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Other than the fully synchronized state, a twisted state can also be an equilibrium solution in the Kuramoto model and its variations. In the present work, we explore the stability of the twisted state in Kuramoto oscillators put on a rim of a planar circle in the two-dimensional space in the presence of power-law decaying interaction strength (â¼r^{-α} with the distance r) and time delays due to a finite speed of information transfer. For example, our model can phenomenologically mimic a large sports stadium where many people try to sing or clap their hands in unison; the sound intensity decays with the distance and there can exist a time delay proportional to the distance due to the finiteness of sound speed. We first consider the case without the time delay effect and numerically find that stable twisted states emerge when the exponent α exceeds a critical value of α_{c}≈2. In other words, for α<α_{c}, the fully synchronized state, not the twisted state, is the only stable fixed point of the dynamics. In our analytic approach, we also derive an equation for α_{c} and discuss its solutions. In the presence of time delay, we find that it is possible that the synchronized state becomes unstable while twisted states are stable.
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Background/Aims: Despite the possible role of systemic low-grade inflammation on frailty, the majority of previous studies have focused solely on the phenotypic frailty with limited participant numbers, thereby weakening the evidence supporting the notion that circulating C-reactive protein (CRP) could be a potential frailty biomarker. Methods: This study is a nationally representative, population-based, cross-sectional analysis from the Korea National Health and Nutrition Examination Survey, involving 5,359 participants aged 65 and older. We generated a deficit accumulation frailty index (FI) based on 38 items, encompassing physical, cognitive, psychological, and social status. Frailty was classified as non-frail (FI ≤ 0.15), pre-frail (0.15 < FI ≤ 0.25), or frail (FI > 0.25). Serum high-sensitivity CRP (hsCRP) levels were measured by immunoturbidometric method. Results: After adjusting for confounders including age, sex, income, education, smoking, hypertension, diabetes, dyslipidemia, stroke, cardiovascular diseases, and body mass index, serum hsCRP levels were 29.4% higher in frail participants compared to their non-frail counterparts (p = 0.001). Additionally, circulating hsCRP concentrations positively correlated with the FI (p = 0.003), and the odds ratio for frailty per standard deviation increase in serum hsCRP was 1.18 (p = 0.001). Moreover, older adults in the highest hsCRP quartile exhibited a significant higher FI with a 1.59-fold increased odds ratio for frailty than those in the lowest quartile (p = 0.002 and 0.001, respectively). Conclusions: These findings validate the impact of age-related systemic low-grade inflammation on frailty and support the utility of serum hsCRP as a potential biomarker for detecting frailty in older adults.
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Antireflection, vital in optoelectronics devices such as solar cells and photodetectors, reduces light reflection and increases absorption. Antireflective structures (ARS), a primary method by which to realize this effect, control the refractive index (RI) profile based on their shape. The antireflection efficiency depends on the refractive index profile, with the quintic RI profile being recognized as ideal for superior antireflection. However, fabricating nano-sized structures with a desired shape, particularly in silicon with a quintic RI profile, has been a challenge. In this study, we introduce a funnel-shaped silicon (Si) ARS with a quintic RI profile. Its antireflective properties are demonstrated through reflectance measurements and by an application to a photodetector surface. Compared to the film Si and cone-shaped ARS types, which are common structures to achieve antireflection, the funnel-shaped ARS showed reflectance of 4.24% at 760 nm, whereas those of the film Si and cone-shaped ARS were 32.8% and 10.6%, respectively. Photodetectors with the funnel-shaped ARS showed responsivity of 0.077 A/W at 950 nm, which is 19.54 times higher than that with the film Si and 2.45 times higher than that with the cone-shaped ARS.
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Endocrine therapies (ET) with CDK4/6 inhibition are the standard treatment for estrogen receptor-α-positive (ER+) breast cancer, however drug resistance is common. In this study, proteogenomic analyses of 22 ER+ breast cancer patient-derived xenografts (PDXs) demonstrated that PKMYT1, a WEE1 homolog, is estradiol (E2) regulated in E2-dependent PDXs and constitutively expressed when growth is E2-independent. In clinical samples, high PKMYT1 mRNA levels associated with resistance to both ET and CDK4/6 inhibition. The PKMYT1 inhibitor lunresertib (RP-6306) with gemcitabine selectively and synergistically reduced the viability of ET and palbociclib-resistant ER+ breast cancer cells without functional p53. In vitro the combination increased DNA damage and apoptosis. In palbociclib-resistant, TP53 mutant PDX organoids and xenografts, RP-6306 with low-dose gemcitabine induced greater tumor volume reduction compared to treatment with either single agent. Our study demonstrates the clinical potential of RP-6306 in combination with gemcitabine for ET and CDK4/6 inhibitor resistant TP53 mutant ER+ breast cancer.
