at higher protein intakes. Meanwhile, the inverse relationship between protein intake per ABW and frailty showed a gradual decrease at 1.4 g/kg ABW/day for protein in women. CONCLUSIONS AND IMPLICATIONS: A non-linear relationship was found between calibrated protein intake and frailty, with a U-shaped association in men and an L-shaped association in women. Adequate protein intake in healthy Japanese older adults was higher than the current recommended daily allowance.
Asunto(s)
Fragilidad , Anciano , Lista de Verificación , Estudios Transversales , Registros de Dieta , Femenino , Fragilidad/epidemiología , Humanos , Japón/epidemiología , Masculino , PrevalenciaRESUMEN
A multi-energy soft x-ray pinhole camera has been designed, built, and deployed at the Madison Symmetric Torus to aid the study of particle and thermal transport, as well as MHD stability physics. This novel imaging diagnostic technique employs a pixelated x-ray detector in which the lower energy threshold for photon detection can be adjusted independently on each pixel. The detector of choice is a PILATUS3 100 K with a 450 µm thick silicon sensor and nearly 100 000 pixels sensitive to photon energies between 1.6 and 30 keV. An ensemble of cubic spline smoothing functions has been applied to the line-integrated data for each time-frame and energy-range, obtaining a reduced standard-deviation when compared to that dominated by photon-noise. The multi-energy local emissivity profiles are obtained from a 1D matrix-based Abel-inversion procedure. Central values of Te can be obtained by modeling the slope of the continuum radiation from ratios of the inverted radial emissivity profiles over multiple energy ranges with no a priori assumptions of plasma profiles, magnetic field reconstruction constraints, high-density limitations, or need of shot-to-shot reproducibility. In tokamak plasmas, a novel application has recently been tested for early detection, 1D imaging, and study of the birth, exponential growth, and saturation of runaway electrons at energies comparable to 100 × Te,0; thus, early results are also presented.
RESUMEN
Cranial rib fractures during dystocia and the ensuing callus formations in calves often cause tracheal stenosis. Rib fractures may affect the lung since ribs tend to fracture above the costochondral junction during delivery. Considering that calving assistance rates for dystocia are high, calves with fractured ribs may develop respiratory disease which results in economic loss. The objective of this study was to elucidate the contribution of rib fractures to economic loss through respiratory disease in calves. Of 163 sick calves delivered from Holstein-Friesian dams included in this study, a total of 18 rib fractured calves was found, giving an incidence of rib fracture in sick calves of 11.0%. There were significant differences in incidence by the rib involved, indicating the 2nd to 7th ribs tend to break. Many of the rib fractured calves showed dyspnea and pyrexia. In this study, four of five scanned or necropsied calves had pneumonia lesions despite the fact that these four calves did not have tracheal stenosis. Rib fractured calves sold at below market value with a median difference from average sale price of minus 64,861 yen. Survival analysis indicated an overall association between rib fracture and time to death. In this study, we demonstrated that rib fractures happened most frequently in the 2nd to 7th ribs, and these cases tended to cause pneumonia, which decreased sale prices and longevity. Farmers should work to reduce risks and rates of dystocia so as to lessen economic loss and poor welfare in calves due to rib fractures.
RESUMEN
Methotrexate (MTX)-induced intestinal mucosal injury in animals has been studied to understand how MTX can cause gastrointestinal disorders, but the pathogenesis of gastrointestinal disorders is still uncertain. We have attempted to reveal how dietary factors influence intestinal toxicity due to MTX. Mice were fed normal chow (NC) or a high-fat high-sucrose diet (HFHSD) before oral administration of MTX. While MTX significantly decreased the survival rates of mice fed HFHSD, the intestinal epithelial injury was detected. MTX excretion in the feces of mice fed HFHSD was reduced. Change of diets between NC and HFHSD influences the survival. The survival rates of the mice fed a high-sucrose diet or control diet were higher than those fed HFHSD. Higher survival rates were observed in mice fed a high-fat high-sucrose diet modified (HFHSD-M) in which casein was replaced by soybean-derived proteins. The survival rates of mice treated with vancomycin were lower than those administered neomycin. Microbiome and metabolome analyses on feces suggest a similarity of the intestinal environments of mice fed NC and HFHSD-M. HFHSD may modify MTX-induced toxicity in intestinal epithelia on account of an altered MTX distribution as a result of change in the intestinal environment.
