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This study reported a family of MLH1 mutation-induced Muir-Torre syndrome (MTS) and evaluated it's clinical and genetic characteristics. A 51 year-old patient with extraorbital cystic sebaceous and colon adenocarcinoma diagnosed in November 2021 in Zhongshan Hospital of Xiamen University was included. The clinical data of the family were collected and a pedigree chart was drawn, which was in line with the Chinese Lynch syndrome diagnostic criteria and was a typical MTS family. NM_000249.4:c.298C>T(p.R100*) of MLH1 gene in exon 3 was detected by whole exome sequencing and multiplex ligation dependent amplification, which is a pathogenic mutation. After the pathogenic mutation was identified, Sanger sequencing was performed on 4 direct members of the family for MLH1 gene, and 3 family members were found to have detected the mutation and included in MTS risk control. Until December 25 2023, follow-up showed the proband patients were not suffered from recurrence or new occurrence of skin or gastrointestinal tumors. The study reported a typical MTS family and found a possible pathogenic nonsense mutation in the MLH1 gene, which provides new evidence for the pathogenicity of this mutation.
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Adenocarcinoma Sebáceo , Síndrome de Muir-Torre , Proteína 1 Homóloga a MutL , Neoplasias das Glândulas Sebáceas , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adenocarcinoma Sebáceo/genética , Sequenciamento do Exoma , Éxons , Síndrome de Muir-Torre/genética , Mutação , Proteína 1 Homóloga a MutL/genética , Linhagem , Neoplasias das Glândulas Sebáceas/genéticaRESUMO
Global climate change has markedly influenced the structure and distribution of mid-high-latitude forests. In the forest region of Northeast China, the magnitude of climate warming surpasses the global average, which presents immense challenges to the survival and habitat sustainability of dominant tree species. We predicted the potential changes in aboveground biomass, dominant tree species composition, and distribution in the forest region of Northeast China over the next century under different climatic conditions encompassing the current scenario and future scenarios (RCP2.6, RCP4.5, and RCP8.5). Forest ecosystem process model LINKAGES 3.0 was used to simulate dynamic changes in species-level aboveground biomass under four climate scenarios at the homogeneous land-type unit level. The potential spatial distribution of tree species was investigated based on three indicators: extinction, colonization, and persistence. The results showed that LINKAGES 3.0 model effectively simulated the aboveground biomass of 17 dominant tree species in the forest region of Northeast China, achieving a high accuracy with R² = 0.88. Under the current, RCP2.6, and RCP4.5 climate scenarios, the dominant tree species presented gradual increases in aboveground biomass, whereas under RCP8.5, an initial increase and subsequent decline were observed. With increasing warming magnitude, cold-temperate coniferous tree species will gradually be replaced by other temperate broad-leaved tree species. Furthermore, a large temperature increase under RCP8.5 will likely produce a significant contraction in the potential distribution range of tree species like Larch, Scotch pine, Ribbed birch, Spruce and Fir, while most temperate broad-leaved tree species and Korean pine are expected to demonstrate a northward migration. These findings provide guidance for enhancing the adaptability and resilience of forest ecosystems in middle and high latitudes and addressing the threats posed by climate warming.
