Cancers of epithelial origin such as breast, prostate, cervical, gastric, colon and lung cancer account for a large proportion of deaths worldwide. Better treatment of metastasis, the main cause of ...cancer deaths, is therefore urgently required. Several of these tumours have been shown to have an abnormally high concentration of Na+ (Na+) and emerging evidence points to this accumulation being due to elevated intracellular Na+. This poses intriguing questions about the cellular mechanisms underlying Na+ dysregulation in cancer, and its pathophysiological significance. Elevated intracellular Na+ may be due to alterations in activity of the Na+/K+‐ATPase, and/or increased influx via Na+ channels and Na+‐linked transporters. Maintenance of the electrochemical Na+ gradient across the plasma membrane is vital to power many cellular processes that are highly active in cancer cells, including glucose and glutamine import. Na+ channels are also upregulated in cancer cells, which in turn promotes tumour growth and metastasis. For example, ENaC and ASICs are overexpressed in cancers, increasing invasion and proliferation. In addition, voltage‐gated Na+ channels are also upregulated in a range of tumour types, where they promote metastatic cell behaviours via various mechanisms, including membrane potential depolarisation and altered pH regulation. Together, recent findings relating to elevated Na+ in the tumour microenvironment and how this may be regulated by several classes of Na+ channels provide a link between altered Na+ handling and poor clinical outcome. There are new opportunities to leverage this altered Na+ microenvironment for therapeutic benefit, as exemplified by several ongoing clinical trials.
figure legend
Mechanisms of Na+ channel and transporter‐dependent proliferation, migration and invasion. Na+ enters through VGSC, ENaC and ASIC channels and through the SGLT2 cotransporter and the NHE1 exchanger. These mechanisms may be responsible for elevating intracellular Na+. Na+ is removed from the cell via the Na+/K+‐ATPase. VGSCs depolarise the cell membrane potential (Vm), which leads to increased migration. VGSCs also regulate transcription of genes involved in proliferation, migration and invasion. VGSCs increase the activity of NHE1, further elevating intracellular Na+ and extracellular H+. This acidifies the extracellular environment and aids cellular invasion through extracellular matrix. The low extracellular pH will then affect the Na+ channels, increasing the inward Na+ current through these in a positive feedback mechanism which increases intracellular Na+ and extracellular H+.
Sodium homeostasis in the tumour microenvironment Leslie, Theresa K.; James, Andrew D.; Zaccagna, Fulvio ...
Biochimica et biophysica acta. Reviews on cancer,
12/2019, Letnik:
1872, Številka:
2
Journal Article
Recenzirano
Odprti dostop
The concentration of sodium ions (Na+) is raised in solid tumours and can be measured at the cellular, tissue and patient levels. At the cellular level, the Na+ gradient across the membrane powers ...the transport of H+ ions and essential nutrients for normal activity. The maintenance of the Na+ gradient requires a large proportion of the cell’s ATP. Na+ is a major contributor to the osmolarity of the tumour microenvironment, which affects cell volume and metabolism as well as immune function. Here, we review evidence indicating that Na+ handling is altered in tumours, explore our current understanding of the mechanisms that may underlie these alterations and consider the potential consequences for cancer progression. Dysregulated Na+ balance in tumours may open opportunities for new imaging biomarkers and re-purposing of drugs for treatment.
