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Psychosocial stress has profound effects on the body, including the immune system and the brain1,2. Although a large number of pre-clinical and clinical studies have linked peripheral immune system alterations to stress-related disorders such as major depressive disorder (MDD)3, the underlying mechanisms are not well understood. Here we show that expression of a circulating myeloid cell-specific proteinase, matrix metalloproteinase 8 (MMP8), is increased in the serum of humans with MDD as well as in stress-susceptible mice following chronic social defeat stress (CSDS). In mice, we show that this increase leads to alterations in extracellular space and neurophysiological changes in the nucleus accumbens (NAc), as well as altered social behaviour. Using a combination of mass cytometry and single-cell RNA sequencing, we performed high-dimensional phenotyping of immune cells in circulation and in the brain and demonstrate that peripheral monocytes are strongly affected by stress. In stress-susceptible mice, both circulating monocytes and monocytes that traffic to the brain showed increased Mmp8 expression following chronic social defeat stress. We further demonstrate that circulating MMP8 directly infiltrates the NAc parenchyma and controls the ultrastructure of the extracellular space. Depleting MMP8 prevented stress-induced social avoidance behaviour and alterations in NAc neurophysiology and extracellular space. Collectively, these data establish a mechanism by which peripheral immune factors can affect central nervous system function and behaviour in the context of stress. Targeting specific peripheral immune cell-derived matrix metalloproteinases could constitute novel therapeutic targets for stress-related neuropsychiatric disorders.
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Trastorno Depresivo Mayor , Metaloproteinasa 8 de la Matriz , Monocitos , Estrés Psicológico , Animales , Humanos , Ratones , Trastorno Depresivo Mayor/sangre , Trastorno Depresivo Mayor/enzimología , Trastorno Depresivo Mayor/genética , Trastorno Depresivo Mayor/metabolismo , Espacio Extracelular/metabolismo , Metaloproteinasa 8 de la Matriz/sangre , Metaloproteinasa 8 de la Matriz/deficiencia , Metaloproteinasa 8 de la Matriz/genética , Metaloproteinasa 8 de la Matriz/metabolismo , Ratones Endogámicos C57BL , Monocitos/química , Monocitos/inmunología , Monocitos/metabolismo , Núcleo Accumbens/metabolismo , Núcleo Accumbens/patología , Tejido Parenquimatoso/metabolismo , Análisis de Expresión Génica de una Sola Célula , Conducta Social , Aislamiento Social , Estrés Psicológico/sangre , Estrés Psicológico/genética , Estrés Psicológico/inmunología , Estrés Psicológico/metabolismoRESUMEN
Blood-brain barrier (BBB) models derived from human stem cells are powerful tools to improve our understanding of cerebrovascular diseases and to facilitate drug development for the human brain. Yet providing stem cell-derived endothelial cells with the right signaling cues to acquire BBB characteristics while also retaining their vascular identity remains challenging. Here, we show that the simultaneous activation of cyclic AMP and Wnt/ß-catenin signaling and inhibition of the TGF-ß pathway in endothelial cells robustly induce BBB properties in vitro. To target this interaction, we present a small-molecule cocktail named cARLA, which synergistically enhances barrier tightness in a range of BBB models across species. Mechanistically, we reveal that the three pathways converge on Wnt/ß-catenin signaling to mediate the effect of cARLA via the tight junction protein claudin-5. We demonstrate that cARLA shifts the gene expressional profile of human stem cell-derived endothelial cells toward the in vivo brain endothelial signature, with a higher glycocalyx density and efflux pump activity, lower rates of endocytosis, and a characteristic endothelial response to proinflammatory cytokines. Finally, we illustrate how cARLA can improve the predictive value of human BBB models regarding the brain penetration of drugs and targeted nanoparticles. Due to its synergistic effect, high reproducibility, and ease of use, cARLA has the potential to advance drug development for the human brain by improving BBB models across laboratories.