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With the escalating global awareness of air quality management, the need for continuous and reliable monitoring of toxic gases by using low-power operating systems has become increasingly important. One of which, semiconductor metal oxide gas sensors have received great attention due to their high/fast response and simple working mechanism. More specifically, self-heating metal oxide gas sensors, wherein direct thermal activation in the sensing material, have been sought for their low power-consuming characteristics. However, previous works have neglected to address the temperature distribution within the sensing material, resulting in inefficient gas response and prolonged response/recovery times, particularly due to the low-temperature regions. Here, we present a unique metal/metal oxide/metal (MMOM) nanowire architecture that conductively confines heat to the sensing material, achieving high uniformity in the temperature distribution. The proposed structure enables uniform thermal activation within the sensing material, allowing the sensor to efficiently react with the toxic gas. As a result, the proposed MMOM gas sensor showed significantly enhanced gas response (from 6.7 to 20.1% at 30 ppm), response time (from 195 to 17 s at 30 ppm), and limit of detection (â¼1 ppm) when compared to those of conventional single-material structures upon exposure to carbon monoxide. Furthermore, the proposed work demonstrated low power consumption (2.36 mW) and high thermal durability (1500 on/off cycles), demonstrating its potential for practical applications in reliable and low-power operating gas sensor systems. These results propose a new paradigm for power-efficient and robust self-heating metal oxide gas sensors with potential implications for other fields requiring thermal engineering.
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Gases , Nanocables , Óxidos , Nanocables/química , Gases/química , Gases/análisis , Óxidos/química , Metales/químicaRESUMEN
BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic and the consequent social distancing period are thought to have influenced the incidence of osteoporotic fracture in various ways, but the exact changes have not yet been well elucidated. The purpose of this study was to investigate the impact of the COVID-19 pandemic on the incidence of osteoporotic fracture using a nationwide cohort. METHODS: The monthly incidence rates of vertebral; hip; and non-vertebral, non-hip fractures were collected from a nationwide database of the Korean National Health Insurance Review and Assessment from July 2016 to June 2021. Segmented regression models were used to assess the change in levels and trends in the monthly incidence of osteoporotic fractures. RESULTS: There was a step decrease in the incidence of vertebral fractures for both males (6.181 per 100,000, P=0.002) and females (19.299 per 100,000, P=0.006). However, there was a negative trend in the incidence of hip fracture among both males (-0.023 per 100,000 per month, P=0.023) and females (-0.032 per 100,000 per month, P=0.019). No impact of COVID-19-related social distancing was noted. CONCLUSIONS: In conclusion, during the early days of the COVID-19 pandemic, vertebral fracture incidence considerably decreased with the implementation of social distancing measures.
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Protein kinases are frequently dysregulated and/or mutated in cancer and represent essential targets for therapy. Accurate quantification is essential. For breast cancer treatment, the identification and quantification of the protein kinase ERBB2 is critical for therapeutic decisions. While immunohistochemistry (IHC) is the current clinical diagnostic approach, it is only semiquantitative. Mass spectrometry-based proteomics offers quantitative assays that, unlike IHC, can be used to accurately evaluate hundreds of kinases simultaneously. The enrichment of less abundant kinase targets for quantification, along with depletion of interfering proteins, improves sensitivity and thus promotes more effective downstream analyses. Multiple kinase inhibitors were therefore deployed as a capture matrix for kinase inhibitor pulldown (KiP) assays designed to profile the human protein kinome as broadly as possible. Optimized assays were initially evaluated in 16 patient derived xenograft models (PDX) where KiP identified multiple differentially expressed and biologically relevant kinases. From these analyses, an optimized single-shot parallel reaction monitoring (PRM) method was developed to improve quantitative fidelity. The PRM KiP approach was then reapplied to low quantities of proteins typical of yields from core needle biopsies of human cancers. The initial prototype targeting 100 kinases recapitulated intrinsic subtyping of PDX models obtained from comprehensive proteomic and transcriptomic profiling. Luminal and HER2 enriched OCT-frozen patient biopsies subsequently analyzed through KiP-PRM also clustered by subtype. Finally, stable isotope labeled peptide standards were developed to define a prototype clinical method. Data are available via ProteomeXchange with identifiers PXD044655 and PXD046169.