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OBJECTIVES: The obesity prevalence in South Korea in 2021 stood at 38.4%. South Korea faces unique challenges in providing essential and emergency guidelines for weight management because of stepping into an aging society. We aimed to determine the daily diet patterns among the general Korean population and to investigate the association between such patterns and different obesity. STUDY DESIGN: Longitudinal prospective cohort study. METHODS: A total of 6539 adult participants (mean age 50.8 years, 52.9% male) with normal-weight adults were included from the Ansan-Ansung cohort of 10,030 Korean adults aged 40 or older and followed for an average of 11 years. Obesity was defined according to the criteria from the Korean Society for The Study of Obesity. Baseline dietary intake was assessed using a validated 103-item food frequency questionnaire. Dietary patterns were derived from k-means cluster analysis. RESULTS: In the multivariate analysis, referring to white rice + baechu kimchi, participants from multigrain rice + baechu kimchi showed lower HR for obesity development (waist circumference defined-obesity; HR: 0.87, 95% CI: 0.79, 0.95; body fat percentage defined-obesity; HR: 0.89, 95% CI: 0.80, 0.98). Further analysis documented that except for body fat percentage defined-obesity, consuming milk or dairy products was linked to a reduced incidence of the other three obesity (body mass index defined-obesity; HR: 0.84, 95% CI: 0.72, 0.99; waist circumference defined-obesity; HR: 0.82, 95% CI: 0.71, 0.94; waist-to-hip ratio defined-obesity; HR: 0.75, 95% CI: 0.61, 0.91). CONCLUSIONS: Following a diet that includes multigrain rice, fermented baechu kimchi, and dairy products is linked to a decreased risk of obesity in Korean adults. Public health programs and policies could incorporate these dietary recommendations, targeting specific population groups such as schoolchildren, adults, and the elderly. Additionally, further research is needed to explore the synergistic effects of various foods and their interactions within dietary patterns on obesity outcomes.
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Dieta , Obesidade , Humanos , Masculino , República da Coreia/epidemiologia , Obesidade/epidemiologia , Estudos Longitudinais , Estudos Prospectivos , Pessoa de Meia-Idade , Feminino , Adulto , Dieta/estatística & dados numéricos , Comportamento Alimentar , Idoso , Padrões DietéticosRESUMO
PURPOSE OF REVIEW: There are no current drug therapies to limit abdominal aortic aneurysm (AAA) growth. This review summarizes evidence suggesting that inhibiting proprotein convertase subtilisin/kexin type 9 (PCSK9) may be a drug target to limit AAA growth. RECENT FINDINGS: Mendelian randomization studies suggest that raised LDL and non-HDL-cholesterol are causal in AAA formation. PCSK9 was reported to be upregulated in human AAA samples compared to aortic samples from organ donors. PCSK9 gain of function viral vectors promoted aortic expansion in C57BL/6 mice infused with angiotensin II. The effect of altering PCSK9 expression in the aortic perfusion elastase model was reported to be inconsistent. Mutations in the gene encoding PCSK9, which increase serum cholesterol, were associated with increased risk of human AAA. Patients with AAA also have a high risk of cardiovascular death, myocardial infarction and stroke. Recent research suggests that PCSK9 inhibition would substantially reduce the risk of these events. SUMMARY: Past research suggests that drugs that inhibit PCSK9 have potential as a novel therapy for AAA to both limit aneurysm growth and reduce risk of cardiovascular events. A large multinational randomized controlled trial is needed to test if PCSK9 inhibition limits AAA growth and cardiovascular events.
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Institutional support is crucial for the successful career advancement of all faculty but in particular those who are women. Evolving from the past, in which gender disparities were prevalent in many institutions, recent decades have witnessed significant progress in supporting the career advancement of women faculty in science and academic medicine. However, continued advancement is necessary as previously unrecognized needs and new opportunities for improvement emerge. To identify the needs, opportunities, and potential challenges encountered by women faculty, the Women's Leadership Committee of the Arteriosclerosis, Thrombosis, and Vascular Biology Council developed an initiative termed GROWTH (Generating Resources and Opportunities for Women in Technology and Health). The committee designed a survey questionnaire and interviewed 19 leaders with roles and responsibilities in faculty development from a total of 12 institutions across various regions of the United States. The results were compiled, analyzed, and discussed. Based on our interviews and analyses, we present the current status of these representative institutions in supporting faculty development, highlighting efforts specific to women faculty. Through the experiences, insights, and vision of these leaders, we identified success stories, challenges, and future priorities. Our article provides a primer and a snapshot of institutional efforts to support the advancement of women faculty. Importantly, this article can serve as a reference and resource for academic entities seeking ideas to gauge their commitment level to women faculty and to implement new initiatives. Additionally, this article can provide guidance and strategies for women faculty as they seek support and resources from their current or prospective institutions when pursuing new career opportunities.
