Tumor recurrence following treatment remains a major clinical challenge. Evidence from xenograft models and human trials indicates selective enrichment of cancer-initiating cells (CICs) in tumors ...that survive therapy. Together with recent reports showing that CIC gene signatures influence patient survival, these studies predict that targeting self-renewal, the key 'stemness' property unique to CICs, may represent a new paradigm in cancer therapy. Here we demonstrate that tumor formation and, more specifically, human colorectal CIC function are dependent on the canonical self-renewal regulator BMI-1. Downregulation of BMI-1 inhibits the ability of colorectal CICs to self-renew, resulting in the abrogation of their tumorigenic potential. Treatment of primary colorectal cancer xenografts with a small-molecule BMI-1 inhibitor resulted in colorectal CIC loss with long-term and irreversible impairment of tumor growth. Targeting the BMI-1-related self-renewal machinery provides the basis for a new therapeutic approach in the treatment of colorectal cancer.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
The uEXPLORER total-body PET/CT system provides a very high level of detection sensitivity and simultaneous coverage of the entire body for dynamic imaging for quantification of tracer kinetics. This ...article describes the fundamentals and potential benefits of total-body kinetic modeling and parametric imaging focusing on the noninvasive derivation of blood input function, multiparametric imaging, and high-temporal resolution kinetic modeling. Along with its attractive properties, total-body kinetic modeling also brings significant challenges, such as the large scale of total-body dynamic PET data, the need for organ and tissue appropriate input functions and kinetic models, and total-body motion correction. These challenges, and the opportunities using deep learning, are discussed.
Child maltreatment rates are strongly linked to adult male behavior, suggesting that labor market conditions, by influencing male behaviors, can influence maltreatment rates. Using the unemployment ...rate as the sole measure of labor market conditions, past studies generally conclude that employment conditions do not systematically influence child maltreatment rates. By contrast, this study found that state-level child maltreatment rates were statistically significant and inversely related to the state-level employment rates of men, aged 20 to 34yrs old. It also found that the interaction of child poverty and living in a single-parent household is positively related to child maltreatment rates. Policies to reduce employment problems are discussed.
•Male employment rates were inversely related to child maltreatment rates in the US.•Interaction of singleheadedness and poverty contributes to child maltreatment rates.•Race does not influence maltreatment once other factors are accounted for.
Methadone, a long-acting μ-opioid agonist, is an effective treatment for heroin addiction. Our previous data show that 6 of 10 methadone maintenance treatment (MMT) patients had central sleep apnea ...(CSA). This study aims to confirm these results and to investigate the pathogenesis of the CSA.
Twenty-five male and 25 female MMT patients and 20 age-, sex-, and body mass index (BMI)-matched normal subjects were tested with polysomnography, blood toxicology, and ventilatory responses to hypoxia and hypercapnia. Resting cardiorespiratory tests were performed in the MMT group
MMT patients and normal subjects were 35 ± 9 years old (mean ± SD), and BMI values were 27 ± 6 kg/m2 and 27 ± 5 kg/m2, respectively. Thirty percent of MMT patients had a central apnea index (CAI) > 5, and 20% had a CAI > 10. All normal subjects had a CAI < 1, and no difference was found in obstructive apnea-hypopnea index between the two groups. Methadone blood concentration was the only significant variable (t = 2.33, p = 0.025) associated with CAI and explains 12% of the variance. Awake Paco2, antidepressant use, reduced ventilatory response to hypercapnia, and widened awake alveolar-arterial oxygen pressure gradient together explain a further 17% of the CAI variance.
Thirty percent of stable MMT patients have CSA, a minority of which can be explained by blood methadone concentration. Other physiologic variables may also play a role in the pathogenesis of CSA in MMT patients, and further research is indicated in this area.
