Cancer stem cells (CSCs) are inherently resistant to chemotherapy, and CSCs in chemotherapy-failed recurrent tumors are enriched; however, the cellular origin of chemotherapy-induced CSC enrichment ...remains unclear. Communication with stromal fibroblasts may induce cancer cell dedifferentiation into CSCs through secreted factors. We recently demonstrated that fibroblast-derived exosomes promote chemoresistance in colorectal cancer (CRC). Here, we report that fibroblasts confer CRC chemoresistance via exosome-induced reprogramming (dedifferentiation) of bulk CRC cells to phenotypic and functional CSCs. At the molecular level, we provided evidence that the major reprogramming regulators in fibroblast-exosomes are Wnts. Exosomal Wnts were found to increase Wnt activity and drug resistance in differentiated CRC cells, and inhibiting Wnt release diminished this effect in vitro and in vivo. Together, our results indicate that exosomal Wnts derived from fibroblasts could induce the dedifferentiation of cancer cells to promote chemoresistance in CRC, and suggest that interfering with exosomal Wnt signaling may help to improve chemosensitivity and the therapeutic window.
A heterodimer of ultraspiracle (USP) and ecdysone receptor (EcR) mediates 20‐hydroxyecdysone (20E) signalling cascade to regulate insect moulting and metamorphosis. However, at least two questions ...remain to be addressed in terms of the molecular importance of USP in insect species. First, is USP involved in both regulation of ecdysteroidogenesis and mediation of 20E signalling in non‐drosophilid insects, as in Drosophila melanogaster? Second, does USP play any role in larval metamorphosis except as the partner of heterodimeric receptor to activate the downstream 20E signalling genes? In this paper, we found that RNA interference (RNAi) of LdUSP in the final (fourth) instar larvae reduced the messenger RNA levels of four ecdysteroidogenesis genes (Ldspo, Ldphm, Lddib and Ldsad) and 20E titre, and repressed the expression of five 20E signal genes (EcRA, HR3, HR4, E74 and E75) in Leptinotarsa decemlineata. The LdUSP RNAi larvae remained as prepupae, with developing antennae, legs and discs of forewings and hindwings. Dietary supplement with 20E restored the expression of the five 20E signal genes, but only partially alleviated the decreased pupation rate in LdUSP RNAi beetles. Knockdown of LdUSP at the penultimate (third) instar larvae did not affect third–fourth instar moulting. However, silencing LdUSP caused similar but less severe impairments on pupation. Accordingly, we propose that USP is undoubtedly necessary for ecdysteroidogenesis, for mediation of 20E signalling and for initiation of metamorphosis in L. decemlineata.
Background
Delirium is common in elderly patients after surgery and is associated with poor outcomes. This study aimed to investigate the impact of intraoperative dexmedetomidine on the incidence of ...delirium in elderly patients undergoing major surgery.
Methods
This was a randomized double‐blind placebo‐controlled trial. Elderly patients (aged 60 years or more) scheduled to undergo major non‐cardiac surgery were randomized into two groups. Patients in the intervention group received a loading dose of dexmedetomidine 0·6 μg/kg 10 min before induction of anaesthesia followed by a continuous infusion (0·5 μg per kg per h) until 1 h before the end of surgery. Patients in the control group received volume‐matched normal saline in the same schedule. The primary outcome was the incidence of delirium during the first 5 days after surgery. Delirium was assessed with the Confusion Assessment Method (CAM) for non‐ventilated patients and CAM for the Intensive Care Unit for ventilated patients.
Results
In total, 309 patients who received dexmedetomidine and 310 control patients were included in the intention‐to‐treat analysis. The incidence of delirium within 5 days of surgery was lower with dexmedetomidine treatment: 5·5 per cent (17 of 309) versus 10·3 per cent (32 of 310) in the control group (relative risk (RR) 0·53, 95 per cent c.i. 0·30 to 0·94; P = 0·026). The overall incidence of complications at 30 days was also lower after dexmedetomidine (19·4 per cent (60 of 309) versus 26·1 per cent (81 of 310) for controls; RR 0·74, 0·55 to 0·99, P = 0·047).