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Mobilidade Ocupacional , Docentes de Medicina , Liderança , Médicas , Humanos , Feminino , Docentes de Medicina/tendências , Médicas/tendências , Estados Unidos , Mulheres Trabalhadoras , Equidade de Gênero , Sexismo/tendências , Inquéritos e Questionários , Desenvolvimento de Pessoal/tendências , Pesquisa Biomédica/tendênciasRESUMO
CLINICAL PROBLEM: Most abdominal aortic aneurysms (AAAs) are small with low rupture risk (<1%/y) when diagnosed but slowly expand to ≥55 mm and undergo surgical repair. Patients and clinicians require medications to limit AAA growth and rupture, but drugs effective in animal models have not translated to patients. RECOMMENDATIONS FOR INCREASING TRANSLATION FROM MOUSE MODELS: Use models that simulate human AAA tissue pathology, growth patterns, and rupture; focus on the clinically relevant outcomes of growth and rupture; design studies with the rigor required of human clinical trials; monitor AAA growth using reproducible ultrasound; and perform studies in both males and females. SUMMARY OF STRENGTHS AND WEAKNESSES OF MOUSE MODELS: The aortic adventitial elastase oral ß-aminopropionitrile model has many strengths including simulating human AAA pathology and modeling prolonged aneurysm growth. The Ang II (angiotensin II) model performed less well as it better simulates acute aortic syndrome than AAA. The elastase plus TGFß (transforming growth factor-ß) blocking antibody model displays a high rupture rate, making prolonged monitoring of AAA growth not feasible. The elastase perfusion and calcium chloride models both display limited AAA growth.
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Aneurisma da Aorta Abdominal , Ruptura Aórtica , Modelos Animais de Doenças , Animais , Aneurisma da Aorta Abdominal/diagnóstico por imagem , Aneurisma da Aorta Abdominal/patologia , Humanos , Ruptura Aórtica/prevenção & controle , Ruptura Aórtica/diagnóstico por imagem , Ruptura Aórtica/patologia , Elastase Pancreática , Camundongos , Aorta Abdominal/patologia , Aorta Abdominal/efeitos dos fármacos , Aorta Abdominal/diagnóstico por imagem , Aorta Abdominal/metabolismo , Feminino , Progressão da Doença , MasculinoRESUMO
Atmospheric vapor pressure deficit (VPD) increases with climate warming and may limit plant growth. However, gross primary production (GPP) responses to VPD remain a mystery, offering a significant source of uncertainty in the estimation of global terrestrial ecosystems carbon dynamics. In this study, in-situ measurements, satellite-derived data, and Earth System Models (ESMs) simulations were analysed to show that the GPP of most ecosystems has a similar threshold in response to VPD: first increasing and then declining. When VPD exceeds these thresholds, atmospheric drought stress reduces soil moisture and stomatal conductance, thereby decreasing the productivity of terrestrial ecosystems. Current ESMs underscore CO2 fertilization effects but predict significant GPP decline in low-latitude ecosystems when VPD exceeds the thresholds. These results emphasize the impacts of climate warming on VPD and propose limitations to future ecosystems productivity caused by increased atmospheric water demand. Incorporating VPD, soil moisture, and canopy conductance interactions into ESMs enhances the prediction of terrestrial ecosystem responses to climate change.
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The effects of rising atmospheric CO2 concentrations (Ca) with climate warming on intrinsic water-use efficiency and radial growth in boreal forests are still poorly understood. We measured tree-ring cellulose δ13C, δ18O, and tree-ring width in Larix dahurica (larch) and Betula platyphylla (white birch), and analyzed their relationships with climate variables in a boreal permafrost region of northeast China over past 68 years covering a pre-warming period (1951-1984; base period) and a warm period (1985-2018; warm period). We found that white birch but not larch significantly increased their radial growth over the warm period. The increased intrinsic water-use efficiency in both species was mainly driven by elevated Ca but not climate warming. White birch but not larch showed significantly positive correlations between tree-ring δ13C, δ18O and summer maximum temperature as well as vapor pressure deficit in the warm period, suggesting a strong stomatal response in the broad-leaved birch to temperature changes. The climate warming-induced radial growth enhancement in white birch is primarily associated with a conservative water-use strategy. In contrast, larch exhibits a profligate water-use strategy. It implies an advantage for white birch over larch in the warming permafrost regions.