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Barrera Hematoencefálica , Células Endoteliales , Barrera Hematoencefálica/metabolismo , Humanos , Células Endoteliales/metabolismo , Animales , Vía de Señalización Wnt , Claudina-5/metabolismo , Claudina-5/genética , AMP Cíclico/metabolismo , Ratones , Células Madre/metabolismo , Células Madre/citología , Uniones Estrechas/metabolismo , beta Catenina/metabolismoRESUMEN
Claudin-25 (CLDN-25), also known as Claudin containing domain 1, is an uncharacterized claudin family member. It has less conserved amino acid sequences when compared to other claudins. It also has a very broad tissue expression profile and there is currently a lack of functional information from murine knockout models. Here, we report a de novo missense heterozygous variant in CLDN25 (c. 745G>C, p. A249P) found in a patient diagnosed with Pelizaeus-Merzbacher-like leukodystrophy and presenting with symptoms such as delayed motor development, several episodes of tonic absent seizures and generalized dystonia. The variant protein does not localize to the cell-cell borders where it would normally be expected to be expressed. Amino acid position 249 is located 4 amino acids from the C-terminal end of the protein where most claudin family members have a conserved binding motif for the key scaffolding protein ZO-1. However, CLDN-25 does not contain this motif. Here, we show that the C-terminal end of CLDN-25 is required for its junctional localization in a ZO-1 independent manner. The A249P mutant protein as well as a deletion mutant lacking its last 5 C-terminal amino acids also failed to localize to the cell-cell border in vitro. Intriguingly, cellular knockout of CLDN25, in vitro, appeared to increase the integrity of the tight junction between 2 contacting cells, while driving highly unusual increased movement of solutes between cells. We propose that the barrier function of CLDN-25 is akin to a decoy claudin, whereby decreasing its expression in "leaky" epithelial cells and endothelial cells will drive dynamic changes in the adhesion and interaction capacity of cell-cell contact points. While it remains unclear how this de novo CLDN-25 mutant induces leukodystrophy, our findings strongly suggest that this mutation induces haploinsufficiency of CLDN-25. Elucidating the function of this uncharacterized claudin protein will lead to a better understanding of the role of claudin proteins in health and disease.
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Claudinas , Enfermedad de Pelizaeus-Merzbacher , Humanos , Claudinas/genética , Claudinas/metabolismo , Enfermedad de Pelizaeus-Merzbacher/genética , Enfermedad de Pelizaeus-Merzbacher/metabolismo , Mutación con Pérdida de Función , Masculino , Mutación Missense , Femenino , Animales , Secuencia de AminoácidosRESUMEN
BACKGROUND: Metastatic phaeochromocytomas and paragangliomas (MPPGs) are orphan diseases. Up to 50% of MPPGs are associated with germline pathogenic variants of the SDHB gene. These tumours and many non-familial MPPGs exhibit a phenotype that is characterised by abnormal angiogenesis. We aimed to assess the activity and safety of cabozantinib, an antiangiogenic multi-tyrosine kinase inhibitor, in patients with MPPGs. METHODS: The Natalie Trial is a single-arm, phase 2 clinical trial being conducted at The University of Texas MD Anderson Cancer Center (Houston, TX, USA). Patients aged 18 years or older with histologically confirmed, progressive, and unresectable MPPGs, with an Eastern Cooperative Oncology Group performance status of 0-2, were treated with oral cabozantinib 60 mg/day. The primary endpoint was the investigator-assessed overall response rate per the Response Evaluation Criteria in Solid Tumours version 1.1 criteria. All outcomes were assessed in all evaluable participants who received any amount of study treatment. The trial is registered with ClinicalTrials.gov (NCT02302833) and is active but not recruiting. FINDINGS: From March 10, 2015, to May 11, 2021, 17 patients (13 male participants and four female participants) were enrolled. The median follow-up was 25 months (IQR 18-49). The overall response rate was 25·0% (95% CI 7·3-52·4; four of 16 patients). Seven grade 3 adverse events were reported in six patients, including single cases of hand-and-foot syndrome, hypertension, rectal fistula, QT prolongation, and asymptomatic hypomagnesaemia, and two cases of asymptomatic elevations of amylase and lipase. There were no grade 4 adverse events and no patient died on-study. INTERPRETATION: Cabozantinib shows promising activity in patients with MPPGs. FUNDING: Team NAT Foundation, Margaret Cazalot, and Clarence P Cazalot.