Asunto(s)
Dieta Alta en Grasa , Microbioma Gastrointestinal/efectos de los fármacos , Enfermedades Intestinales/dietoterapia , Mucosa Intestinal/efectos de los fármacos , Metotrexato/toxicidad , Sacarosa/administración & dosificación , Animales , Dieta Alta en Grasa/métodos , Modelos Animales de Enfermedad , Heces/química , Enfermedades Intestinales/inducido químicamente , Enfermedades Intestinales/microbiología , Enfermedades Intestinales/patología , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiología , Mucosa Intestinal/patología , Masculino , Metaboloma/efectos de los fármacos , Metotrexato/farmacocinética , Ratones Endogámicos C57BL , Análisis de Supervivencia , Distribución TisularRESUMEN
BACKGROUND: In the literature, data is lacking on mid-term results of epicardial pacemaker implantation in neonates and infants. Our aim was to evaluate the mid-term results of epicardial pacemakers implanted in infants under 1 year of age. METHODS AND RESULTS: We conducted a retrospective review of patients who underwent pacemaker implantation between 2000 and 2017. Pacemaker and lead parameters were reviewed at discharge, 2, 4 and more than 5 years after implantation. A total of 71 patients aged 4⯱â¯3 months and weighing 4⯱â¯2â¯kg were included in the study. Indications for pacemaker implantation were: acquired AV-block (nâ¯=â¯44), congenital AV block (nâ¯=â¯22), sick sinus syndrome (nâ¯=â¯4) and AV block type Mobitz II (nâ¯=â¯1). Median follow-up time was 5 years (range: 1 month-17 years). At 5 years of follow-up, atrial lead energy threshold for pacing decreased significantly (0.72⯱â¯0.71⯵J to 0.45⯱â¯0.35⯵J; Pâ¯<â¯0.001) but was stable for ventricular leads (0.57⯵J [0.05; 39.47] to 0.64⯵J [0.13; 9.45], Pâ¯=â¯0.97). Atrial lead impedance increased significantly (569⯱â¯137 Ω to 603⯱â¯134 Ω, Pâ¯<â¯0.001), whereas ventricular lead impedance decreased (603⯱â¯202 Ω to 490⯱â¯150 Ω, Pâ¯<â¯0.001) after 5 years. Repeat operations were required for generator change (nâ¯=â¯55), lead exchange (nâ¯=â¯17) and infection (nâ¯=â¯1). At 2, 5 and 10 years, atrial lead survival was 96%, 91% and 76% and ventricular lead survival was 94%, 82% and 75%, respectively (Pâ¯=â¯0.45). CONCLUSION: Stable pacing thresholds after 5 years indicated that epicardial pacemakers are safe for infants under 1 year of age until at least school enrolment age. However, due to stimulation at higher heart rates in infancy, battery depletion is a frequent occurrence.
Asunto(s)
Electrodos Implantados , Bloqueo Cardíaco/terapia , Cardiopatías Congénitas/complicaciones , Marcapaso Artificial , Factores de Edad , Niño , Preescolar , Falla de Equipo , Femenino , Bloqueo Cardíaco/diagnóstico , Bloqueo Cardíaco/etiología , Cardiopatías Congénitas/cirugía , Humanos , Lactante , Recién Nacido , Masculino , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
Studies on regulatory T cells (Treg ) have focused on thymic Treg as a stable lineage of immunosuppressive T cells, the differentiation of which is controlled by the transcription factor forkhead box protein 3 (Foxp3). This lineage perspective, however, may constrain hypotheses regarding the role of Foxp3 and Treg in vivo, particularly in clinical settings and immunotherapy development. In this review, we synthesize a new perspective on the role of Foxp3 as a dynamically expressed gene, and thereby revisit the molecular mechanisms for the transcriptional regulation of Foxp3. In particular, we introduce a recent advancement in the study of Foxp3-mediated T cell regulation through the development of the Timer of cell kinetics and activity (Tocky) system, and show that the investigation of Foxp3 transcriptional dynamics can reveal temporal changes in the differentiation and function of Treg in vivo. We highlight the role of Foxp3 as a gene downstream of T cell receptor (TCR) signalling and show that temporally persistent TCR signals initiate Foxp3 transcription in self-reactive thymocytes. In addition, we feature the autoregulatory transcriptional circuit for the Foxp3 gene as a mechanism for consolidating Treg differentiation and activating their suppressive functions. Furthermore, we explore the potential mechanisms behind the dynamic regulation of epigenetic modifications and chromatin architecture for Foxp3 transcription. Lastly, we discuss the clinical relevance of temporal changes in the differentiation and activation of Treg .
