RESUMO
BACKGROUND: CDK4/6 inhibitors (CDK4/6i) have shown great efficacy in prolonging progression-free survival and is the current standard of care for hormone positive (HR(+)) metastatic breast cancer (mBC). Despite well tolerability and ease of use, the most common side effect of CDK4/6i is myelosuppression, with neutropenia the most prevalent adverse effect. Studies show that the prevalence and severity of neutropenia are more marked in Asian patients, although details remain obscure. METHODS: In this study, we retrospectively analyzed 105 Taiwanese patients who received palbociclib for HR(+) HER2(-) mBC at the Taipei Veterans General Hospital. To investigate a possible genetic association for high prevalence of neutropenia, we queried the Taiwan Biobank with publicly available germline databases (ALFA, gnomAD, ExAC, 1000 Genomes project, HapMap), for the allele frequencies of 4 neutropenia-related SNPs (ABCB1_rs1045642, ABCB1_rs1128503, ERCC1_rs3212986, ERCC1_rs11615) and compared between different ethnicities. In addition, one of the patients was a long-term patient with peritoneal dialysis. We quantified the levels of palbociclib in her serum and peritoneal fluid by liquid chromatography-mass spectrometry (LC-MS). RESULTS: Interestingly, in our cohort, early neutropenia nadir (occurred within 56 days of start) was associated with worse treatment outcome, while occurrence of grade 3/4 neutropenia was associated with better outcome. We observed an extremely high incidence of neutropenia (96.2% any grade, 70.4% grade 3/4). In the analyzed germline databases, we discovered a higher SNP frequency of the T allele in ABCB1_rs1128503, a lower frequency of T allele in ABCB1_rs1045642, and a higher SNP frequency of G allele in ERCC1_rs11615. We observed that palbociclib levels in peritoneal dialysate ranged from around 20-50 ppb, and serum levels reached 100-110 ppb during drug administration and decreased to <10 ppb during discontinuation. CONCLUSION: Our retrospective analysis of real world palbociclib use reveals an association with grade 3/4 neutropenia with better outcome and early neutropenia nadir with worse outcome. Our findings of Asian specific SNPs support a predisposition toward profound and prevalent neutropenia in Asian patients under CDK4/6i. We also report the first pharmacokinetics analysis on a patient with peritoneal dialysis receiving CDK4/6i. In summary, our study provides novel clinical and genotypic insights into CDK4/6i associated neutropenia.
Assuntos
Neoplasias da Mama , Neutropenia , Piperazinas , Piridinas , Feminino , Humanos , Estudos Retrospectivos , Prevalência , Receptor ErbB-2/genética , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Neutropenia/induzido quimicamente , Neutropenia/epidemiologia , Neutropenia/genética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Quinase 4 Dependente de CiclinaRESUMO
Despite recent tremendous progress in optical imaging and metrology1-6, there remains a substantial resolution gap between atomic-scale transmission electron microscopy and optical techniques. Is optical imaging and metrology of nanostructures exhibiting Brownian motion possible with such resolution, beyond thermal fluctuations? Here we report on an experiment in which the average position of a nanowire with a thermal oscillation amplitude of â¼150 pm is resolved in single-shot measurements with subatomic precision of 92 pm, using light at a wavelength of λ = 488 nm, providing an example of such sub-Brownian metrology with â¼λ/5,300 precision. To localize the nanowire, we employ a deep-learning analysis of the scattering of topologically structured light, which is highly sensitive to the nanowire's position. This non-invasive metrology with absolute errors down to a fraction of the typical size of an atom, opens a range of opportunities to study picometre-scale phenomena with light.
Assuntos
Nanoestruturas , Nanofios , ElétronsRESUMO
Autophagy, involved in protein degradation and amino acid recycling, plays a key role in plant development and stress responses. However, the relationship between autophagy and phytohormones remains unclear. We used diverse methods, including CRISPR/Cas9, ultra-performance liquid chromatography coupled with tandem mass spectrometry, chromatin immunoprecipitation, electrophoretic mobility shift assays, and dual-luciferase assays to explore the molecular mechanism of strigolactones in regulating autophagy and the degradation of ubiquitinated proteins under cold stress in tomato (Solanum lycopersicum). We show that cold stress induced the accumulation of ubiquitinated proteins. Mutants deficient in strigolactone biosynthesis were more sensitive to cold stress with increased accumulation of ubiquitinated proteins. Conversely, treatment with the synthetic strigolactone analog GR245DS enhanced cold tolerance in tomato, with elevated levels of accumulation of autophagosomes and transcripts of autophagy-related genes (ATGs), and reduced accumulation of ubiquitinated proteins. Meanwhile, cold stress induced the accumulation of ELONGATED HYPOCOTYL 5 (HY5), which was triggered by strigolactones. HY5 further trans-activated ATG18a transcription, resulting in autophagy formation. Mutation of ATG18a compromised strigolactone-induced cold tolerance, leading to decreased formation of autophagosomes and increased accumulation of ubiquitinated proteins. These findings reveal that strigolactones positively regulate autophagy in an HY5-dependent manner and facilitate the degradation of ubiquitinated proteins under cold conditions in tomato.