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Neoplasias de las Glándulas Suprarrenales , Anilidas , Paraganglioma , Feocromocitoma , Piridinas , Humanos , Piridinas/uso terapéutico , Piridinas/efectos adversos , Femenino , Masculino , Persona de Mediana Edad , Anilidas/uso terapéutico , Anilidas/efectos adversos , Feocromocitoma/tratamiento farmacológico , Feocromocitoma/patología , Feocromocitoma/genética , Paraganglioma/tratamiento farmacológico , Paraganglioma/patología , Adulto , Neoplasias de las Glándulas Suprarrenales/tratamiento farmacológico , Neoplasias de las Glándulas Suprarrenales/secundario , Anciano , Inhibidores de Proteínas Quinasas/uso terapéutico , Inhibidores de Proteínas Quinasas/efectos adversosRESUMEN
BACKGROUND: Adrenocortical carcinoma is a rare malignancy with poor response to systemic chemotherapy. Mitotane is the only approved therapy for adrenocortical carcinoma. Cabozantinib is a multikinase inhibitor approved in multiple malignancies. This is the first prospective trial to explore the anti-tumour activity, safety, and pharmacokinetic profile of cabozantinib in patients with advanced adrenocortical carcinoma. METHODS: This investigator-initiated, single-arm, phase 2 trial in adult patients (aged ≥18 years) with advanced adrenocortical carcinoma was done at the University of Texas MD Anderson Cancer Center (Houston, TX, USA). Eligible patients had histologically confirmed adrenocortical carcinoma, were not candidates for surgery with curative intent, had measurable disease, had an estimated life expectancy of at least 3 months, and an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 with adequate organ function. Patients who had used mitotane within 6 months of study participation were required to have a serum mitotane level of less than 2 mg/L. Patients were given oral cabozantinib 60 mg daily with the option of dose reduction to manage adverse events. The primary endpoint was progression-free survival at 4 months, assessed in all patients who received at least one dose of study drug per protocol. This study is registered with ClinicalTrials.gov, NCT03370718, and is now complete. FINDINGS: Between March 1, 2018, and May 31, 2021, we enrolled 18 patients (ten males and eight females), all of whom received at least one dose of study treatment. Of the 18 patients, eight (44%) had an ECOG performance status of 0, nine (50%) patients had a performance status of 1, and one (6%) patient had a performance status of 2. Median follow-up was 36·8 months (IQR 30·2-50·3). At 4 months, 13 (72·2%; 95% CI 46·5-90·3) of 18 patients had progression-free survival and median progression-free survival was 6 months (95% CI 4·3 to not reached). One patient remains on treatment. Treatment-related adverse events of grade 3 or worse occurred in 11 (61%) of 18 patients. The most common grade 3 adverse events were lipase elevation (three [17%] of 18 patients), elevated γ-glutamyl transferase concentrations (two [11%] patients), elevated alanine aminotransferase concentrations (two [11%] patients), hypophosphatemia (two [11%] patients), and hypertension (two [11%] patients). One (6%) of 18 patients had grade 4 hypertension. No treatment related deaths occurred on study. INTERPRETATION: Cabozantinib in advanced adrenocortical carcinoma showed promising efficacy with a manageable and anticipated safety profile. Further prospective studies with cabozantinib alone and in combination with immune checkpoint therapy are ongoing. FUNDING: Exelixis.
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Neoplasias de la Corteza Suprarrenal , Carcinoma Corticosuprarrenal , Anilidas , Piridinas , Humanos , Anilidas/uso terapéutico , Anilidas/administración & dosificación , Anilidas/efectos adversos , Anilidas/farmacocinética , Piridinas/uso terapéutico , Piridinas/administración & dosificación , Piridinas/efectos adversos , Femenino , Masculino , Persona de Mediana Edad , Carcinoma Corticosuprarrenal/tratamiento farmacológico , Carcinoma Corticosuprarrenal/patología , Carcinoma Corticosuprarrenal/mortalidad , Adulto , Neoplasias de la Corteza Suprarrenal/tratamiento farmacológico , Neoplasias de la Corteza Suprarrenal/patología , Neoplasias de la Corteza Suprarrenal/mortalidad , Anciano , Estudios Prospectivos , Supervivencia sin Progresión , Inhibidores de Proteínas Quinasas/uso terapéutico , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/farmacocinéticaRESUMEN
BACKGROUND: Image-guided therapies (IGTs) are commonly used in oncology, but their role in adrenocortical carcinoma (ACC) is not well defined. MATERIALS AND METHODS: A retrospective review of patients with ACC treated with IGTs. We assessed response to therapy using RECIST v1.1, time to next line of systemic therapy, disease control rate (DCR), local tumor progression-free survival (LTPFS), and complications of IGTs (based on the Common Terminology Criteria for Adverse Events [CTCAE] version 5.0). RESULTS: Our cohort included 26 patients (median age 56 years [range 38-76]; nâ =â 18 female) who had 51 IGT sessions to treat 86 lesions. IGTs modalities included cryoablation (nâ =â 49), microwave ablation (nâ =â 21), combined microwave and bland trans-arterial embolization (nâ =â 8), bland trans-arterial embolization alone (nâ =â 3), radio-embolization (nâ =â 3), and radiofrequency ablation (nâ =â 2). DCR was 81.4% (70 out of 86), of which 66.3% of tumors showed complete response, 18.6% showed progressive disease, 8.1% showed partial response, and 7.0% showed stable disease. LTPFS rates were 73% and 63% at 1 and 2 years, respectively. Fourteen lesions underwent re-ablation for incomplete response on initial treatment. Sixteen patients (61.5%) received new systemic therapy following IGTs, with a median time to systemic therapy of 12.5 months (95% CI: 8.6 months upper limit not reached). There was 1 reported CTCAE grade 3 adverse event (biloma) following IGT. CONCLUSIONS: IGT use in properly selected patients with ACC is safe and associated with prolonged disease control and delay in the need for systemic therapy.