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In vitro and animal experiments demonstrated that lumican exerts anabolic effects on bone and muscle by stimulating osteoblastogenesis, suppressing osteoclastogenesis and increasing myogenesis. However, the relationship between circulating lumican and musculoskeletal phenotypes in humans remains unclear. We aimed to analyze the relationship between serum lumican levels and osteosarcopenia in older adults. Blood samples were collected from 134 participants (age: 65 years and older) who underwent comprehensive assessment of bone and muscle phenotypes. Osteoporosis and sarcopenia were diagnosed based on World Health Organization and Asian consensus guidelines, respectively. Osteosarcopenia was defined as the simultaneous presence of osteoporosis and sarcopenia. After adjusting for sex, age, and body mass index, older adults with osteosarcopenia had 20.2 % lower serum lumican levels than those without (P = 0.010). The odds ratio (OR) for osteosarcopenia per standard deviation decrease in serum lumican level was 4.17 (P = 0.003). Consistently, higher serum lumican levels were correlated with higher bone mass at all measured sites (P = 0.004 to 0.045) and higher grip strength (P = 0.023). Furthermore, participants in the lowest tertile (T1) had 7.56-fold higher OR for osteosarcopenia (P = 0.024) than those in the highest lumican tertile (T3). In conclusion, these findings clinically validate previous experimental data showing the musculoskeletal protective effects of lumican and suggest that blood lumican levels could be used as a potential biomarker to assess the risk of not only osteosarcopenia but also osteoporosis or sarcopenia in older adults.
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Osteoporosis , Sarcopenia , Anciano , Humanos , Biomarcadores , Fuerza de la Mano/fisiología , Lumican , Osteoporosis/diagnóstico , Sarcopenia/diagnósticoRESUMEN
Toxic gases have surreptitiously influenced the health and environment of contemporary society with their odorless/colorless characteristics. As a result, a pressing need for reliable and portable gas-sensing devices has continuously increased. However, with their negligence to efficiently microstructure their bulky supportive layer on which the sensing and heating materials are located, previous semiconductor metal-oxide gas sensors have been unable to fully enhance their power efficiency, a critical factor in power-stringent portable devices. Herein, an ultrathin insulation layer with a unique serpentine architecture is proposed for the development of a power-efficient gas sensor, consuming only 2.3 mW with an operating temperature of 300 °C (≈6% of the leading commercial product). Utilizing a mechanically robust serpentine design, this work presents a fully suspended standalone device with a supportive layer thickness of only ≈50 nm. The developed gas sensor shows excellent mechanical durability, operating over 10â¯000 on/off cycles and ≈2 years of life expectancy under continuous operation. The gas sensor detected carbon monoxide concentrations from 30 to 1 ppm with an average response time of ≈15 s and distinguishable sensitivity to 1 ppm (ΔR/R0 = 5%). The mass-producible fabrication and heating efficiency presented here provide an exemplary platform for diverse power-efficient-related devices.