RESUMO
Thermomorphogenesis is, among other traits, characterized by enhanced hypocotyl elongation due to the induction of auxin biosynthesis genes like YUCCA8 by transcription factors, most notably PHYTOCHROME INTERACTING FACTOR 4 (PIF4). Efficient binding of PIF4 to the YUCCA8 locus under warmth depends on HISTONE DEACETYLASE 9 (HDA9) activity, which mediates histone H2A.Z depletion at the YUCCA8 locus. However, HDA9 lacks intrinsic DNA-binding capacity, and how HDA9 is recruited to YUCCA8, and possibly other PIF4-target sites, is currently not well understood. The Mediator complex functions as a bridge between transcription factors bound to specific promoter sequences and the basal transcription machinery containing RNA polymerase II. Mutants of Mediator component Mediator25 (MED25) exhibit reduced hypocotyl elongation and reduced expression of YUCCA8 at 27°C. In line with a proposed role for MED25 in thermomorphogenesis in Arabidopsis (Arabidopsis thaliana), we demonstrated an enhanced association of MED25 to the YUCCA8 locus under warmth and interaction of MED25 with both PIF4 and HDA9. Genetic analysis confirmed that MED25 and HDA9 operate in the same pathway. Intriguingly, we also showed that MED25 destabilizes HDA9 protein. Based on our findings, we propose that MED25 recruits HDA9 to the YUCCA8 locus by binding to both PIF4 and HDA9.
Assuntos
Proteínas de Arabidopsis , Arabidopsis , Fitocromo , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Complexo Mediador/genética , Complexo Mediador/metabolismo , Fitocromo/metabolismo , Arabidopsis/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Histona Desacetilases/genética , Histona Desacetilases/metabolismo , Regulação da Expressão Gênica de Plantas , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismoRESUMO
BACKGROUND: Increased prevalence of hepatocellular carcinoma (HCC) remains a global health challenge. HCC chemoresistance is a clinical obstacle for its management. Aberrant miRNA expression is a hallmark for both cancer progression and drug resistance. However, it is unclear which miRNAs are involved in HCC chemoresistance. METHODS: MicroRNA microarray analysis revealed a differential expression profile of microRNAs between the hepatocellular carcinoma HA22T cell line and the HDACi-R cell line, which was validated by quantitative real-time PCR (qRT-PCR). To determine the biological function of miR-342-5p and the mechanism of the microRNA-342-5p/CFL1 axis in hepatocellular carcinoma HDACi resistance, loss- and gain-of-function studies were conducted in vitro. RESULTS: Here we demonstrated the molecular mechanism of histone deacetylase inhibitor (HDACi) resistance in HCC. Differential miRNA expression analysis showed significant down regulation of miR-342-5p in HDACi-R cells than in parental HA22T cells. Mimics of miR-342-5p enhanced apoptosis through upregulation of Bax, cyto-C, cleaved-caspase-3 expressions with concomitant decline in anti-apoptotic protein (Bcl-2) in HDACi-R cells. Although HDACi did not increase cell viability of HDACi-R, overexpression of miR-342-5p decreased cofilin-1 expression, upregulated reactive oxygen species (ROS) mediated apoptosis, and sensitized HDACi-R to HDACi in a dose-dependent manner. CONCLUSION: Our findings demonstrated the critical role of miR-342-5p in HDACi resistance of HCC and that this mechanism might be attributed to miR-342-5p/cofilin-1 regulation.
RESUMO
BACKGROUND: DEHP, a common plasticizer known for its hormone-disrupting properties, has been associated with asthma. However, a significant proportion of adult asthma cases are "non-atopic", lacking a clear etiology. METHODS: In a case-control study conducted between 2011 and 2015, 365 individuals with current asthma and 235 healthy controls from Kaohsiung City were enrolled. The control group comprised individuals without asthma, Type 2 Diabetes Mellitus (T2DM), hypertension, or other respiratory/allergic conditions. The study leveraged asthma clusters (Clusters A to F) established in a prior investigation. Analysis involved the examination of urinary DEHP metabolites (MEHP and MEHHP), along with the assessment of oxidative stress, sphingolipid metabolites, and inflammatory biomarkers. Statistical analyses encompassed Spearman's rank correlation coefficients, multiple logistic regression, and multinomial logistic regression. RESULTS: Asthma clusters (E, D, C, F, A) exhibited significantly higher ORs of MEHHP exposures compared to the control group. When considering asthma-related comorbidities (T2DM, hypertension, or both), patients without comorbidities demonstrated significantly higher ORs of the sum of primary and secondary metabolites (MEHP + MEHHP) and MEHHP compared to those with asthma comorbidities. A consistent positive correlation between urinary HEL and DEHP metabolites was observed, but a consistent negative correlation between DEHP metabolites and selected cytokines was identified. CONCLUSION: The current study reveals a heightened risk of MEHHP and MEHP + MEHHP exposure in specific asthma subgroups, emphasizing its complex relationship with asthma. The observed negative correlation with cytokines suggests a new avenue for research, warranting robust evidence from epidemiological and animal studies.