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BACKGROUND: Tivozanib has been approved as a third-line or later therapy for advanced renal cell carcinoma based on the TIVO-3 trial, which was conducted before immune checkpoint therapies (ICT), cabozantinib, and lenvatinib/everolimus became incorporated in the current sequential treatment paradigm for advanced clear cell RCC (ccRCC). METHODS: We performed a retrospective study of patients with advanced ccRCC treated with tivozanib at MD Anderson Cancer Center during 6/2021-7/2023. A blinded radiologist assessed tumor response by RECIST v1.1. We assessed overall response rate (ORR), clinical benefit rate (CBR) [percentage of all treated patients who achieved radiologic response or stable disease (SD) forâ ≥â 6 months], progression-free survival (PFS), overall survival (OS), and safety. RESULTS: Of 30 analyzed patients, 23% had performance statusâ ≥â 2; 47% had International Metastatic RCC Database Consortium (IMDC) poor-risk disease. Median number of prior therapies was 4 (range 1-8). All patients received prior ICT, 87% cabozantinib and 60% lenvatinib ± everolimus. Of 26 evaluable patients, 2 patients had confirmed partial response (ORR 7.7%); 5 patients had SD forâ ≥â 6 months (CBR 23.3%). Median PFS was 3.8 months (range 0.7-13.9); median OS was 14.1 months (range 0.3-28.5). Fifteen patients (50%) hadâ ≥â 1 treatment-related adverse event (TRAE). There were 6 gradeâ ≥â 3 TRAEs [hypertension, congestive heart failure (3), mucositis, and GI perforation (grade 5)]. CONCLUSIONS: In this cohort of heavily pretreated patients with advanced ccRCC, tivozanib yielded a modest clinical benefit in a minority of patients who received prior ICT, cabozantinib, and lenvatinib ± everolimus. TRAEs were consistent with previously published reports.
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Carcinoma de Células Renales , Neoplasias Renales , Compuestos de Fenilurea , Quinolinas , Humanos , Carcinoma de Células Renales/tratamiento farmacológico , Femenino , Masculino , Anciano , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/patología , Quinolinas/uso terapéutico , Quinolinas/efectos adversos , Persona de Mediana Edad , Estudios Retrospectivos , Compuestos de Fenilurea/uso terapéutico , Compuestos de Fenilurea/efectos adversos , Adulto , Anciano de 80 o más AñosRESUMEN
BACKGROUND: Venous thromboembolism (VTE) is a leading cause of death in patients with cancer. Limited data exist about VTE in patients with adrenocortical carcinoma (ACC). The primary objective of this study was to identify the prevalence of VTE in a cohort of patients with ACC. Secondary objectives were to determine the impact of VTE events on overall survival (OS) and to describe the characteristics of VTE in patients with ACC. PATIENTS AND METHODS: We retrospectively reviewed data from 289 patients with ACC cared for at a major referral center from February 2010 to June 2022. RESULTS: VTE prevalence was 18.7% (54 events). Thirty patients (55.6%) had pulmonary embolism (PE); 12 patients (22.2%) had deep vein thrombosis (DVT); and 12 patients (22.2%) had both PE and DVT. VTE occurred after ACC diagnosis in 50 patients (92.6%) including 44 patients (88%) with stage 3 or 4 ACC. VTEs were CTCAE grade ≤2 in 32 cases (59.3%), grade 3 in 17 (31.5%), and grade 4 in 2 (3.7%). Thirteen patients (24%) died within 6 months after VTE diagnosis, although there was no statistically significant association between VTE and overall survival. CONCLUSION: Despite the potential to underestimate the prevalence of VTEs, we found a high frequency of VTE events in patients with ACC. A majority of VTEs occurred in the context of advanced ACC and we observed high short-term mortality. Further studies are needed to validate our findings and investigate mechanisms associated with VTE in ACC.
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Neoplasias de la Corteza Suprarrenal , Carcinoma Corticosuprarrenal , Tromboembolia Venosa , Humanos , Masculino , Carcinoma Corticosuprarrenal/complicaciones , Carcinoma Corticosuprarrenal/mortalidad , Carcinoma Corticosuprarrenal/patología , Femenino , Estudios Retrospectivos , Tromboembolia Venosa/epidemiología , Tromboembolia Venosa/mortalidad , Tromboembolia Venosa/patología , Tromboembolia Venosa/complicaciones , Persona de Mediana Edad , Neoplasias de la Corteza Suprarrenal/complicaciones , Neoplasias de la Corteza Suprarrenal/mortalidad , Neoplasias de la Corteza Suprarrenal/patología , Anciano , Adulto , PrevalenciaRESUMEN
PURPOSE: We initiated a biomarker-informed preoperative study of infigratinib, a fibroblast growth factor receptor (FGFR) inhibitor, in patients with localized upper tract urothelial carcinoma (UTUC), a population with high unmet needs and tumor with a high frequency of FGFR3 alterations. MATERIALS AND METHODS: Patients with localized UTUC undergoing ureteroscopy or nephroureterectomy/ureterectomy were enrolled on a phase 1b trial (NCT04228042). Once-daily infigratinib 125 mg by mouth × 21 days (28-day cycle) was given for 2 cycles. Tolerability was monitored by Bayesian design and predefined stopping boundaries. The primary endpoint was tolerability, and the secondary endpoint was objective response based on tumor mapping, done after endoscopic biopsy and post-trial surgery. Total planned enrollment: 20 patients. Targeted sequencing performed using a NovaSeq 6000 solid tumor panel. RESULTS: From May 2021 to November 2022, 14 patients were enrolled, at which point the trial was closed due to termination of all infigratinib oncology trials. Two patients (14.3%) had treatment-terminating toxicities, well below the stopping threshold. Responses occurred in 6 (66.7%) of 9 patients with FGFR3 alterations. Responders had median tumor size reduction of 67%, with 3 of 5 patients initially planned for nephroureterectomy/ureterectomy converted to ureteroscopy. Median follow-up in responders was 24.7 months (14.9-28.9). CONCLUSIONS: In this first trial of targeted therapy for localized UTUC, FGFR inhibition was well tolerated and had significant activity in FGFR3 altered tumors. Renal preservation was enabled in a substantial proportion of participants. These data support the design of a biomarker-driven phase 2 trial of FGFR3 inhibition in this population with significant unmet clinical needs.