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Betula , Larix , Pergelissolo , Água , Larix/crescimento & desenvolvimento , Larix/fisiologia , Betula/crescimento & desenvolvimento , Betula/fisiologia , Água/metabolismo , China , Mudança Climática , Taiga , Aquecimento GlobalRESUMO
Background: Pharmacological inhibition of megalin (also known as low-density lipoprotein receptor-related protein 2: LRP2) attenuates atherosclerosis in hypercholesterolemic mice. Since megalin is abundant in renal proximal tubule cells (PTCs), the purpose of this study was to determine whether PTC-specific deletion of megalin reduces hypercholesterolemia-induced atherosclerosis in mice. Methods: Female Lrp2 f/f mice were bred with male Ndrg1-Cre ERT2 +/0 mice to develop PTC-LRP2 +/+ and -/- littermates. To study atherosclerosis, all mice were to bred to an LDL receptor -/- background and fed a Western diet to induce atherosclerosis. Results: PTC-specific megalin deletion did not attenuate atherosclerosis in LDL receptor -/- mice in either sex. Serendipitously, we discovered that PTC-specific megalin deletion led to interstitial infiltration of CD68+ cells and tubular atrophy. The pathology was only evident in male PTC-LRP2 -/- mice fed the Western diet, but not in mice fed a normal laboratory diet. Renal pathologies were also observed in male PTC-LRP2 -/- mice in an LDL receptor +/+ background fed the same Western diet, demonstrating that the renal pathologies were dependent on diet and not hypercholesterolemia. By contrast, female PTC-LRP2 -/- mice had no apparent renal pathologies. In vivo multiphoton microscopy demonstrated that PTC-specific megalin deletion dramatically diminished albumin accumulation in PTCs within 10 days of Western diet feeding. RNA sequencing analyses demonstrated the upregulation of inflammation-related pathways in kidney. Conclusions: PTC-specific megalin deletion does not affect atherosclerosis, but leads to tubulointerstitial nephritis in mice fed Western diet, with severe pathologies in male mice.
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BACKGROUND: ß-aminopropionitrile (BAPN) is a pharmacological inhibitor of LOX (lysyl oxidase) and LOXLs (LOX-like proteins). Administration of BAPN promotes aortopathies, although there is a paucity of data on experimental conditions to generate pathology. The objective of this study was to define experimental parameters and determine whether equivalent or variable aortopathies were generated throughout the aortic tree during BAPN administration in mice. METHODS: BAPN was administered in drinking water for a period ranging from 1 to 12 weeks. The impacts of BAPN were first assessed with regard to BAPN dose, and mouse strain, age, and sex. BAPN-induced aortic pathological characterization was conducted using histology and immunostaining. To investigate the mechanistic basis of regional heterogeneity, the ascending and descending thoracic aortas were harvested after 1 week of BAPN administration before the appearance of overt pathology. RESULTS: BAPN-induced aortic rupture predominantly occurred or originated in the descending thoracic aorta in young C57BL/6J or N mice. No apparent differences were found between male and female mice. For mice surviving 12 weeks of BAPN administration, profound dilatation was consistently observed in the ascending region, while there were more heterogeneous changes in the descending thoracic region. Pathological features were distinct between the ascending and descending thoracic regions. Aortic pathology in the ascending region was characterized by luminal dilatation and elastic fiber disruption throughout the media. The descending thoracic region frequently had dissections with false lumen formation, collagen deposition, and remodeling of the wall surrounding the false lumen. Cells surrounding the false lumen were predominantly positive for α-SMA (α-smooth muscle actin). One week of BAPN administration compromised contractile properties in both regions equivalently, and RNA sequencing did not show obvious differences between the 2 aortic regions in smooth muscle cell markers, cell proliferation markers, and extracellular components. CONCLUSIONS: BAPN-induced pathologies show distinct, heterogeneous features within and between ascending and descending aortic regions in mice.