Assuntos
Asma , Diabetes Mellitus Tipo 2 , Dietilexilftalato , Dietilexilftalato/análogos & derivados , Hipertensão , Ácidos Ftálicos , Adulto , Animais , Humanos , Dietilexilftalato/toxicidade , Dietilexilftalato/urina , Exposição Ambiental , Estudos de Casos e Controles , Asma/induzido quimicamente , Asma/diagnóstico , Asma/epidemiologia , CitocinasRESUMO
Postbiotics, as emerging products, were added to infant formula, but their safety and efficacy are unclear. To clarify this issue, we wrote this meta-analysis. We searched PubMed, Embase, Web of Science and ProQuest from its establishment to February 2023. The review was registered on PROSPERO database (CRD42022352405). The effects of infant formula with and without postbiotics were compared, and the incidence of serious adverse events (SAEs), digestive symptoms, concentration of stool secretory immunoglobulin A (SIgA), and growth and development indexes were analyzed. Nine randomized controlled trials with 2065 participants were included. The addition of postbiotics to infant formula was found to increase the concentration of stool SIgA (P < 0.05) with very low certainty of evidence, without significantly impacting the incidence of SAEs, infantile colic, flatulence, diarrhea, vomiting, abdominal pain and gastrointestinal disorders, the daily weight gain, the total gain in body length and the daily head circumference gain (all P > 0.05). Adding postbiotics to the formula is safe for infants, which would not increase the incidence of SAEs, infantile colic, flatulence, diarrhea, vomiting, abdominal pain, and gastrointestinal disorders, and could increase the concentration of stool SIgA. IMPACT: Our study provides evidence that the addition of postbiotics to infant formula is safe but not effective. This is the first systematic review and meta-analysis of postbiotics. This study provides strong evidence for the safety of postbiotics and lays a foundation for related clinical trials.
Assuntos
Cólica , Gastroenteropatias , Lactente , Humanos , Fórmulas Infantis , Flatulência , Dor Abdominal , Vômito/prevenção & controle , Diarreia/prevenção & controle , Imunoglobulina A Secretora , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
OBJECTIVES: Fibromyalgia (FM) is a chronic condition characterised by widespread pain, and cognitive difficulties represent one of the most common symptoms of FM. However, subjective cognitive complaints (SCC) may not necessarily indicate significant abnormalities in objective cognitive performances, and there is limited research investigating the relationship between these two aspects. This study thus aims to analyse the differences between SCC and objective cognitive performance in FM patients and to explore their associations. METHODS: A total of 32 FM female patients (age: 50.91±7.06; years since diagnosis: 4.34±4.53) recruited in this study underwent a comprehensive assessment covering four domains: pain, depression, trait anxiety, SCC, and objective cognitive functions (memory, executive function, and information processing speed). RESULTS: Eighty-seven percent of patients experienced significant negative impacts from pain; meanwhile, 91% and 62% showed marked tendencies towards trait anxiety and depression, respectively. Additionally, 56% of patients reported significantly higher levels of SCC. However, less than one-third of patients demonstrated impairments in various cognitive functions. SCC significantly correlated with pain intensity, depression, information processing speed, and trait anxiety, with pain intensity being a significant predictor (R2=.30). Furthermore, patients with significant SCC exhibited more abnormalities in pain, information processing speed, and trait anxiety compared to those without significant SCC. CONCLUSIONS: SCC may not necessarily correlate with objective cognitive impairments and might be specifically linked to defective information processing speed. It thus merits that clinical assessments for FM patients should incorporate measurements of information processing speed to gain a comprehensive understanding of SCC in FM patients.