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OBJECTIVE: To assess the metabolic effects of adrenalectomy in patients with mild autonomous cortisol secretion (MACS). BACKGROUND: Despite retrospective studies showing the association of adrenalectomy for MACS with beneficial metabolic effects, there have been only 2 randomized prospective studies with some limitations to date. METHODS: A prospective, multicenter study randomized 132 patients with adrenal incidentaloma without any features of Cushing syndrome but with serum cortisol >50 nmol/L after a 1 mg overnight dexamethasone suppression test into an adrenalectomy group (n = 66) or control group (n = 66). The primary outcomes were changes in body weight, glucose, and blood pressure (BP). RESULTS: Among the 118 participants who completed the study with a median follow-up duration of 48 months (range: 3-66), the adrenalectomy group (n = 46) exhibited a significantly higher frequency of improved weight control, glucose control, and BP control (32.6%, 45.7%, and 45.7%, respectively) compared with the control group (n = 46; 6.5%, P = 0.002; 15.2%, P = 0.002; and 23.9%, P = 0.029, respectively) after matching for age and sex. Adrenalectomy [odds ratio (OR) = 10.38, 95% CI = 2.09-51.52, P = 0.004], body mass index (OR = 1.39, 95% CI = 1.08-1.79, P = 0.010), and cortisol after a 1 mg overnight dexamethasone suppression test levels (OR = 92.21, 95% CI = 5.30-1604.07, P = 0.002) were identified as independent factors associated with improved weight control. Adrenalectomy (OR = 5.30, 95% CI = 1.63-17.25, P = 0.006) and diabetes (OR = 8.05, 95% CI = 2.34-27.65, P = 0.001) were independently associated with improved glucose control. Adrenalectomy (OR = 2.27, 95% CI = 0.87-5.94, P = 0.095) and hypertension (OR = 10.77, 95% CI = 3.65-31.81, P < 0.001) demonstrated associations with improved BP control. CONCLUSIONS: adrenalectomy improved weight, glucose, and BP control in patients with MACS.
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Neoplasias de las Glándulas Suprarrenales , Adrenalectomía , Glucemia , Presión Sanguínea , Peso Corporal , Hidrocortisona , Humanos , Masculino , Femenino , Hidrocortisona/sangre , Persona de Mediana Edad , Glucemia/metabolismo , Estudios Prospectivos , Neoplasias de las Glándulas Suprarrenales/cirugía , Neoplasias de las Glándulas Suprarrenales/sangre , Anciano , Adulto , Resultado del Tratamiento , Estudios de SeguimientoRESUMEN
PURPOSE: This study aimed to compare the diagnostic performances of 18 F-FDOPA PET/CT and 123 I-MIBG scintigraphy with SPECT/CT for detection of pheochromocytoma and paraganglioma (PPGL). PATIENTS AND METHODS: We conducted a prospective, single-institution comparative study. Patients suspected of having PPGL or those showing recurrence and/or distant metastasis of PPGL were enrolled. The primary objective was to affirm the noninferiority of 18 F-FDOPA PET/CT for diagnostic sensitivity. Both 123 I-MIBG scintigraphy with SPECT/CT (at 4 and 24 hours) and 18 F-FDOPA PET/CT (at 5 and 60 minutes after radiotracer administration) were performed. The final diagnosis was established either pathologically or via clinical follow-up. Nuclear physicians, unaware of the clinical data, undertook image analysis. RESULTS: Thirty-two patients were evaluated: 14 of 21 with an initial diagnosis and 9 of 11 with recurrence/metastasis had PPGLs in their final diagnoses. In patient-based analyses, 18 F-FDOPA PET/CT (95.7%) exhibited noninferior sensitivity compared with 123 I-MIBG SPECT/CT (91.3%), within the predetermined noninferiority margin of -12% by a 95% confidence interval lower limit of -10%. Both modalities showed no significant difference in specificity (88.9% vs 88.9%). In the region-based analysis for the recurrence/metastasis group, 18 F-FDOPA PET/CT demonstrated significantly higher sensitivity compared with 123 I-MIBG SPECT/CT (86.2% vs 65.5%, P = 0.031) and superior interobserver agreement (κ = 0.94 vs 0.85). The inclusion of an early phase in dual-phase 18 F-FDOPA PET/CT slightly improved diagnostic performance, albeit not to a statistically significant degree. CONCLUSIONS: 18 F-FDOPA PET/CT demonstrated noninferior sensitivity and comparable specificity to 123 I-MIBG SPECT/CT in the diagnosing PPGL. Notably, in the assessment of PPGL recurrence and metastasis, 18 F-FDOPA PET/CT outperformed 123 I-MIBG SPECT/CT in terms of both sensitivity and interobserver agreement.