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Aminopropionitrilo , Aorta Torácica , Ruptura Aórtica , Modelos Animais de Doenças , Camundongos Endogâmicos C57BL , Animais , Aminopropionitrilo/toxicidade , Aminopropionitrilo/farmacologia , Aorta Torácica/patologia , Aorta Torácica/efeitos dos fármacos , Aorta Torácica/metabolismo , Feminino , Masculino , Ruptura Aórtica/induzido quimicamente , Ruptura Aórtica/patologia , Ruptura Aórtica/metabolismo , Ruptura Aórtica/prevenção & controle , Camundongos , Remodelação Vascular/efeitos dos fármacos , Dilatação Patológica , Músculo Liso Vascular/patologia , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/metabolismo , Fatores Etários , Fatores de Tempo , Fatores Sexuais , Proliferação de Células/efeitos dos fármacos , Proteína-Lisina 6-Oxidase/metabolismoRESUMO
Depression in older adults with cognitive impairment increases progression to dementia. Microbiota is associated with current mood and cognition, but the extent to which it predicts future symptoms is unknown. In this work, we identified microbial features that reflect current and predict future cognitive and depressive symptoms. Clinical assessments and stool samples were collected from 268 participants with varying cognitive and depressive symptoms. Seventy participants underwent 2-year follow-up. Microbial community diversity, structure, and composition were assessed using high-resolution 16 S rRNA marker gene sequencing. We implemented linear regression to characterize the relationship between microbiome composition, current cognitive impairment, and depressive symptoms. We leveraged elastic net regression to discover features that reflect current or future cognitive function and depressive symptoms. Greater microbial community diversity associated with lower current cognition in the whole sample, and greater depression in participants not on antidepressants. Poor current cognitive function associated with lower relative abundance of Bifidobacterium, while greater GABA degradation associated with greater current depression severity. Future cognitive decline associated with lower cognitive function, lower relative abundance of Intestinibacter, lower glutamate degradation, and higher baseline histamine synthesis. Future increase in depressive symptoms associated with higher baseline depression and anxiety, lower cognitive function, diabetes, lower relative abundance of Bacteroidota, and lower glutamate degradation. Our results suggest cognitive dysfunction and depression are unique states with an overall biological effect detectable through gut microbiota. The microbiome may present a noninvasive readout and prognostic tool for cognitive and psychiatric states.
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AGT (angiotensinogen) is the unique precursor for the generation of all the peptides of the renin-angiotensin system, but it has received relatively scant attention compared to many other renin-angiotensin system components. Focus on AGT has increased recently, particularly with the evolution of drugs to target the synthesis of the protein. AGT is a noninhibitory serpin that has several conserved domains in addition to the angiotensin II sequences at the N terminus. Increased study is needed on the structure-function relationship to resolve many unknowns regarding AGT metabolism. Constitutive whole-body genetic deletion of Agt in mice leads to multiple developmental defects creating a challenge to use these mice for mechanistic studies. This has been overcome by creating Agt-floxed mice to enable the development of cell-specific deficiencies that have provided considerable insight into a range of cardiovascular and associated diseases. This has been augmented by the recent development of pharmacological approaches targeting hepatocytes in humans to promote protracted inhibition of AGT synthesis. Genetic deletion or pharmacological inhibition of Agt has been demonstrated to be beneficial in a spectrum of diseases experimentally, including hypertension, atherosclerosis, aortic and superior mesenteric artery aneurysms, myocardial dysfunction, and hepatic steatosis. This review summarizes the findings of recent studies utilizing AGT manipulation as a therapeutic approach.