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Carcinoma de Células Transicionales , Neoplasias Ureterales , Humanos , Masculino , Femenino , Anciano , Carcinoma de Células Transicionales/tratamiento farmacológico , Carcinoma de Células Transicionales/cirugía , Carcinoma de Células Transicionales/patología , Carcinoma de Células Transicionales/genética , Persona de Mediana Edad , Neoplasias Ureterales/tratamiento farmacológico , Neoplasias Ureterales/cirugía , Neoplasias Ureterales/patología , Receptor Tipo 3 de Factor de Crecimiento de Fibroblastos/antagonistas & inhibidores , Receptor Tipo 3 de Factor de Crecimiento de Fibroblastos/genética , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/cirugía , Neoplasias Renales/patología , Ureteroscopía/efectos adversos , Nefroureterectomía , Anciano de 80 o más Años , Resultado del Tratamiento , Compuestos de Fenilurea , PirimidinasRESUMEN
A refugial population of the endangered delta smelt (Hypomesus transpacificus) has been maintained at the Fish Conservation and Culture Laboratory (FCCL) at UC Davis since 2008. Despite intense genetic management, fitness differences between wild and cultured fish have been observed at the FCCL. To investigate the molecular underpinnings of hatchery domestication, we used whole-genome bisulfite sequencing to quantify epigenetic differences between wild and hatchery-origin delta smelt. Differentially methylated regions (DMRs) were identified from 104 individuals by comparing the methylation patterns in different generations of hatchery fish (G1, G2, G3) with their wild parents (G0). We discovered a total of 132 significant DMRs (p < .05) between G0 and G1, 132 significant DMRs between G0 and G2, and 201 significant DMRs between G0 and G3. Our results demonstrate substantial differences in methylation patterns emerged between the wild and hatchery-reared fish in the early generations in the hatchery, with a higher proportion of hypermethylated DMRs in hatchery-reared fish. The rearing environment was found to be a stronger predictor of individual clustering based on methylation patterns than family, sex or generation. Our study indicates a reinforcement of the epigenetic status with successive generations in the hatchery environment, as evidenced by an increase in methylation in hypermethylated DMRs and a decrease in methylation in hypomethylated DMRs over time. Lastly, our results demonstrated heterogeneity in inherited methylation pattern in families across generations. These insights highlight the long-term consequences of hatchery practices on the epigenetic landscape, potentially impacting wild fish populations.
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Metilación de ADN , Epigénesis Genética , Osmeriformes , Animales , Osmeriformes/genética , Masculino , Femenino , Conservación de los Recursos Naturales , Especies en Peligro de ExtinciónRESUMEN
Gadopsis (Percichthyidae) is a freshwater genus distributed in south-eastern Australia, including Tasmania, and comprises two recognized species. Previous molecular phylogenetic investigations of the genus, mostly conducted in the pre-genomics era and reflecting a range of geographic and molecular sampling intensities, have supported the recognition of up to seven candidate species. Here we analyze a genome-wide SNP dataset that provides comprehensive geographic and genomic coverage of Gadopsis to produce a robust hypothesis of species boundaries and evolutionary relationships. We then leverage the SNP dataset to characterize relationships within candidate species that lack clear intraspecific phylogenetic relationships. We find further support for the seven previously identified candidate species of Gadopsis and evidence that the Bass Strait centered candidate species (SBA) originated from ancient hybridization. The SNP dataset permits a high degree of intraspecific resolution, providing improvements over previous studies, with numerous candidate species showing intraspecific divisions in phylogenetic analysis. Further population genetic analysis of the Murray-Darling candidate species (NMD) and SBA finds support for K = 6 and K = 7 genetic clusters, respectively. The SNP data generated for this study have diverse applications in natural resource management for these fishes of conservation concern.