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Neoplasias de las Glándulas Suprarrenales , Paraganglioma , Feocromocitoma , Humanos , 3-Yodobencilguanidina , Neoplasias de las Glándulas Suprarrenales/patología , Paraganglioma/patología , Feocromocitoma/diagnóstico por imagen , Feocromocitoma/patología , Tomografía Computarizada por Tomografía de Emisión de Positrones , Estudios Prospectivos , Cintigrafía , Tomografía Computarizada por Tomografía Computarizada de Emisión de Fotón ÚnicoRESUMEN
The high explosiveness of hydrogen gas in the air necessitates prompt detection in settings where hydrogen is used. For this reason, hydrogen sensors are required to offer rapid detection and possess superior sensing characteristics in terms of measurement range, linearity, selectivity, lifetime, and environment insensitivity according to the publicized protocol. However, previous approaches have only partially achieved the standardized requirements and have been limited in their capability to develop reliable materials for spatially accessible systems. Here, an electrical hydrogen sensor with an ultrafast response (â¼0.6 s) satisfying all demands for hydrogen detection is demonstrated. Tailoring structural engineering based on the reaction kinetics of hydrogen and palladium, an optimized heating architecture that thermally activates fully suspended palladium (Pd) nanowires at a uniform temperature is designed. The developed Pd nanostructure, at a designated temperature distribution, rapidly reacts with hydrogen, enabling a hysteresis-free response from 0.1% to 10% and durable characteristics in mechanical shock and repetitive operation (>10,000 cycles). Moreover, the device selectively detects hydrogen without performance degradation in humid or carbon-based interfering gas circumstances. Finally, to verify spatial accessibility, the wireless hydrogen detection system has been demonstrated, detecting and reporting hydrogen leakage in real-time within just 1 s.
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We study evolutionary game dynamics in a growing habitat with vacancies. Fitness is determined by the global effect of the environment and a local prisoner's dilemma among neighbors. We study population growth on a one-dimensional lattice and analyze how the environment affects evolutionary competition. As the environment becomes harsh, an absorbing phase transition from growing populations to extinction occurs. The transition point depends on which strategies are present in the population. In particular, we find a 'cooperative window' in parameter space, where only cooperators can survive. A mutant defector in a cooperative community might briefly proliferate, but over time naturally occurring vacancies separate cooperators from defectors, thereby driving defectors to extinction. Our model reveals that vacancies provide a strong boost for cooperation by spatial selection.
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Conducta Cooperativa , Teoría del Juego , Humanos , Dinámica Poblacional , Crecimiento Demográfico , Ecosistema , Evolución BiológicaRESUMEN
BACKGRUOUND: Despite the protective effects of stromal cell-derived factor 1 (SDF-1) in stimulating muscle regeneration shown in experimental research, there is a lack of clinical studies linking circulating SDF-1 concentrations with muscle phenotypes. In order to elucidate the role of SDF-1 as a potential biomarker reflecting human muscle health, we investigated the association of plasma SDF-1 levels with sarcopenia in older adults. METHODS: This cross-sectional study included 97 community-dwelling participants who underwent a comprehensive geriatric assessment at a tertiary hospital in South Korea. Sarcopenia was defined by specific cutoff values applicable to the Asian population, whereas plasma SDF-1 levels were determined using an enzyme immunoassay. RESULTS: After accounting for sex, age, and body mass index, participants with sarcopenia and low muscle mass exhibited plasma SDF-1 levels that were 21.8% and 18.3% lower than those without these conditions, respectively (P=0.008 and P=0.009, respectively). Consistently, higher plasma SDF-1 levels exhibited a significant correlation with higher skeletal muscle mass index (SMI) and gait speed (both P=0.043), and the risk of sarcopenia and low muscle mass decreased by 58% and 55% per standard deviation increase in plasma SDF-1 levels, respectively (P=0.045 and P=0.030, respectively). Furthermore, participants in the highest SDF-1 tertile exhibited significantly higher SMI compared to those in the lowest tertile (P=0.012). CONCLUSION: These findings clinically corroborate earlier experimental discoveries highlighting the muscle anabolic effects of SDF- 1 and support the potential role of circulating SDF-1 as a biomarker reflecting human muscle health in older adults.