Conclusion
Intraoperative dexmedetomidine halved the risk of delirium in the elderly after major non‐cardiac surgery. Registration number: ChiCTR‐IPR‐15007654 (
www.chictr.org.cn).
Antecedentes
El delirio después de la cirugía es frecuente en los pacientes de edad avanzada y se asocia con malos resultados. El objetivo de este estudio fue investigar el impacto de la administración intraoperatoria de dexmedetomidina en la incidencia de delirio en pacientes mayores sometidos a operaciones de cirugía mayor.
Métodos
Se trataba de un ensayo aleatorizado, doble ciego y controlado con placebo. Un total de 620 pacientes mayores (60 años o más) fueron programados para ser sometidos a intervenciones (no cardiacas) de cirugía mayor y se aleatorizaron a dos grupos. Los pacientes en el grupo de intervención recibieron una dosis de carga de dexmedetomidina (0,6 μg/kg, 10 minutos antes de la inducción anestésica) seguida de una infusión continua (0,5 μg/kg/h) hasta 1 h antes de la finalización de la cirugía. Los pacientes del grupo control recibieron el mismo volumen de suero salino siguiendo la misma pauta. El resultado principal era la incidencia de delirio durante los primeros 5 días postoperatorios. Para la valoración del delirio se utilizó el método para la evaluación de la confusión (Confusion Assessment Method, CAM) en pacientes no intubados y el CAM‐UCI para los pacientes intubados.
Resultados
En total, 309 pacientes que recibieron dexmedetomidina y 310 del grupo control se incluyeron en el análisis por intención de tratar. La incidencia de delirio durante los primeros 5 días tras la cirugía fue inferior en presencia de tratamiento con dexmedetomidina que en ausencia del mismo: 5,5% (17/309) versus 10,3% (32/310); riesgo relativo (RR) 0,53, i.c. del 95% 0,30‐0,94, P = 0,026. La incidencia global de complicaciones a los 30 días excluyendo el delirio también fue inferior en presencia que en ausencia de tratamiento con dexmedetomidina (19,4% (60/309) versus 26,1% (81/301), RR 0,74, i.c. del 95% 0,55‐0,99, P = 0,047).
Conclusión
La administración intraoperatoria de dexmedetomidina reduce la presencia de delirio en los pacientes mayores tras cirugía mayor no cardiaca.
In this RCT, intraoperative infusion of dexmedetomidine was found to reduce the rate of postoperative delirium and surgery‐related complications. The shortcomings of previous studies, such as study design and sample size, were amended, providing more robust evidence for clinical practice.
Halved the rate of delirium
A simplifying assumption in many studies of ocean carbon uptake is that the atmosphere is well‐mixed, such that zonal variations in its carbon dioxide (CO2) content can be neglected in the ...calculation of air‐sea fluxes. Here, we examine this assumption at various scales to quantify the errors it introduces. For global annual averages, we find that positive and negative errors effectively cancel, so the use of atmospheric zonal‐average CO2 introduces reassuringly small errors in fluxes. However, for millions of square kilometers of the North Pacific and Atlantic that are downwind of the highly industrialized northern hemisphere continents, these biases average to over 6% of the annual ocean uptake and can cause errors of up to 30% on a given day. This work highlights the need to use a high quality, spatially‐resolved atmospheric CO2 product for process studies and for accurate long‐term average maps of ocean carbon uptake.