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Conservación de los Recursos Naturales , Explotaciones Pesqueras , Perciformes , Filogenia , Polimorfismo de Nucleótido Simple , Animales , Perciformes/genética , Perciformes/clasificación , Genética de Población , AustraliaRESUMEN
Groundwater is a vital ecosystem of the global water cycle, hosting unique biodiversity and providing essential services to societies. Despite being the largest unfrozen freshwater resource, in a period of depletion by extraction and pollution, groundwater environments have been repeatedly overlooked in global biodiversity conservation agendas. Disregarding the importance of groundwater as an ecosystem ignores its critical role in preserving surface biomes. To foster timely global conservation of groundwater, we propose elevating the concept of keystone species into the realm of ecosystems, claiming groundwater as a keystone ecosystem that influences the integrity of many dependent ecosystems. Our global analysis shows that over half of land surface areas (52.6%) has a medium-to-high interaction with groundwater, reaching up to 74.9% when deserts and high mountains are excluded. We postulate that the intrinsic transboundary features of groundwater are critical for shifting perspectives towards more holistic approaches in aquatic ecology and beyond. Furthermore, we propose eight key themes to develop a science-policy integrated groundwater conservation agenda. Given ecosystems above and below the ground intersect at many levels, considering groundwater as an essential component of planetary health is pivotal to reduce biodiversity loss and buffer against climate change.
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Ecosistema , Agua Subterránea , Biodiversidad , Agua Dulce , Contaminación AmbientalRESUMEN
AIM: To examine the effect of interrupting prolonged sitting with short, frequent, light-intensity activity on postprandial cardiovascular markers in people with type 1 diabetes (T1D). MATERIALS AND METHODS: In a randomized crossover trial, 32 adults with T1D (mean ± SD age 28 ± 5 years, glycated haemoglobin 67.9 ± 12.6 mmol/mol, 17 women) completed two 7-h laboratory visits separated by >7 days. Participants either remained seated for 7 h (SIT) or interrupted sitting with 3-min bouts of self-paced walking at 30-min intervals commencing 1 h after each meal (SIT-LESS). Physical activity, insulin regimen, experimental start times, and meal consumption were standardized during each arm. Plasma levels of interleukin (IL)-1ß, tumour necrosis factor (TNF)-α, plasminogen activator inhibitor (PAI)-1 and fibrinogen were sampled at baseline, 3.5 and 7 h, and assessed for within- and between-group effects using a repeated measures ANOVA. The estimated glucose disposal rate was used to determine the insulin resistance status. RESULTS: Vascular-inflammatory parameters were comparable between SIT and SIT-LESS at baseline (p > .05). TNF-α, IL-1ß, PAI-1 and fibrinogen increased over time under SIT, whereas these rises were attenuated under SIT-LESS (p < .001). Specifically, over the 7 h under SIT, postprandial increases were detected in TNF-α, IL-1ß, PAI-1 and fibrinogen (+67%, +49%, +49% and +62%, respectively; p < .001 for all). Conversely, the SIT-LESS group showed no change in IL-1ß (-9%; p > .50), whereas reductions were observed in TNF-α, PAI-1 and fibrinogen (-22%, -42% and -44%, respectively; p < .001 for all). The intervention showed enhanced effects in insulin-resistant individuals with T1D. CONCLUSIONS: Interrupting prolonged sitting with light-intensity activity ameliorates postprandial increases in vascular-inflammatory markers in T1D. TRIAL REGISTRATION: The trial was prospectively registered (ISRCTN13641847).