Asunto(s)
Factores de Transcripción Forkhead/genética , Factores de Transcripción Forkhead/metabolismo , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo , Animales , Diferenciación Celular , Linaje de la Célula , Citocinas/metabolismo , Epigénesis Genética , Factores de Transcripción Forkhead/inmunología , Regulación de la Expresión Génica , Humanos , Proteínas Luminiscentes/genética , Proteínas Luminiscentes/metabolismo , Activación de Linfocitos , Ratones , Modelos Inmunológicos , Mutación , Transducción de Señal , Transcripción GenéticaRESUMEN
A new tool has been developed to calculate the spectral, spatial, and temporal responses of multi-energy soft x-ray (ME-SXR) pinhole cameras for arbitrary plasma densities (n e,D), temperature (T e), and impurity densities (n Z). ME-SXR imaging provides a unique opportunity for obtaining important plasma properties (e.g., T e, n Z, and Z eff) by measuring both continuum and line emission in multiple energy ranges. This technique employs a pixelated x-ray detector in which the lower energy threshold for photon detection can be adjusted independently. Simulations assuming a tangential geometry and DIII-D-like plasmas (e.g., n e,0 ≈ 8 × 1019 m-3 and T e,0 ≈ 2.8 keV) for various impurity (e.g., C, O, Ar, Ni, and Mo) density profiles have been performed. The computed brightnesses range from few 102 counts pixel-1 ms-1 depending on the cut-off energy thresholds, while the maximum allowable count rate is 104 counts pixel-1 ms-1. The typical spatial resolution in the mid-plane is ≈0.5 cm with a photon-energy resolution of 500 eV at a 500 Hz frame rate.
RESUMEN
A multi-energy soft x-ray pinhole camera has been designed and built for the Madison Symmetric Torus reversed field pinch to aid the study of particle and thermal-transport, as well as MHD stability physics. This novel imaging diagnostic technique combines the best features from both pulse-height-analysis and multi-foil methods employing a PILATUS3 x-ray detector in which the lower energy threshold for photon detection can be adjusted independently on each pixel. Further improvements implemented on the new cooled systems allow a maximum count rate of 10 MHz per pixel and sensitivity to the strong Al and Ar emission between 1.5 and 4 keV. The local x-ray emissivity will be measured in multiple energy ranges simultaneously, from which it is possible to infer 1D and 2D simultaneous profile measurements of core electron temperature and impurity density profiles with no a priori assumptions of plasma profiles, magnetic field reconstruction constraints, high-density limitations, or need of shot-to-shot reproducibility. The expected time and space resolutions will be 2 ms and <1 cm, respectively.
RESUMEN
The hysteresis relation between turbulence and temperature modulation during the heat pulse propagation into a magnetic island is studied for the first time in toroidal plasmas. Lissajous curves of the density fluctuation (n[over Ë]/n) and the electron temperature (T_{e}) modulation show that the (n[over Ë]/n) propagation is faster than the heat pulse propagation near the O point of the magnetic island. This faster n[over Ë]/n propagation is experimental evidence of the turbulence spreading from the X point to the O point of the magnetic island.
RESUMEN
Despite possessing a limited number of neurones compared to vertebrates, honeybees show remarkable learning and memory performance, an example being 'dance communication'. In this phenomenon, foraging honeybees learn the location of a newly discovered food source and transmit the information to nestmates by symbolic abdomen vibrating behaviour, leading to navigation of nestmates to the new food source. As an initial step toward understanding the detailed molecular mechanisms underlying the sophisticated learning and memory performance of the honeybee, we focused on the neural immediate early genes (IEGs), which are specific genes quickly transcribed after neural activity without de novo protein synthesis. Although these have been reported to play an essential role in learning and memory processes in vertebrates, far fewer studies have been performed in insects in this regard. From RNA-sequencing analysis and subsequent assays, we identified three genes, Src homology 3 (SH3) domain binding kinase, family with sequence similarity 46 and GB47136, as novel neural IEGs in the honeybee. Foragers and/or orientating bees, which fly around their hives to memorize the positional information, showed induced expression of these IEGs in the mushroom body, a higher-order centre essential for learning and memory, indicating a possible role for the novel IEGs in foraging-related learning and memory processes in the honeybee.