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Sarcopenia , Anciano , Humanos , Biomarcadores , Quimiocina CXCL12 , Estudios Transversales , Músculo Esquelético/patología , Sarcopenia/epidemiologíaRESUMEN
Triple-negative breast cancer (TNBC) constitutes 10%-15% of all breast tumors. The current standard of care is multiagent chemotherapy, which is effective in only a subset of patients. The original objective of this study was to deploy a mass spectrometry (MS)-based kinase inhibitor pulldown assay (KIPA) to identify kinases elevated in non-pCR (pathologic complete response) cases for therapeutic targeting. Frozen optimal cutting temperature compound-embedded core needle biopsies were obtained from 43 patients with TNBC before docetaxel- and carboplatin-based neoadjuvant chemotherapy. KIPA was applied to the native tumor lysates that were extracted from samples with high tumor content. Seven percent of all identified proteins were kinases, and none were significantly associated with lack of pCR. However, among a large population of "off-target" purine-binding proteins (PBP) identified, seven were enriched in pCR-associated samples (P < 0.01). In orthogonal mRNA-based TNBC datasets, this seven-gene "PBP signature" was associated with chemotherapy sensitivity and favorable clinical outcomes. Functional annotation demonstrated IFN gamma response, nuclear import of DNA repair proteins, and cell death associations. Comparisons with standard tandem mass tagged-based discovery proteomics performed on the same samples demonstrated that KIPA-nominated pCR biomarkers were unique to the platform. KIPA is a novel biomarker discovery tool with unexpected utility for the identification of PBPs related to cytotoxic drug response. The PBP signature has the potential to contribute to clinical trials designed to either escalate or de-escalate therapy based on pCR probability. Significance: The identification of pretreatment predictive biomarkers for pCR in response to neoadjuvant chemotherapy would advance precision treatment for TNBC. To complement standard proteogenomic discovery profiling, a KIPA was deployed and unexpectedly identified a seven-member non-kinase PBP pCR-associated signature. Individual members served diverse pathways including IFN gamma response, nuclear import of DNA repair proteins, and cell death.
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Antineoplásicos , Neoplasias de la Mama Triple Negativas , Humanos , Proteínas Portadoras , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Antineoplásicos/farmacología , Docetaxel , PurinasRESUMEN
NF1 is a key tumor suppressor that represses both RAS and estrogen receptor-α (ER) signaling in breast cancer. Blocking both pathways by fulvestrant (F), a selective ER degrader, together with binimetinib (B), a MEK inhibitor, promotes tumor regression in NF1-depleted ER+ models. We aimed to establish approaches to determine how NF1 protein levels impact B+F treatment response to improve our ability to identify B+F sensitive tumors. We examined a panel of ER+ patient-derived xenograft (PDX) models by DNA and mRNA sequencing and found that more than half of these models carried an NF1 shallow deletion and generally have low mRNA levels. Consistent with RAS and ER activation, RET and MEK levels in NF1-depleted tumors were elevated when profiled by mass spectrometry (MS) after kinase inhibitor bead pulldown. MS showed that NF1 can also directly and selectively bind to palbociclib-conjugated beads, aiding quantification. An IHC assay was also established to measure NF1, but the MS-based approach was more quantitative. Combined IHC and MS analysis defined a threshold of NF1 protein loss in ER+ breast PDX, below which tumors regressed upon treatment with B+F. These results suggest that we now have a MS-verified NF1 IHC assay that can be used for patient selection as a complement to somatic genomic analysis. Significance: A major challenge for targeting the consequence of tumor suppressor disruption is the accurate assessment of protein functional inactivation. NF1 can repress both RAS and ER signaling, and a ComboMATCH trial is underway to treat the patients with binimetinib and fulvestrant. Herein we report a MS-verified NF1 IHC assay that can determine a threshold for NF1 loss to predict treatment response. These approaches may be used to identify and expand the eligible patient population.