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Biomarcadores , Estudios Cruzados , Diabetes Mellitus Tipo 1 , Inhibidor 1 de Activador Plasminogénico , Periodo Posprandial , Caminata , Humanos , Diabetes Mellitus Tipo 1/sangre , Diabetes Mellitus Tipo 1/terapia , Diabetes Mellitus Tipo 1/fisiopatología , Femenino , Periodo Posprandial/fisiología , Masculino , Adulto , Caminata/fisiología , Biomarcadores/sangre , Inhibidor 1 de Activador Plasminogénico/sangre , Factor de Necrosis Tumoral alfa/sangre , Interleucina-1beta/sangre , Fibrinógeno/metabolismo , Fibrinógeno/análisis , Adulto Joven , Resistencia a la Insulina , Conducta Sedentaria , Inflamación/sangre , Glucemia/metabolismo , Glucemia/análisisRESUMEN
BACKGROUND: Enfortumab vedotin (EV) is an antibody-drug conjugate directed against Nectin-4 that is used to treat urothelial carcinoma. Nectin-4 is inherently expressed in the skin and adnexal structures. Since therapeutic options for cutaneous adnexal carcinomas are limited, we sought to evaluate Nectin-4 expression in adnexal carcinomas and benign adnexal neoplasms to identify tumors that are potentially targetable with EV. METHODS: Eight sebaceous carcinomas (seven periocular and one lymph node metastasis), eight digital papillary adenocarcinomas, seven squamoid eccrine ductal carcinomas, eight poromas, eight trichilemmomas, and seven sebaceous adenomas were subjected to immunohistochemical staining for anti-Nectin-4 antibody. H-scores for Nectin-4 expression were calculated. RESULTS: Benign adnexal neoplasms had a significantly lower mean (±SD) Nectin-4 H-score (142.6 ± 39.1) than did the adnexal carcinomas (198 ± 90.8; p = 0.006). Nectin-4 was expressed in 91% (21/23) of adnexal carcinomas. Sebaceous carcinomas frequently exhibited high expression of Nectin-4 (88% [7/8]), with a mean (±SD) H-score (258.1 ± 58.4) significantly higher than those for digital papillary adenocarcinomas (197.5 ± 52.5; p = 0.035) and squamoid eccrine ductal carcinomas (131.4 ± 114.1; p = 0.031). Sebaceous carcinomas also had significantly higher H-scores than did sebaceous adenomas (186.4 ± 25.0; p = 0.013). CONCLUSIONS: Increased Nectin-4 expression in a subset of cutaneous adnexal carcinomas, particularly sebaceous carcinomas, reveals that EV is a potential therapeutic option for these tumors.
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Adenocarcinoma Papilar , Anticuerpos Monoclonales , Nectinas , Neoplasias de Anexos y Apéndices de Piel , Neoplasias Cutáneas , Humanos , Adenoma , Carcinoma Ductal , Carcinoma de Apéndice Cutáneo , Carcinoma de Células Transicionales , Neoplasias de Anexos y Apéndices de Piel/tratamiento farmacológico , Neoplasias de las Glándulas Sebáceas/patología , Neoplasias Cutáneas/patología , Neoplasias de las Glándulas Sudoríparas/tratamiento farmacológicoRESUMEN
INTRODUCTION: Failure of the patent ductus arteriosus to close is common among extremely low birth weight neonates and has been associated with increased morbidities. The objective of this study was to compare outcomes between early and late surgical ligation in extremely low birth weight patients. METHODS: This was a single-centre retrospective cohort study of infants who required surgical closure of patent ductus arteriosus between January 2017 and August 2022. RESULTS: A total of 43 neonates were identified with birth weight less than 1 kg that underwent surgical patent ductus arteriosus ligation. Compared to the late ligation group, the early ligation group experienced fewer total days of mechanical ventilation (43.9 days vs. 97.2 days, p < 0.05) and a shorter length of hospital stay (114.2 days vs. 169.0 days, p < 0.05). CONCLUSION: Early surgical ligation of haemodynamically significant patent ductus arteriosus in extremely low birth weight neonates may improve hospital morbidity, including improved ventilatory outcomes and a shorter length of stay.
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In this issue of Neuron, Biswas et al.1 demonstrate the roles of glutamatergic neuronal activity in the regulation of angiogenesis and retinal vascular endothelial barrier maturation using three different knockout mouse models. Their findings shed light on how aberrant glutamatergic activity can impact neural vascular function and barrier integrity.
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Ácido Glutámico , Animales , Ácido Glutámico/metabolismo , Ratones , Neovascularización Fisiológica/fisiología , Barrera Hematorretinal/metabolismo , Barrera Hematorretinal/fisiología , Humanos , Vasos Retinianos/metabolismo , AngiogénesisRESUMEN
Advancements in genome sequencing and assembly techniques have increased the documentation of structural variants in wild organisms. Of these variants, chromosomal inversions are especially prominent due to their large size and active recombination suppression between alternative homokaryotypes. This suppression enables the 2 forms of the inversion to be maintained and allows the preservation of locally adapted alleles. The Barramundi Perch (BP; Lates calcarifer) is a widespread species complex with 3 main genetic lineages located in the biogeographic regions of Australia and New Guinea (AUS + NG), Southeast Asia (SEA), and the Indian Subcontinent (IND). BP are typically considered to be a protandrous sequential hermaphrodite species that exhibits catadromy. Freshwater occupancy and intraspecific variation in life history (e.g. partially migratory populations) exist and provide opportunities for strongly divergent selection associated with, for example, salinity tolerance, swimming ability, and marine dispersal. Herein, we utilize genomic data generated from all 3 genetic lineages to identify and describe 3 polymorphic candidate chromosomal inversions. These candidate chromosomal inversions appear to be fixed for ancestral variants in the IND lineage and for inverted versions in the AUS + NG lineage and exhibit variation in all 3 inversions in the SEA lineage. BP have a diverse portfolio of life history options that includes migratory strategy as well as sexual system (i.e. hermaphroditism and gonochorism). We propose that the some of the life history variabilities observed in BP may be linked to inversions and, in doing so, we present genetic data that might be useful in enhancing aquaculture production and population management.