Assuntos
Ansiedade , Cognição , Depressão , Fibromialgia , Humanos , Fibromialgia/psicologia , Fibromialgia/diagnóstico , Fibromialgia/complicações , Fibromialgia/fisiopatologia , Feminino , Pessoa de Meia-Idade , Ansiedade/psicologia , Ansiedade/diagnóstico , Adulto , Depressão/psicologia , Depressão/diagnóstico , Disfunção Cognitiva/diagnóstico , Disfunção Cognitiva/psicologia , Disfunção Cognitiva/etiologia , Função Executiva , Testes Neuropsicológicos , Medição da Dor , Memória , Dados Preliminares , Velocidade de ProcessamentoRESUMO
Damage associated molecular patterns (DAMPs), including calreticulin (CRT) exposure, high-mobility group box 1 protein (HMGB1) elevation, and ATP release, characterize immunogenic cell death (ICD) and may play a role in cancer immunotherapy. Triple negative breast cancer (TNBC) is an immunogenic subtype of breast cancer with higher lymphocyte infiltration. Here, we found that regorafenib, a multi-target angiokinase inhibitor previously known to suppress STAT3 signaling, induced DAMPs and cell death in TNBC cells. Regorafenib induced the expression of HMGB1 and CRT, and the release of ATP. Regorafenib-induced HMGB1 and CRT were attenuated following STAT3 overexpression. In a 4T1 syngeneic murine model, regorafenib treatment increased HMGB1 and CRT expression in xenografts, and effectively suppressed 4T1 tumor growth. Immunohistochemical staining revealed increased CD4+ and CD8+ tumor-infiltrating T cells in 4T1 xenografts following regorafenib treatment. Regorafenib treatment or programmed death-1 (PD-1) blockade using anti-PD-1 monoclonal antibody reduced lung metastasis of 4T1 cells in immunocompetent mice. While regorafenib increases the proportion of MHC II high expression on dendritic cells in mice with smaller tumors, the combination of regorafenib and PD-1 blockade did not show a synergistic effect on anti-tumor activity. These results suggest that regorafenib induces ICD and suppresses tumor progression in TNBC. It should be carefully evaluated when developing a combination therapy with an anti-PD-1 antibody and a STAT3 inhibitor.
Assuntos
Proteína HMGB1 , Neoplasias de Mama Triplo Negativas , Camundongos , Humanos , Animais , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/metabolismo , Proteína HMGB1/farmacologia , Morte Celular , Trifosfato de Adenosina/farmacologia , Linhagem Celular TumoralRESUMO
Acute promyelocytic leukemia (APL) stands out as a distinctive form of acute leukemia, exhibiting a higher occurrence of thrombotic events when contrasted with other leukemia subtypes. Since thrombosis is a relatively rare but unfavorable condition with poor prognostic implications, it is crucial to determine the risk factors for thrombotic events in APL(thrombosis in large venous or arterial from onset to differentiation therapy in 30d). We performed a retrospective study involving 950 APL patients between January 2000 and October 2022, from which 123 were excluded by younger than 16 years of age, 95 were excluded by incomplete data, and 6 were excluded by thrombosis related to CVC or PICC. A total of 23 APL patients with thrombosis for inclusion in our analysis were performed a 1:5 ratio matching based on sex (perfect match) and age (within 5 years) to patients without thrombosis. These patients were continuously monitored in the outpatient department over a period of 5 years. We meticulously examined clinical and laboratory data to pinpoint the risk factors related to thrombotic events in APL. Our primary clinical endpoints were all-cause mortality and achieving complete remission, while secondary clinical outcomes included APL relapse. Thrombotic events were observed in 2.4% (23/950) of APL patients. Compared to patients without thrombosis, patients with thrombosis had higher lactate dehydrogenase (LDH) [313 (223, 486) vs. 233 (188, 367) U/L, p = 0.020], higher indirect bilirubin [11.2 (7.4, 18.6) vs.8.3 (6.0, 10.7) umol/L, p = 0.004], higher creatinine [72 (62, 85) vs. 63 (54, 74) umol/L, p = 0.026], higher CD2 expression (65.2 vs. 15.2%, p < 0.001), higher CD15 expression (60.9 vs. 24.3%, p = 0.001), and PML/RARαisoforms (p < 0.001). Multivariate-logistic-regression analysis revealed several factors that were markedly related to thrombosis, including LDH (OR≈1.003, CIs≈1.000-1.006, p = 0.021), indirect bilirubin (OR≈1.084, CIs≈1.000-1.188, p = 0.043), CD2 expression positive (OR≈16.629, CIs≈4.001-62.832, p < 0.001), and CD15 expression positive (OR≈7.747, CIs≈2.005-29.941, p = 0.003). The S-type (OR≈0.012, CIs≈0.000-0.310, p = 0.008) and L-type (OR≈0.033, CIs≈0.002-0.609, p = 0.022) PML/RARα isoforms were negatively associated with thrombosis. Kaplan-Meier curves indicated that the survival rates were remarkably varied between APL patients with and without thrombosis (HR:21.34, p < 0.001). LDH and indirect bilirubin are variables significantly associated with thrombosis in APL, S-type and L-type PML/RARαisoforms exhibit a negative association with thrombotic events. The thrombotic events of APL can predict the subsequent survival of thrombosis. The findings of our study have the potential to facilitate early detection of thrombosis and enhance the prognosis for individuals with APL who develop thrombosis. Further validation of our findings will be essential through future prospective or multicenter studies.