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Angiotensinogênio , Doenças Cardiovasculares , Doenças Metabólicas , Animais , Humanos , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/genética , Angiotensinogênio/metabolismo , Angiotensinogênio/genética , Doenças Metabólicas/tratamento farmacológico , Doenças Metabólicas/metabolismo , Doenças Metabólicas/genética , Sistema Renina-Angiotensina/efeitos dos fármacos , Terapia de Alvo MolecularRESUMO
AIM: To compare the image quality of virtual noncontrast (VNC) and true noncontrast (TNC) CT images and to evaluate the clinical feasibility of VNC CT images for assessing osteochondral lesions of the talus (OLTs). MATERIALS AND METHODS: Forty-five OLT patients who underwent ankle CT arthrography (CTA) using dual-layer spectral detector CT were enrolled. Reconstruction of VNC and three-dimensional volume rendering images was performed. Afterward, image noise, the signal-to-noise ratio (SNR), and the contrast-to-noise ratio (CNR) were measured. For the subjective evaluation, two board-certified musculoskeletal radiologists [R2-1] assessed spatial resolution, overall image quality, and lesion conspicuity. The accuracy rate for OLT grading was determined in 23 patients who underwent arthroscopic surgery. RESULTS: While VNC images showed significantly less noise than TNC images, TNC images showed better SNRs and CNRs (p<.01). In the subjective analysis, TNC images showed better overall image quality (p<.001). For the 3D volume rendering images, VNC images scored significantly higher for lesion conspicuity (p<.001). The accuracy rates of CTA and CTA with VNC images for OLT grading were 79.2% and 83.3%, respectively. Regarding confidence level, when CTA and VNC images were evaluated together, the confidence level was significantly higher than that when only CTA images were evaluated (p<.001). CONCLUSION: VNC imaging can provide better confidence level of OLT grading and evaluation of the integrity of the subchondral bone plate when combined with conventional CTA without additional radiation dose to the patient. In addition, VNC images-based 3D volume rendering reconstruction would be helpful for preoperative planning in OLT patients.
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Artrografia , Estudos de Viabilidade , Tálus , Tomografia Computadorizada por Raios X , Humanos , Tálus/diagnóstico por imagem , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Tomografia Computadorizada por Raios X/métodos , Artrografia/métodos , Imageamento Tridimensional/métodos , Adulto Jovem , Idoso , Adolescente , Razão Sinal-Ruído , Estudos Retrospectivos , Interpretação de Imagem Radiográfica Assistida por Computador/métodosRESUMO
This study investigated the anti-inflammatory effects of cell-free supernatant of Lactococcus lactis IDCC 2301 on lipopolysaccharide (LPS)-induced RAW 264.7 macrophages. Expression of inflammatory mediators and cytokines, and the production of nitric oxide (NO) and prostaglandin E2 (PGE2) were qualitatively analysed. The expression of signal transductors in inflammatory cascades was quantified by western blot. Treatment with cell-free supernatant of L. lactis IDCC 2301 significantly decreased the mRNA expression levels of tumour necrosis factor (TNF-α) and interleukins including IL-1ß and IL-6. The levels of inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX-2) were also remarkably reduced in LPS-induced macrophages after the treatment. Furthermore, L. lactis IDCC 2301 reduced the levels of both dephosphorylated and phosphorylated forms of nuclear factor-kappa B (NF-κB), IκB-α, extracellular signal-regulated kinases (ERK), c-Jun amino-terminal kinases (JNK), and p38 in LPS-induced RAW 264.7 cells. Therefore, L. lactis IDCC 2301 shows anti-inflammatory activity by suppressing the NF-κB and mitogen-activated protein kinase (MAPK) signaling pathways.