Eslicarbazepine acetate (ESL) is a dibenzazepine anticonvulsant approved as adjunctive treatment for partial-onset epileptic seizures. Following first pass hydrolysis of ESL, S-licarbazepine (S-Lic) ...represents around 95% of circulating active metabolites. S-Lic is the main enantiomer responsible for anticonvulsant activity and this is proposed to be through the blockade of voltage-gated Na
+
channels (VGSCs). ESL and S-Lic both have a voltage-dependent inhibitory effect on the Na
+
current in N1E-115 neuroblastoma cells expressing neuronal VGSC subtypes including Na
v
1.1, Na
v
1.2, Na
v
1.3, Na
v
1.6, and Na
v
1.7. ESL has not been associated with cardiotoxicity in healthy volunteers, although a prolongation of the electrocardiographic PR interval has been observed, suggesting that ESL may also inhibit cardiac Na
v
1.5 isoform. However, this has not previously been studied. Here, we investigated the electrophysiological effects of ESL and S-Lic on Na
v
1.5 using whole-cell patch clamp recording. We interrogated two model systems: (1) MDA-MB-231 metastatic breast carcinoma cells, which endogenously express the “neonatal” Na
v
1.5 splice variant, and (2) HEK-293 cells stably over-expressing the “adult” Na
v
1.5 splice variant. We show that both ESL and S-Lic inhibit transient and persistent Na
+
current, hyperpolarise the voltage-dependence of fast inactivation, and slow the recovery from channel inactivation. These findings highlight, for the first time, the potent inhibitory effects of ESL and S-Lic on the Na
v
1.5 isoform, suggesting a possible explanation for the prolonged PR interval observed in patients on ESL treatment. Given that numerous cancer cells have also been shown to express Na
v
1.5, and that VGSCs potentiate invasion and metastasis, this study also paves the way for future investigations into ESL and S-Lic as potential invasion inhibitors.
Breast cancer remains a leading cause of death in women and novel imaging biomarkers are urgently required. Here, we demonstrate the diagnostic and treatment-monitoring potential of non-invasive ...sodium (
Na) MRI in preclinical models of breast cancer.
Female Rag2
Il2rg
and Balb/c mice bearing orthotopic breast tumours (MDA-MB-231, EMT6 and 4T1) underwent MRI as part of a randomised, controlled, interventional study. Tumour biology was probed using ex vivo fluorescence microscopy and electrophysiology.
Na MRI revealed elevated sodium concentration (Na
) in tumours vs non-tumour regions. Complementary proton-based diffusion-weighted imaging (DWI) linked elevated tumour Na
to increased cellularity. Combining
Na MRI and DWI measurements enabled superior classification accuracy of tumour vs non-tumour regions compared with either parameter alone. Ex vivo assessment of isolated tumour slices confirmed elevated intracellular Na
(Na
); extracellular Na
(Na
) remained unchanged. Treatment with specific inward Na
conductance inhibitors (cariporide, eslicarbazepine acetate) did not affect tumour Na
. Nonetheless, effective treatment with docetaxel reduced tumour Na
, whereas DWI measures were unchanged.
Orthotopic breast cancer models exhibit elevated tumour Na
that is driven by aberrantly elevated Na
. Moreover,
Na MRI enhances the diagnostic capability of DWI and represents a novel, non-invasive biomarker of treatment response with superior sensitivity compared to DWI alone.
The reproducibility movement in psychology has resulted in numerous highly publicized instances of replication failures. The goal of the present work was to investigate people’s reactions to a ...psychology replication failure vs. success, and to test whether a failure elicits harsher reactions when the researcher is a woman vs. a man. We examined these questions in a pre-registered experiment with a working adult sample, a conceptual replication of that experiment with a student sample, and an analysis of data compiled and posted by a psychology researcher on their public weblog with the stated goal to improve research replicability by rank-ordering psychology researchers by their “estimated false discovery risk.” Participants in the experiments were randomly assigned to read a news article describing a successful vs. failed replication attempt of original work from a male vs. female psychological scientist, and then completed measures of researcher competence, likability, integrity, perceptions of the research, and behavioral intentions for future interactions with the researcher. In both working adult and student samples, analyses consistently yielded large main effects of replication outcome, but no interaction with researcher gender. Likewise, the coding of weblog data posted in July 2021 indicated that 66.3% of the researchers scrutinized were men and 33.8% were women, and their rank-ordering was not correlated with researcher gender. The lack of support for our pre-registered gender-replication hypothesis is, at first glance, encouraging for women researchers’ careers; however, the substantial effect sizes we observed for replication outcome underscore the tremendous negative impact the reproducibility movement can have on psychologists’ careers. We discuss the implications of such negative perceptions and the possible downstream consequences for women in the field that are essential for future study.