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Neoplasias de la Mama , Proteogenómica , Humanos , Femenino , Neoplasias de la Mama/tratamiento farmacológico , Neurofibromina 1/genética , Fulvestrant/farmacología , Receptores de Estrógenos/genética , Inhibidores de Proteínas Quinasas/farmacología , Factores de Transcripción NFI , ARN Mensajero , Quinasas de Proteína Quinasa Activadas por MitógenosRESUMEN
A new target that stimulates bone formation is needed to overcome limitations of current anti-osteoporotic drugs. Myokines, factors secreted from muscles, may modulate it. In this study, we investigated the role of aortic carboxypeptidase-like protein (ACLP), which is highly expressed in skeletal muscles, on bone formation. MC3T3-E1 cells and/or calvaria osteoblasts were treated with recombinant N-terminal mouse ACLP containing a signal peptide [rmACLP (N)]. The expression and secretion of ACLP were higher in skeletal muscle and differentiated myotube than in other tissues and undifferentiated myoblasts, respectively. rmACLP (N) increased bone formation, ALP activity, and phosphorylated p38 mitogen-activated protein (MAP) kinase in osteoblasts; reversal was achieved by pre-treatment with a TGF-ß receptor inhibitor. Under H2 O2 treatment, rmACLP (N) increased osteoblast survival, phosphorylated p38 MAP kinase, and the nuclear translocation of FoxO3a in osteoblasts. H2 O2 treatment caused rmACLP (N) to suppress its apoptotic, oxidative, and caspase-9 activities. rmACLP (N)-stimulated osteoblast survival was reversed by pre-treatment with a p38 inhibitor, a TGF-ß-receptor II blocking antibody, and a FoxO3a shRNA. Conditioned media (CM) from muscle cells stimulated osteoblast survival under H2 O2 treatment, in contrast to CM from ACLP knockdown muscle cells. rmACLP (N) increased the expressions of FoxO3a target anti-oxidant genes such as Sod2, Trx2, and Prx5. In conclusion, ACLP stimulated the differentiation and survival of osteoblasts. This led to the stimulation of bone formation by the activation of p38 MAP kinase and/or FoxO3a via TGF-ß receptors. These findings suggest a novel role for ACLP in bone metabolism as a putative myokine.
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Carboxipeptidasas , Proteínas Quinasas p38 Activadas por Mitógenos , Animales , Ratones , Diferenciación Celular/fisiología , Carboxipeptidasas/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Osteogénesis , Osteoblastos/metabolismo , FosforilaciónRESUMEN
Myonectin is a muscle-secreted factor that helps maintain homeostasis in the body by regulating several functions, including lipid metabolism. Previous studies suggested that myonectin may play a role in muscle health in an autocrine manner, but its impact on human skeletal muscle is still unclear. We aimed to investigate the relationship of serum myonectin levels with sarcopenia and related muscle parameters. We conducted a cross-sectional study of 142 older adults whose muscle mass, grip strength, gait speed, chair stands, and short physical performance battery (SPPB) were evaluated in the geriatric clinic of a tertiary medical center. Sarcopenia was defined based on Asian-specific cutoff values, and circulating myonectin levels were measured using an enzyme immunoassay. Before and after adjusting for age, sex, and body mass index, the serum myonectin level was not significantly different when the patients were stratified by status of sarcopenia, muscle mass, muscle strength, and physical performance. Furthermore, whether given as a continuous variable or divided into quartile groups, the serum myonectin level had no association with the skeletal muscle mass, grip strength, gait speed, chair stand test, or SPPB score. Our findings did not confirm the potential role of myonectin in muscle metabolism observed in experimental research. Thus, serum myonectin levels cannot predict the risk of sarcopenia in older Asian adults.
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Colágeno , Sarcopenia , Anciano , Humanos , Estudios Transversales , Fuerza de la Mano/fisiología , Fuerza Muscular/fisiología , Músculo Esquelético/fisiología , Sarcopenia/sangre , Sarcopenia/epidemiología , Colágeno/sangreRESUMEN
Transcriptionally active ESR1 fusions (ESR1-TAF) are a potent cause of breast cancer endocrine therapy (ET) resistance. ESR1-TAFs are not directly druggable because the C-terminal estrogen/anti-estrogen-binding domain is replaced with translocated in-frame partner gene sequences that confer constitutive transactivation. To discover alternative treatments, a mass spectrometry (MS)-based kinase inhibitor pulldown assay (KIPA) was deployed to identify druggable kinases that are upregulated by diverse ESR1-TAFs. Subsequent explorations of drug sensitivity validated RET kinase as a common therapeutic vulnerability despite remarkable ESR1-TAF C-terminal sequence and structural diversity. Organoids and xenografts from a pan-ET-resistant patient-derived xenograft model that harbors the ESR1-e6>YAP1 TAF were concordantly inhibited by the selective RET inhibitor pralsetinib to a similar extent as the CDK4/6 inhibitor palbociclib. Together, these findings provide preclinical rationale for clinical evaluation of RET inhibition for the treatment of ESR1-TAF-driven ET-resistant breast cancer. SIGNIFICANCE: Kinome analysis of ESR1 translocated and mutated breast tumors using drug bead-based mass spectrometry followed by drug-sensitivity studies nominates RET as a therapeutic target. See related commentary by Wu and Subbiah, p. 3159.