Assuntos
Leucemia Promielocítica Aguda , Trombose , Humanos , Leucemia Promielocítica Aguda/sangue , Leucemia Promielocítica Aguda/complicações , Leucemia Promielocítica Aguda/mortalidade , Masculino , Fatores de Risco , Feminino , Trombose/etiologia , Trombose/sangue , Trombose/mortalidade , Estudos Retrospectivos , Adulto , Pessoa de Meia-Idade , Análise por Pareamento , Adolescente , Adulto Jovem , L-Lactato Desidrogenase/sangue , Idoso , Bilirrubina/sangue , Prognóstico , Indução de RemissãoRESUMO
INTRODUCTION: Patients with subdural hemorrhage (SDH) and a Glasgow Coma Scale (GCS) score of 13-15 are typically categorized as having mild traumatic brain injury. We hypothesize that patients without a maximum GCS score - specifically, patients with GCS scores of 13 and 14 - may exhibit poorer neurological outcomes. METHOD: Between January 1, 2019, and December 31, 2020, SDH patients with GCS scores ranging from 13 to 15 were retrospectively studied. We compared outcomes between patients with a maximum GCS score of 15 and those with scores of either 13 or 14. Independent factors associated with neurological deterioration among patients with a GCS score of 15 were evaluated using multivariate logistic regression (MLR) analysis. RESULTS: During the study period, 470 patients with SDH and GCS scores between 13 and 15 were examined. Compared to patients with a maximum GCS score (N = 375), those in the GCS 13-14 group (N = 95) showed significantly higher rates of neurological deterioration (33.7% vs. 10.4%, p value <0.001) and neurosurgical interventions (26.3% vs. 16.3%, p value <0.024). Moreover, the GCS 13-14 group had a significantly poorer prognosis than patients with a GCS score of 15 [mortality rate: 7.4% vs. 2.4%, p value <0.017; rate of impaired consciousness at discharge: 21.1% vs. 4.0%, p value <0.001; and rate of neurological disability at discharge: 29.5% vs. 6.9%, p value <0.001]. The MLR analysis revealed that SDH thickness (odds ratio = 1.127, p value = 0.006) was an independent risk factor for neurological disability at discharge in patients with a GCS score of 15. CONCLUSION: Among SDH patients with mild TBI, those with GCS scores of 13-14 exhibited poorer neurological outcomes than those with a maximum GCS score. The thickness of the SDH is positively associated with neurological disability in SDH patients with a maximum GCS score.
Assuntos
Coma , Hematoma Subdural , Humanos , Estudos Retrospectivos , Hematoma Subdural/etiologia , Escala de Coma de Glasgow , Alta do Paciente , PrognósticoRESUMO
BACKGROUND: Physician burnout is rising, especially among academic physicians facing pressures to increase their clinical workload, lead administrative tasks and committees, and be active in research. There is a concern this could have downstream effects on learners' experiences and academic physician's ability to teach learners on the team. METHODS: A 29-question RedCap survey was electronically distributed to 54 attending physicians within an academic learning health system who oversaw the General Medicine inpatient teaching services during the 2022-2023 academic year. The aims were to assess this cohort of attending physicians' experiences, attitudes, and perceptions on their ability to effectively teach learners on the team, feeling valued, contributors to work-life balance and symptoms of burnout, Fisher's Exact Tests were used for data analysis. RESULTS: Response rate was 56%. Attendings splitting time 50% inpatient / 50% outpatient felt that team size and type of admissions model affected their ability to effectively teach learners (p = 0.022 and p = 0.049). Attendings with protected administrative time felt that non-patient care obligations affected their ability to effectively teach the learners (p = 0.019). Male attendings and attendings with ≤ 5 years of General Medicine inpatient teaching experience felt less valued by residency leadership (p = 0.019 and p = 0.026). 80% of attendings experienced emotional exhaustion, and those with > 10 weeks on a General Medicine inpatient teaching service were more likely to experience emotional exhaustion (p = 0.041). Attendings with > 10 weeks on a General Medicine inpatient teaching service and those who were a primary caregiver were more likely to experience depersonalization (p = 0.012 and p = 0.031). 57% of attendings had reduced personal achievement. CONCLUSIONS: Institutions should seek an individual and organizational approach to professional fulfillment. Special attention to these certain groups is warranted to understand how they can be better supported. Further research, such as with focus groups, is needed to address these challenges.
Assuntos
Esgotamento Profissional , Humanos , Masculino , Feminino , Inquéritos e Questionários , Atitude do Pessoal de Saúde , Internato e Residência , Adulto , Corpo Clínico Hospitalar/psicologia , Corpo Clínico Hospitalar/educação , Pacientes Internados/psicologia , Ensino , Equilíbrio Trabalho-VidaRESUMO
Periodic mammography and/or sonography examinations are conducted across numerous hospitals nationalwidely, especially for antedees with a positive mammography screening. Despite the regular practice, clinical efficacy of hospital-based breast cancer surveillance remains unclear. Specifically, the impact of surveillance interval upon survival and prognostic surrogates stratified by menopausal status, as well as malignant transition rate should be deciphered. We retrieved cancer registry to ascertain 841 breast cancers with surveillance history through administration data. Healthy controls underwent breast surveillance and were concurrently free of cancer. More benign diseases rather than cancers were identified from premenopausal women (age ≤50 years) with sonography alone within one year, as well as older women (age >50) with both mammography and sonography one to two years before a cancer or benign diagnosis. Among breast cancers, mammography alone during the antecedent one to two years had a protective effect for diagnosing carcinoma in situ rather than invasive cancer (age-adjusted odds ratio: 0.048, P = 0.016). Three-state time homogeneous Markov model showed that hospital-based breast surveillance within 2 years of disease onset reduced the malignant transition rate by 65.16% (59.79-76.74%). The clinical efficacy of breast cancer surveillance was evidenced.