Plain Language Summary
Closing the global carbon budget is key to keeping tabs on society's progress toward a stabilized climate. Therefore, oceanographers go to great lengths to reduce uncertainty in the quantification of ocean carbon uptake. While there has been much attention on improving almost every aspect of the calculation of air‐sea exchange of carbon dioxide, one aspect has been seldom examined: How atmospheric carbon dioxide (CO2) concentrations vary across the globe. For instance, westerly winds draw elevated CO2 from Asia and North America over the neighboring oceans. This promotes higher ocean CO2 uptake than would be estimated if we neglect that spatial variation. Luckily, the errors introduced by ignoring spatial variability average to a very small number over large enough scales (though this was not a foregone conclusion, given that the elevated atmospheric concentrations are found over very windy, high ocean uptake regions). However, in the “tailpipe” of the industrialized continents (i.e., the western North Pacific and North Atlantic), neglecting the elevated atmospheric CO2 concentrations would lead to a low bias in ocean carbon uptake estimates. Overall, the work suggests that local ocean carbon uptake studies should measure atmospheric CO2 locally or make use of atmospheric CO2 estimates that resolve spatial variability.
Key Points
Atmospheric CO2 is elevated downwind of highly industrialized continents, the “tailpipe regions,” east of Asia and North America
Atmospheric CO2 anomalies swept over the neighboring ocean enhance ocean uptake above estimates using zonal mean atmospheric CO2
Errors average out over hemispheric‐scales, but introduce important biases on local scales
Epidermal growth factor receptor (EGFR) signaling regulates cell growth and survival, and its overactivation drives cancer development. One important branch of EGFR signaling is through activation of ...GTPase Rac1, which further promotes cell proliferation, survival and cancer metastasis. Here, we show that EGFR activates Rac1 via inducing the accumulation of its specific guanine nucleotide exchange factor, T-cell lymphoma invasion and metastasis 1 (Tiam1) in non-small-cell lung cancer and colon cancer cells. Conversely, elevated Tiam1 is required for EGFR-induced tumorigenesis. In human lung adenocarcinoma and colon cancer specimens, Tiam1 expression strongly correlates with EGFR expression. We further reveal that AKT, a key downstream protein kinase of EGFR, phosphorylates Tiam1 at several consensus sites, facilitates the interaction of Tiam1 with scaffold proteins 14-3-3 and leads to an increase of Tiam1 stability. Subsequently, Tiam1 is dephosporylated and destabilized by PP2A. Together, our study identifies a bidirectional (phosphorylation and dephosphorylation) regulatory mechanism controlling Tiam1 stability and provides new insights on how EGFR signaling triggers Rac1 activation and cancer development.
We evaluated the effects of supplementing bacterial direct-fed microbial (DFM) on performance, apparent total-tract digestibility, rumen fermentation, and immune parameters of lactating dairy cows. ...One hundred fourteen multiparous Holstein cows (41 ± 7 DIM) were used in a randomized complete block design with an experiment comprising 14 d of a covariate (pre-experimental sample and data collection) and 91 d of an experimental period. Cows were blocked based on energy-corrected milk (ECM) yield during the covariate period and the following treatments were randomly assigned within each block: (1) control (CON), corn silage-based total mixed ration without DFM; (2) PRO-A, basal diet top-dressed with a mixture of Lactobacillus animalis and Propionibacterium freudenreichii at 3 × 10
cfu/d; and 3) PRO-B, basal diet top-dressed with a mixture of L. animalis, P. freudenreichii, Bacillus subtilis, and Bacillus licheniformis at 11.8 × 10
cfu/d. Milk yield, dry matter intake (DMI), and body weight were measured daily, while milk samples for component analysis were taken on 2 consecutive days of each week of data collection. Feces, urine, rumen, and blood samples were taken during the covariate period, wk 4, 7, 10, and 13 for estimation of digestibility, N-partitioning, rumen fermentation, plasma nutrient status and immune parameters. Treatments had no effect on DMI and milk yield. Fat-corrected milk (3.5% FCM) and milk fat yield were improved with PRO-B, while milk fat percent and feed efficiency (ECM/DMI) tended to increase with PRO-B compared with PRO-A and CON. Crude fat digestibility was greater with PRO-B compared with CON. Feeding CON and PRO-A resulted in higher total volatile fatty acid concentration relative to PRO-B. Percentage of neutrophils tended to be reduced with PRO-A compared with CON and PRO-B. The mean fluorescence intensity (MFI) of anti-CD44 antibody on granulocytes tended to be higher in PRO-B compared with CON. The MFI of anti-CD62L antibody on CD8+ T cells was lower in PRO-A than PRO-B, with PRO-A also showing a tendency to be lower than CON. This study indicates the potential of DFM to improve fat digestibility with consequential improvement in fat corrected milk yield, feed efficiency and milk fat yield by lactating dairy cows. The study findings also indicate that dietary supplementation with DFM may augment immune parameters or activation of immune cells, including granulocytes and T cells; however, the overall effects on immune parameters are inconclusive.