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Inversión Cromosómica , Especiación Genética , Percas , Animales , Percas/genética , Variación Estructural del Genoma , Adaptación Fisiológica/genética , Genoma , Filogenia , Genómica/métodosRESUMEN
Cisplatin-based chemotherapy has been the standard of care in metastatic urothelial cancer (mUC) for more than two decades. However, many patients with comorbidities cannot receive cisplatin or its alternative, carboplatin. 'Cisplatin-ineligible' and 'platinum-ineligible' patients lacked effective therapy options. However, the recent combination of enfortumab vedotin (EV), an antibody-drug conjugate targeting Nectin-4, with pembrolizumab (P), an antibody targeting the programmed death-1 (PD-1) immune checkpoint, is changing the status quo of frontline mUC treatment, with potential synergy seen in the EV-103 and EV-302 clinical trials. First, we review the working definitions of 'cisplatin ineligibility' and 'platinum ineligibility' in mUC clinical trials and the standard of care in both categories. Then, we review select clinical trials for frontline treatment of cisplatin- and platinum-ineligible mUC patients on ClinicalTrials.gov. We classify the investigated drugs in these trials by their therapeutic strategies. Alongside chemotherapy combinations, the field is witnessing more immunotherapy combinations with fibroblast growth factor receptor (FGFR) inhibitors, bicycle toxin conjugates, bispecific antibodies, innovative targeted therapies, and many others. Most importantly, we rethink the value of classifying patients by cisplatin or platinum ineligibility in the frontline setting in the post-EVP era. Lastly, we discuss new priority goals to tailor predictive, monitoring, and prognostic biomarkers to these emergent therapies.
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Multiple studies in a range of taxa have found links between structural variants and the development of ecologically important traits. Such variants are becoming easier to find due, in large part, to the increase in the amount of genome-wide sequence data in nonmodel organisms. The salmonids (salmon, trout, and charr) are a taxonomic group with abundant genome-wide datasets due to their importance in aquaculture, fisheries, and variation in multiple ecologically important life-history traits. Previous research on rainbow trout (Oncorhynchus mykiss) has documented a large pericentric (â¼55â Mb) chromosomal inversion (CI) on chromosome 5 (Omy05) and a second smaller (â¼14â Mb) chromosome inversion on Omy20. While the Omy05 inversion appears to be associated with multiple adaptive traits, the inversion on Omy20 has received far less attention. In this study, we re-analyze RAD-seq and amplicon data from several populations of rainbow trout (O. mykiss) to better document the structure and geographic distribution of variation in the Omy20 CI. Moreover, we utilize phylogenomic techniques to characterize both the age- and the protein-coding gene content of the Omy20 CI. We find that the age of the Omy20 inversion dates to the early stages of O. mykiss speciation and predates the Omy05 inversion by â¼450,000 years. The 2 CIs differ further in terms of the frequency of the homokaryotypes. While both forms of the Omy05 CI are found across the eastern Pacific, the ancestral version of the Omy20 CI is restricted to the southern portion of the species range in California. Furthermore, the Omy20 inverted haplotype is comparable in genetic diversity to the ancestral form, whereas derived CIs typically show substantially reduced genetic diversity. These data contribute to our understanding of the age and distribution of a large CI in rainbow trout and provide a framework for researchers looking to document CIs in other nonmodel species.
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Inversión Cromosómica , Oncorhynchus mykiss , Animales , Oncorhynchus mykiss/genética , Genética de Población , Genoma , Filogenia , Variación GenéticaRESUMEN
Multiple evolutionary processes influence genome-wide allele frequencies and quantifying effects of genetic drift, and multiple forms of selection remain challenging in natural populations. Here, we investigate variation at major effect loci in contrast to patterns of neutral drift across a wide collection of steelhead (Oncorhynchus mykiss) populations that have declined in abundance due to anthropogenic impacts. Whole-genome resequencing of 74 populations of steelhead revealed genome-wide patterns (~8 million SNPs) consistent with expected neutral population structure. However, allelic variation at major effect loci associated with adult migration timing (chromosome 28: GREB1L/ROCK1) and age at maturity (chromosome 25: SIX6) reflected how selection has acted on phenotypic variation in contrast with neutral structure. Variation at major effect loci was influenced by evolutionary processes with differing signals between the strongly divergent Coastal and Inland lineages, while allele frequencies within and among populations within the Inland lineage have been driven by local natural selection as well as recent anthropogenic influences. Recent anthropogenic effects appeared to have influenced the frequency of major effect alleles including artificial selection for specific traits in hatchery stocks with subsequent gene flow into natural populations. Selection from environmental factors at various scales has also likely influenced variation for major effect alleles. These results reveal evolutionary mechanisms that influence allele frequencies at major effect loci that are critical for conservation of phenotypic traits and life history variation of this protected species.