Assuntos
Neoplasias da Mama , Feminino , Humanos , Idoso , Pessoa de Meia-Idade , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/epidemiologia , Mamografia , Ultrassonografia , Exame Físico , Resultado do Tratamento , Programas de Rastreamento , Detecção Precoce de CâncerRESUMO
Aeromagnetic surveys are widely used in geological exploration, mineral resource assessment, environmental monitoring, military reconnaissance, and other areas. It is necessary to perform magnetic compensation for interference in these fields. In recent years, large unmanned aerial vehicles (UAVs) have been more suitable for magnetic detection missions because of the greater loads they can carry. This article proposes some methods for the magnetic compensation of large multiload UAVs. Because of the interference of the large platform and instrument noise, the standard deviations (stds) of the compensation data used in this paper are larger. At the beginning of this article, using the traditional T-L model, we avoid the shortcomings of the anti-magnetic interference ability of triaxial magnetic gate magnetometers. The direction cosine information is obtained by using an inertial navigation system, the global positioning system, and a triaxial magnetic gate magnetometer. Then, we increase the amplitude of the maneuvers in the compensation process; this reduces the multicollinearity problems in the compensation matrix to a certain extent, but it also results in greater magnetic field interference. Lastly, we employ the method of Lasso regularization Newton iteration (LRNM). Compared to the traditional methods of least squares (LS) and singular value decomposition (SVD), LRNM provides improvements of 34% and 27%, respectively. In summary, this series of schemes can be used to perform effective compensation for large multi-load UAVs and improve the actual use of large UAVs, making them more accurate in the measurement of aeromagnetic survey data.
RESUMO
Currently, magnetic gradient tensor-based localization methods face challenges such as significant errors in geomagnetic field estimation, susceptibility to local optima in optimization algorithms, and inefficient performance. In addressing these issues, this article propose a two-point localization method under the constraint of overlaying geometric invariants. This method initially establishes the relationship between the target position and the magnetic gradient tensor by substituting an intermediate variable for the magnetic moment. Exploiting the property of the eigenvector corresponding to the minimum absolute eigenvalue being perpendicular to the target position vector, this constraint is superimposed to formulate a nonlinear system of equations of the target's position. In the process of determining the target position, the Nara method is employed for obtaining the initial values, followed by the utilization of the Levenberg-Marquardt algorithm to derive a precise solution. Experimental validation through both simulations and experiments confirms the effectiveness of the proposed method. The results demonstrate its capability to overcome the challenges faced by a single-point localization method in the presence of some errors in geomagnetic field estimation. In comparison to traditional two-point localization methods, the proposed method exhibits the highest precision. The localization outcomes under different noise conditions underscore the robust noise resistance and resilience of the proposed method.
RESUMO
The aim of this study was to elucidate molecular profiling in HER2-low tumors based on a promising dataset. A total of 615 consecutive HER2-negative breast cancer samples were assayed. The genomic mutations in the two groups with different HER2 expression levels (HER2-0 vs. HER2-low) were compared. The mutation types obtained via next-generation targeted sequencing were correlated with the clinicopathological features of the patients with HER2-0 and HER2-low breast cancer. The results showed that there was a significantly higher percentage of receptor-positive (ER/PR) tumors and more low-level Ki-67 tumors, but a lower incidence of stage I/II tumors in the HER2-low group compared to the HER2-0 group. There was a significantly higher frequency of 17.62% (65/369) for PIK3CA_SNA in the HER2-low group than in the HER2-0 group, which had a frequency of only 9.35% (23/246) (p = 0.006). When the called gene alterations in the triple-negative breast cancer (TNBC) group were compared with those in the luminal-like breast cancer group, there was a significantly high frequency of 28.17% (140/497) for ERBB2_SNA in a luminal-like group than in the TNBC group(16.95% (20/118)).We conclude that the early detection of PIK3CA mutations is likely to be important and might help therapeutic decision making in patients with HER2-low tumors.