Objectives
To investigate the mortality and causes of death in Chinese patients with systemic lupus erythematosus.
Methods
We collected the clinical data of all consecutive adult systemic lupus ...erythematosus patients at the Rheumatology department of Peking University First Hospital between January 2007 and December 2015. The primary causes of death were identified, the standardized mortality ratio and years of life lost were calculated, and the survival and variables associated with mortality were determined by Kaplan–Meier and Cox regression analysis respectively.
Results
The mean age of all 911 patients (814 females and 97 males) was 37.8 ± 14.7 years, the median disease duration at recruitment was 2.6 (0.5–7.0) years, and the median follow-up duration was 3.0 (1.4–5.1) years. Among the 911 patients who were successfully followed up, 45 patients died. Infection (31.1%) was the leading cause of death followed by renal failure, pulmonary arterial hypertension and cerebrovascular diseases. The overall age and sex-adjusted standardized mortality ratio was 3.2 (95% confidence interval 2.4–4.0), and the years of life lost for women and men were 29.8 and 9.4 respectively. Overall survival at 1, 5 and 10 years was 98.2%, 95.3% and 93.7% respectively. Older age at disease onset, infection, autoimmune hemolytic anemia, thrombocytopenia and pulmonary arterial hypertension were independent risk factors for the mortality of systemic lupus erythematosus patients, and longer disease duration at recruitment was an independent protective factor.
Conclusions
Mortality of systemic lupus erythematosus patients in China was substantial, especially in females, with infection the leading cause of death. Older age at disease onset, infection, autoimmune hemolytic anemia, thrombocytopenia and pulmonary arterial hypertension were associated with poor outcomes.
We compare strongly coupled data assimilation (SCDA) and weakly coupled data assimilation (WCDA) by analyzing the assimilation effect on the estimation of the ocean and the atmosphere variables. The ...AWI climate model (AWI‐CM‐1.1) is coupled with the parallel data assimilation framework (PDAF). Only satellite sea surface temperature data are assimilated. For WCDA, only the ocean variables are directly updated by the assimilation. For SCDA, both the ocean and the atmosphere variables are directly updated by the assimilation. Both WCDA and SCDA improve ocean state and yield similar errors. In the atmosphere, WCDA gives slightly smaller errors for the near‐surface temperature and wind velocity than SCDA. In the free atmosphere, SCDA yields smaller errors for the temperature, wind velocity, and specific humidity than WCDA in the Arctic region, while in the tropical region, the errors are generally larger.
Plain Language Summary
Satellite sea surface temperature observations are combined with a coupled ocean‐atmosphere model to improve the estimation of the ocean as well as the atmosphere variables. This is done by the so‐called strongly coupled data assimilation, which updates not only the ocean state but uses the cross‐covariance to update the atmosphere variables directly through the assimilation algorithm. The results are compared with the weakly coupled data assimilation, which only updates the ocean state directly. Both of the two assimilation algorithms improve the estimation of the ocean temperature. In the atmosphere, the strongly coupled data assimilation outperforms the weakly coupled data assimilation only in the Arctic region while in the low latitudes the strongly coupled data assimilation deteriorates the results.
Key Points
Strongly coupled data assimilation is implemented for a coupled ocean atmosphere model
Satellite sea surface temperatures are the only observations for assimilation
Strongly coupled data assimilation performs better in the Arctic region than the weakly coupled data assimilation
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