Acute respiratory distress syndrome (ARDS) is characterized by an acute inflammatory response that compromises alveolar-capillary membrane integrity. Clinical symptoms include refractory hypoxemia, ...noncardiogenic edema, and decreased lung compliance. The purpose of this review is to summarize the different ARDS large-animal models in terms of similarity to the clinical disease and underlying pathophysiology. The repeated lavage, oleic acid, endotoxin, and smoke/burn ARDS models will be discussed in this review. While each model has significant benefits, none is without weaknesses. Thus, the choice of large-animal ARDS model must be carefully considered based upon the study focus and investigative team experience.
•W-GW interactions investigated at basin scale over 49 years.•Recent trend is for increase in number of losing reaches.•Our models cannot not simulate this change in direction of SW-GW exchange flux.
...The Murray-Darling Basin is Australia’s most stressed water resource and most contentious in the sharing of those water resources. Our hydrological models used for water management have no information on the surface water – groundwater interactions within a reach and so implicitly assume that their relationship is stationary. This study seeks to test this assumption by looking at the direction of surface water – groundwater exchanges and how they have changed over the 49-year period from 1970 to 2019 at the whole of basin scale (492 river reaches). This was achieved by comparing the groundwater level at 59,340 bores to the elevation of the surface water at the closest point on the stream network. Each point evaluated on the stream network was classified as either gaining (water from groundwater) or losing (water to groundwater) at an annual scale. These point scale observations were aggregated to the reach scale (as used in river systems models) for analysis of trends though time. The proportion of bores predicting losing conditions was falling through the 1970’s and 1980’s before reaching a minimum of 48% in 1995/96. From this period the proportion of bores predicting losing conditions increased to a maximum at the end of the analysis period of 78% in 2018/19. This finding at the point scale is replicated at the reach scale. The reaches with greater than 80% of bores predicting losing conditions had a minimum in 1993/94 (at 40%) and increased to 66% at the end of the analysis period. These observations are consistent with the management challenges of the time. In the 1980’s and 1990’s gaining conditions leading to increasing salt loads in the streams caused by groundwater discharge were a major problem for downstream water users. Since the turn of the century drought and water scarcity have been the major challenges with falling groundwater levels leading to increases in losing conditions. This study has shown that the surface water – groundwater interactions are not stationary and have been changing through time with many reaches having changed direction from gaining to losing throughout the analysis period. This is highlighting a deficiency in our hydrological models that cannot replicate this change in flux direction and therefore leading to errors in predicting low flows.
Parametric imaging has been shown to provide better quantitation physiologically than SUV imaging in PET. With the increased sensitivity from a recently developed total-body PET scanner, whole-body ...scans with higher temporal resolution become possible for dynamic analysis and parametric imaging. In this paper, we focus on deriving the parameter k1 using compartmental modeling and on developing a method to acquire whole-body 18F-FDG PET parametric images using only the first 90 s of the postinjection scan data with the total-body PET system. Methods: Dynamic projections were acquired with a time interval of 1 s for the first 30 s and a time interval of 2 s for the following minute. Image-derived input functions were acquired from the reconstructed dynamic sequences in the ascending aorta. A 1-tissue-compartment model with 4 parameters (k1, k2, blood fraction, and delay time) was used. A maximum-likelihood–based estimation method was developed with the 1-tissue-compartment model solution. The accuracy of the acquired parameters was compared with the ones estimated using a 2-tissue-compartment irreversible model with 1-h-long data. Results: All 4 parametric images were successfully calculated using data from 2 volunteers. By comparing the time–activity curves acquired from the volumes of interest, we showed that the parameters estimated using our method were able to predict the time–activity curves of the early dynamics of 18F-FDG in different organs. The delay-time effects for different organs were also clearly visible in the reconstructed delay-time image with delay variations of as large as 40 s. The estimated parameters using both 90-s data and 1-h data agreed well for k1 and blood fraction, whereas a large difference in k2 was found between the 90-s and 1-h data, suggesting k2 cannot be reliably estimated from the 90-s scan. Conclusion: We have shown that with total-body PET and the increased sensitivity, it is possible to estimate parametric images based on the very early dynamics after 18F-FDG injection. The estimated k1 might potentially be used clinically as an indicator for identifying abnormalities.