Assuntos
Neoplasias da Mama , Neoplasias de Mama Triplo Negativas , Feminino , Humanos , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Genômica , Mutação , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Receptores de Progesterona/metabolismo , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/metabolismoRESUMO
Psychological stress increases risk of gastrointestinal tract diseases. However, the mechanism behind stress-induced gastrointestinal injury is not well understood. The objective of our study is to elucidate the putative mechanism of stress-induced gastrointestinal injury and develop an intervention strategy. To achieve this, we employed the restraint stress mouse model, a well-established method to study the pathophysiological changes associated with psychological stress in mice. By orally administering gut-nonabsorbable Evans blue dye and monitoring its plasma levels, we were able to track the progression of gastrointestinal injury in live mice. Additionally, flow cytometry was utilized to assess the viability, death, and inflammatory status of splenic leukocytes, providing insights into the stress-induced impact on the innate immune system associated with stress-induced gastrointestinal injury. Our findings reveal that neutrophils represent the primary innate immune leukocyte lineage responsible for stress-induced inflammation. Splenic neutrophils exhibited elevated expression levels of the pro-inflammatory cytokine IL-1, cellular reactive oxygen species, mitochondrial burden, and cell death following stress challenge compared to other innate immune cells such as macrophages, monocytes, and dendritic cells. Regulated cell death analysis indicated that NETosis is the predominant stress-induced cell death response among other analyzed regulated cell death pathways. NETosis culminates in the formation and release of neutrophil extracellular traps, which play a crucial role in modulating inflammation by binding to pathogens. Treatment with the NETosis inhibitor GSK484 rescued stress-induced neutrophil extracellular trap release and gastrointestinal injury, highlighting the involvement of neutrophil extracellular traps in stress-induced gastrointestinal inflammation. Our results suggest that neutrophil NETosis could serve as a promising drug target for managing psychological stress-induced gastrointestinal injuries.
Assuntos
Inflamação , Neutrófilos , Restrição Física , Estresse Psicológico , Animais , Camundongos , Neutrófilos/imunologia , Neutrófilos/metabolismo , Estresse Psicológico/complicações , Estresse Psicológico/imunologia , Inflamação/patologia , Masculino , Camundongos Endogâmicos C57BL , Armadilhas Extracelulares/metabolismo , Gastroenteropatias/etiologia , Modelos Animais de Doenças , Espécies Reativas de Oxigênio/metabolismoRESUMO
To replace the obsolete ponding system, palm oil mill effluent (POME) steam reforming (SR) over net-acidic LaNiO3 and net-basic LaCoO3 were proposed as the POME primary treatments, with promising H2-rich syngas production. Herein, the long-term evaluation of POME SR was scrutinized with both catalysts under the optimal conditions (600 °C, 0.09 mL POME/min, 0.3 g catalyst, & 74-105 µm catalyst particle size) to examine the catalyst microstructure changes, transient process stability, and final effluent evaluation. Extensive characterization proved the (i) adsorption of POME vapour on catalysts before SR, (ii) deposition of carbon and minerals on spent SR catalysts, and (iii) dominance of coking deactivation over sintering deactivation at 600 °C. Despite its longer run, spent LaCoO3 (50.54 wt%) had similar carbon deposition with spent LaNiO3 (50.44 wt%), concurring with its excellent coke resistance. Spent LaCoO3 (6.12 wt%; large protruding crystals) suffered a harsher mineral deposition than spent LaNiO3 (3.71 wt%; thin film coating), confirming that lower reactivity increased residence time of reactants. Transient syngas evolution of both SR catalysts was relatively steady up to 4 h but perturbed by coking deactivation thereafter. La2O2CO3 acted as an intermediate species that hastened the coke removal via reverse Boudouard reaction upon its decarbonation. La2O2CO3 decarbonation occurred continuously in LaCoO3 system but intermittently in LaNiO3 system. LaNiO3 system only lasted for 13 h as its compact ash blocked the gas flow. LaCoO3 system lasted longer (17 h) with its porous ash, but it eventually failed because KCl crystallites blocked its active sites. Relatively, LaCoO3 system offered greater net H2 production (72.78%) and POME treatment volume (30.77%) than LaNiO3 system. SR could attain appreciable POME degradation (>97% COD, BOD5, TSS, & colour intensity). Withal, SR-treated POME should be polished to further reduce its incompliant COD and BOD5.