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Anti-Inflamatórios , Lactococcus lactis , Lipopolissacarídeos , Macrófagos , NF-kappa B , Óxido Nítrico , Lactococcus lactis/metabolismo , Lactococcus lactis/genética , Animais , Camundongos , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , NF-kappa B/metabolismo , Anti-Inflamatórios/farmacologia , Células RAW 264.7 , Óxido Nítrico/metabolismo , Citocinas/metabolismo , Citocinas/genética , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Dinoprostona/metabolismo , Transdução de Sinais/efeitos dos fármacos , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , Meios de Cultivo Condicionados/farmacologia , Fator de Necrose Tumoral alfa/metabolismo , Fator de Necrose Tumoral alfa/genéticaRESUMO
Oncogene-driven expression and activation of receptor tyrosine kinases promotes tumorigenesis and contributes to drug resistance. Increased expression of the kinases discoidin domain receptor 2 (DDR2), RET Proto-Oncogene (RET), Platelet Derived Growth Factor Receptor Alpha (PDGFRA), KIT Proto-Oncogene (KIT), MET Proto-Oncogene (MET), and anaplastic lymphoma kinase (ALK) independently correlate with decreased overall survival and event free survival of pediatric neuroblastoma. The multikinase inhibitor sitravatinib targets DDR2, RET, PDGFRA, KIT, and MET with low nanomolar activity and we therefore tested its efficacy against orthotopic and syngeneic tumor models. Sitravatinib markedly reduced cell proliferation and migration in vitro independently of N-Myc proto-oncogene (MYCN), ALK, or c-Myc proto-oncogene status and inhibited proliferation and metastasis of human orthotopic xenografts. Oral administration of sitravatinib to homozygous Th-MYCN transgenic mice (Th-MYCN+/+) after tumor initiation completely arrested further tumor development with no mice dying of disease while maintained on sitravatinib treatment (control cohort 57 days median time to sacrifice). Among these top kinases, DDR2 expression has the strongest correlation with poor survival and high stage at diagnosis and the highest sensitivity to the drug. We confirmed on-target inhibition of collagen-mediated activation of DDR2. Genetic knockdown of DDR2 partially phenocopies sitravatinib treatment, limiting tumor development and metastasis across tumor models. Analysis of single-cell sequencing data demonstrated that DDR2 is restricted to mesenchymal-type tumor subpopulations and is enriched in Schwann cell precursor subpopulations found in high-risk disease. These data define an unsuspected role for sitravatinib as a therapeutic agent in neuroblastoma and reveal a novel function for DDR2 as a driver of tumor growth and metastasis.
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Receptor com Domínio Discoidina 2 , Neuroblastoma , Proto-Oncogene Mas , Transdução de Sinais , Neuroblastoma/patologia , Neuroblastoma/metabolismo , Neuroblastoma/genética , Neuroblastoma/tratamento farmacológico , Animais , Humanos , Camundongos , Receptor com Domínio Discoidina 2/metabolismo , Receptor com Domínio Discoidina 2/genética , Metástase Neoplásica , Proliferação de Células , Ensaios Antitumorais Modelo de Xenoenxerto , Linhagem Celular Tumoral , Camundongos Transgênicos , FemininoRESUMO
Snow cover phenology (SCP) strongly affects forest spring phenology (the start of growing season, SOS), but the underlying mechanism of the relationship varies. In this study, we aimed to analyze the relationship between forest SOS and SCP, and investigate the mechanisms about how changes of SCP affect forest SOS. To do so, we extracted forest SOS and SCP from multiple remote sensing datasets and analyzed the spatio-temporal patterns of both in Changbai Mountains (2001-2020). We assessed the relationships between SCP and forest SOS using partial least squares regression analysis and investigated the potential mechanism of SCP changes affecting on forest SOS using path analysis. We found earlier forest SOS (-0.5 days/year), prolonged snow cover duration (SCD, 0.43 day/year), and earlier snow cover end day (SCED, -0.1 days/year) in the region. The results indicated that SCD showed negative influence while SCED showed positive influence on forest SOS in most of the region. Results revealed that the influence of SCP on forest SOS was mainly through altering spring temperature and the dominant path of SCP influencing forest SOS followed hydrothermal gradients. Our study reveals new insights into the influence of changing SCP on forest SOS, which provides the theoretical basis for including SCP in the phenological models.
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Florestas , Estações do Ano , Neve , China , Monitoramento Ambiental , Mudança Climática , ÁrvoresRESUMO
Aspirin-exacerbated respiratory disease (AERD) is a clinical syndrome characterized by chronic rhinosinusitis with nasal polyps, asthma and the development of significant airway symptoms following the ingestion of aspirin and other nonsteroid anti-inflammatory drugs (NSAIDs). At present, aspirin challenge is the gold standard for diagnosis. Aspirin desensitization and aspirin therapy after desensitization (ATAD) is one of the classical therapies. This paper described the application of aspirin desensitization and ATAD in AERD and provided the reference for the comprehensive treatment of AERD.