Elevated concentrations of arsenic, up to 161μg/L, have been identified in groundwater samples from the confined basal aquifer underlying the aquitard of the Pearl River Delta (PRD). Both aquatic ...arsenic in pore water and solid arsenic in the sediments in the basal aquifer and aquitard were identified. Arsenic speciation of groundwater in the basal aquifer was elucidated on a pH-Eh diagram. In the PRD, arsenic is enriched in groundwater having both low and high salinity, and arsenic enriched groundwater is devoid of dissolved oxygen, has negative Eh values, is slightly alkaline, and has abnormally high concentrations of ammonium and dissolved organic carbon, but low concentrations of nitrate and nitrite. Results of geochemical and hydrochemical analyses and sequential extraction analysis suggest that reductive dissolution of iron oxyhydroxide could be one of the important processes that mobilized solid arsenic. We speculate that mineralization of sedimentary organic matter could also contribute to aquatic arsenic. Scanning electron microscope analysis confirms that abundant authigenic pyrite is present in the sediments. Sulphate derived from paleo-seawater served as the important sulfur source for authigenic pyrite formation. Co-precipitation of arsenic with authigenic pyrite significantly controlled concentrations of aquatic arsenic in the coastal aquifer–aquitard system.
► Coastal aquifer and aquitard are treated as an integrate system. ► Both aquatic arsenic and solid arsenic are observed. ► Aquatic arsenic is derived from reductive dissolution of iron oxyhydroxide. ► Aquatic arsenic can also derived from mineralization of sedimentary organic matter. ► Co-precipitation of arsenic with authigenic pyrite is significant in such a system.
Quantitative dynamic PET with compartmental modeling has the potential to enable multiparametric imaging and more accurate quantification than static PET imaging. Conventional methods for parametric ...imaging commonly use a single kinetic model for all image voxels and neglect the heterogeneity of physiologic models, which can work well for single-organ parametric imaging but may significantly compromise total-body parametric imaging on a scanner with a long axial field of view. In this paper, we evaluate the necessity of voxelwise compartmental modeling strategies, including time delay correction (TDC) and model selection, for total-body multiparametric imaging.
Ten subjects (5 patients with metastatic cancer and 5 healthy volunteers) were scanned on a total-body PET/CT system after injection of 370 MBq of
F-FDG. Dynamic data were acquired for 60 min. Total-body parametric imaging was performed using 2 approaches. One was the conventional method that uses a single irreversible 2-tissue-compartment model with and without TDC. The second approach selects the best kinetic model from 3 candidate models for individual voxels. The differences between the 2 approaches were evaluated for parametric imaging of microkinetic parameters and the
F-FDG net influx rate,
TDC had a nonnegligible effect on kinetic quantification of various organs and lesions. The effect was larger in lesions with a higher blood volume. Parametric imaging of
with the standard 2-tissue-compartment model introduced vascular-region artifacts, which were overcome by the voxelwise model selection strategy.
The time delay and appropriate kinetic model vary in different organs and lesions. Modeling of the time delay of the blood input function and model selection improved total-body multiparametric imaging.
The impacts of adverse childhood experiences (ACEs) have been well documented. One possible consequence of ACEs is dissociation, which is a major feature of post-traumatic psychopathology and is also ...associated with considerable impairment and health care costs. Although ACEs are known to be associated with both psychoform and somatoform dissociation, much less is known about the mechanisms behind this relationship. Little is known about whether social and interpersonal factors such as family environments would moderate the relationship between ACEs and somatoform dissociation. This paper discusses the importance of having a positive and healthy family environment in trauma recovery. We then report the findings of a preliminary study in which we examined whether the association between ACEs and somatoform dissociation would be moderated by family well-being in a convenience sample of Hong Kong adults (N = 359). The number of ACEs was positively associated with somatoform dissociative symptoms, but this association was moderated by the level of family well-being. The number of ACEs was associated with somatoform dissociation only when the family well-being scores were low. These moderating effects were medium. The findings point to the potential importance of using family education and intervention programs to prevent and treat trauma-related dissociative symptoms, but further investigation is needed.
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