Assuntos
Compostos de Cálcio , Coque , Óleos de Plantas , Titânio , Óleo de Palmeira , Óleos de Plantas/química , Vapor , Lantânio , Óxidos , Carbono , Resíduos IndustriaisRESUMO
The present study, as one part of a larger project that aimed to investigate the effects of dietary berberine (BBR) on fish growth and glucose regulation, mainly focused on whether miRNAs involve in BBR's modulation of glucose metabolism in fish. Blunt snout bream Megalobrama amblycephala (average weight of 20.36 ± 1.44 g) were exposed to the control diet (NCD, 30% carbohydrate), the high-carbohydrate diet (HCD, 43% carbohydrate) and the berberine diet (HCB, HCD supplemented with 50 mg/kg BBR). After 10 weeks' feeding trial, intraperitoneal injection of glucose was conducted, and then, the plasma and liver were sampled at 0 h, 1 h, 2 h, 6 h, and 12 h. The results showed the plasma glucose levels in all groups rose sharply and peaked at 1 h after glucose injection. Unlike the NCD and HCB groups, the plasma glucose in the HCD group did not decrease after 1 h, while remained high level until at 2 h. The NCD group significantly increased liver glycogen content at times 0-2 h compared to the other two groups and then liver glycogen decreased sharply until at times 6-12 h. To investigate the role of BBR that may cause the changes in plasma glucose and liver glycogen, miRNA high-throughput sequencing was performed on three groups of liver tissues at 2 h time point. Eventually, 20 and 12 differentially expressed miRNAs (DEMs) were obtained in HCD vs NCD and HCB vs HCD, respectively. Through function analyzing, we found that HCD may affect liver metabolism under glucose loading through the NF-κB pathway; and miRNAs regulated by BBR mainly play roles in adipocyte lipolysis, niacin and nicotinamide metabolism, and amino acid transmembrane transport. In the functional exploration of newly discovered novel:Chr12_18892, we found its target gene, adenylate cyclase 3 (adcy3), was widely involved in lipid decomposition, amino acid metabolism, and other pathways. Furthermore, a targeting relationship of novel:Chr12_18892 and adcy3 was confirmed by double luciferase assay. Thus, BBR may promote novel:Chr12_18892 to regulate the expression of adcy3 and participate in glucose metabolism.
Assuntos
Berberina , Cyprinidae , Glucose , Fígado , MicroRNAs , Animais , MicroRNAs/genética , MicroRNAs/metabolismo , Berberina/farmacologia , Cyprinidae/genética , Cyprinidae/metabolismo , Glucose/metabolismo , Fígado/metabolismo , Fígado/efeitos dos fármacos , Glicemia , Dieta/veterinária , Ração Animal/análiseRESUMO
Garment pattern-making is one of the most important parts of the apparel industry. However, traditional pattern-making is an experience-based work, very time-consuming and ignores the body shape difference. This paper proposes a parametric design method for garment pattern based on body dimensions acquired from a body scanner and body features (body feature points and three segmented body part shape classification) identified by designers according to their professional knowledge. By using this method, we construct a men's shirt pattern recommendation system oriented to personalised fit. The system consists of two databases and three models. The two databases include a relational database (Database I) and a personalised basic pattern (PBP) database (Database II). The Database I is based on manual and three-dimensional (3D) measurements of human bodies by using designer's knowledge. And Database I is a relational database, which is organised in terms of the relational model of the body part shape and its key body feature dimensions. After a deep analysis of measured data, the irrelevant measured dimensions to human body shape have been excluded by designers and extract representative human body feature dimensions. In addition, the relations between body shapes and previously identified body feature dimensions have been modelled. From the above relational model, we label key feature point positions on the corresponding 3D body model obtained from 3D body scanning and correct the whole 3D human upper body model into the semantically interpretable one. The 3D personalised basic pattern is drawn on the corrected model based on these key feature points. By using three-dimensional to two-dimensional (3D-to-2D) flattening technology, a 2D flatten graph of the 3D personalised basic pattern of the interpretable model is obtained and slightly adjusted to the form suitable for industrial production, i.e., PBP and the PBP database (Database II) is built. In addition, the three models include a basic pattern parametric model (Model I) (characterizing the relations between the basic pattern and its key influencing human dimensions (chest girth and back length)), a regression model (Model II) which enables to infer from basic pattern to PBP for three body parts based on the one-to-one correspondence of key points between the PBPs and the basic patterns and a personalised shirt pattern parametric model (Model III) (characterizing the structural relations between the personalised shirt pattern (PBPshirt) and PBP). The initial input items of the recommendation system are the body dimension constraint parameters, including chest girth, back length and the body feature dimensions used to determine each body part shape as well as three shirt style constraint parameters (slim, regular and loose). By using Model I, the corresponding basic pattern can be generated through the user's chest girth and back length. Body feature dimensions determine the three body parts' shapes. Then, Model II is used to generate the PBP for the corresponding body parts shape. Based on the shirt style chosen by the user, Mode III is used to generate the PBPshirt from the PBP. The output of the recommendation system is a fit-oriented PBPshirt. Moreover, if the PBPshirt is unsatisfactory after a virtual try-on, four adjustable parameters (front side-seam dart, back side-seam dart, waist dart and garment bodice length) are designed to adjust the PBPshirt generated by the proposed recommendation system.
The proposed recommendation system combines the designer's knowledge of manual measurement of the human body, traditional 2D pattern-making methods and 3D-to-2D flattening technology to generate personalised shirt patterns automatically and quickly, thus significantly improving pattern-making efficiency. The reliance on designers in the garment production process is reduced. Even users with no pattern-making knowledge can also develop professional shirt patterns by using our proposed system.