Asunto(s)
Abejas/fisiología , Genes Inmediatos-Precoces/genética , Proteínas de Insectos/genética , Memoria , Animales , Abejas/genética , Conducta Alimentaria , Proteínas de Insectos/metabolismo , AprendizajeRESUMEN
There is little evidence of sensation in individuals with diabetes mellitus (DM) in the dental research field. We investigated whether pain thresholds (PTs) differ between individuals with and without DM (non-DM; NDM). To this end, we assessed whether PTs obtained from the oral cavity, hands, and feet differed from each other and across groups, and whether PTs differed for the three current frequencies used for testing (2000 Hz, 250 Hz, and 5 Hz). Pain threshold measurements were obtained from the oral mucosa and the tips of the fingers and toes of 56 volunteers, including 21 individuals with DM (12 men and 9 women, average age: 72.1 ± 4.7 years) and 35 NDM individuals (17 males and 18 females, average age: 51.2 ± 23.9 years) using the Neurometer CPT/C® device to deliver electrical stimulation. A single operator obtained PT measurements from around the left greater palatine foramen and from the tip of the left first finger and of the left great toe. Individuals with DM had significantly lower PT values than those without DM. The PT values for the oral cavity, hands, and feet differed significantly from each other (foot > hand, foot > oral cavity, hand > oral cavity). Moreover, there was a significant difference in the PT values for 5 Hz and 2000 Hz, as well as for 250 Hz and 2000 Hz. This study concluded that PT values derived from DM participants are lower than those from NDM participants, although PT measurements varied across regions and with current frequency.
Asunto(s)
Diabetes Mellitus/fisiopatología , Neuropatías Diabéticas/diagnóstico , Neuropatías Diabéticas/fisiopatología , Estimulación Eléctrica , Umbral del Dolor/fisiología , Umbral Sensorial/fisiología , Anciano , Proceso Alveolar/fisiopatología , Encuestas de Salud Bucal , Femenino , Pie/fisiopatología , Mano/fisiopatología , Humanos , Masculino , Persona de Mediana Edad , Dimensión del Dolor/métodos , Nervios Periféricos/fisiopatología , Valor Predictivo de las Pruebas , Reproducibilidad de los ResultadosRESUMEN
We describe the general occurrence in animal cells of elastic components ("tethers") that connect individual chromosomes moving to opposite poles during anaphase. Tethers, originally described in crane-fly spermatocytes, exert force on chromosome arms opposite to the direction the anaphase chromosomes move. We show that they exist in a broad range of animal cells. Thus tethers are previously unrecognised components of general mitotic mechanisms that exert force on chromosomes and they need to be accounted for in general models of mitosis in terms of forces on chromosomes and in terms of what their roles might be.
Asunto(s)
Anafase/genética , Segregación Cromosómica/genética , Mitosis/genética , Espermatocitos/citología , Animales , Dípteros/citología , Dípteros/genética , Cinetocoros , Masculino , Espermatocitos/metabolismo , Huso Acromático/genéticaRESUMEN
INTRODUCTION: Coexisting decreased muscle mass and increased visceral fat, an ageassociated change called sarcopenic obesity, results in fragility and cardiovascular disease. To assess the pathogenesis of sarcopenic obesity, we assessed the associations of clinical parameters with psoas muscle mass in elderly male subjects with obesity and type 2 diabetes. METHODS: The subjects were 55 patients, over 65 years of age and with a visceral fat area exceeding 100 cm2, with type 2 diabetes. The crosssectional area of the psoas muscle is considered to provide an estimation of overall muscle mass. Sarcopenia was considered to be present when the total psoas muscle area was low, defined as a value below 500 mm2 m−2 on a computed tomographic scan. RESULTS: The maximum intimamedia thickness (max IMT) and urinary 8isoprostane values were significantly higher in the sarcopenic group. Multiple linear regression analysis revealed max IMT to be an independent variable related to muscle mass decline. In addition, logistic analysis showed max IMT and urinary 8isoprostane to be variables independently contributing to total psoas muscle area <500 mm2 m−2. CONCLUSION: Worsening surrogate markers for systemic oxidative stress and atherosclerosis were associated with declining muscle mass in elderly subjects with obesity and type 2 diabetes. These results indicate that systemic oxidative stress is among the mechanisms underlying atherosclerosis development in subjects with sarcopenic obesity.