Abstract Solid tumours have abnormally high intracellular Na + . The activity of various Na + channels may underlie this Na + accumulation. Voltage-gated Na + channels (VGSCs) have been shown to be ...functionally active in cancer cell lines, where they promote invasion. However, the mechanisms involved, and clinical relevance, are incompletely understood. Here, we show that protein expression of the Na v 1.5 VGSC subtype strongly correlates with increased metastasis and shortened cancer-specific survival in breast cancer patients. In addition, VGSCs are functionally active in patient-derived breast tumour cells, cell lines, and cancer-associated fibroblasts. Knockdown of Na v 1.5 in a mouse model of breast cancer suppresses expression of invasion-regulating genes. Na v 1.5 activity increases ATP demand and glycolysis in breast cancer cells, likely by upregulating activity of the Na + /K + ATPase, thus promoting H + production and extracellular acidification. The pH of murine xenograft tumours is lower at the periphery than in the core, in regions of higher proliferation and lower apoptosis. In turn, acidic extracellular pH elevates persistent Na + influx through Na v 1.5 into breast cancer cells. Together, these findings show positive feedback between extracellular acidification and the movement of Na + into cancer cells which can facilitate invasion. These results highlight the clinical significance of Na v 1.5 activity as a potentiator of breast cancer metastasis and provide further evidence supporting the use of VGSC inhibitors in cancer treatment.
The genetic base for soybean cultivars is narrow compared to most other crop species. Twenty‐seven wild perennial Glycine species comprise the tertiary gene pool to soybean that may contain many ...genes of economic importance for soybean improvement. We evaluated 16 accessions of G. argyrea, G. clandestina, G. dolichocarpa, and G. tomentella for resistance to Heterodera glycines (HG), also known as the soybean cyst nematode, and to multiple isolates of Phakopsora pachyrhizi, the causal fungus of soybean rust. All 16 accessions were classified as resistant to H. glycines HG Type 2.5.7, based on number of cysts per root mass with plant introductions (PIs) 483227, 509501, 563892, and 573064 (all G. tomentella) void of any cysts indicating no reproduction by this pest. All 16 accessions had an immune reaction to one isolate of P. pachyrhizi. Regardless of isolate, no sporulating uredinia were observed on G. argyrea (PI 505151) and G. tomentella (PIs 483227, 509501, and 573064). These results demonstrate that some accessions within the perennial Glycine species harbour resistance to both H. glycines and P. pachyrhizi and would be good candidates for wide hybridization programs seeking to transfer potentially unique multiple resistance genes into soybean.
Unintentional window falls represent a preventable source of injury and death in children. Despite major campaigns in some larger cities, there continue to be unintentional falls from windows ...throughout the United States. We aimed to identify risk factors and trends in unintentional window falls in the pediatric population in a national and regional sample.
A retrospective analysis of annual emergency department (ED) visits from the National Electronic Injury Surveillance System using product codes specific to windows, as well as patient encounters for unintentional window falls from January 2007 to August 2017 using site-specific trauma registries from 10 tertiary care children's hospitals in New England. National and state-specific census population estimates were used to compute rates per 100,000 population.
There were 38,840 ED visits and 496 regional patients who unintentionally fell from a window across the study period between 0 and 17 years old. The majority of falls occurred in children under the age of 6 and were related to falls from a second story or below. A decreased trend in national ED visits was seen, but no change in rates over time for regional trauma center encounters. A high number of falls was found to occur in smaller cities surrounding metropolitan areas and from single family residences.
Falls from windows represent a low proportion of overall types of unintentional sources of injury in children but are a high risk for severe disability. These results provide updated epidemiologic data for targeted intervention programs, as well as raise awareness for continued education and advocacy.
Eslicarbazepine acetate (ESL) is a dibenzazepine anticonvulsant approved as adjunctive treatment for partial-onset epileptic seizures. Following first pass hydrolysis of ESL, S-licarbazepine (S-Lic) ...represents around 95% of circulating active metabolites. S-Lic is the main enantiomer responsible for anticonvulsant activity and this is proposed to be through the blockade of voltage-gated Na
channels (VGSCs). ESL and S-Lic both have a voltage-dependent inhibitory effect on the Na
current in N1E-115 neuroblastoma cells expressing neuronal VGSC subtypes including Na
1.1, Na
1.2, Na
1.3, Na
1.6, and Na
1.7. ESL has not been associated with cardiotoxicity in healthy volunteers, although a prolongation of the electrocardiographic PR interval has been observed, suggesting that ESL may also inhibit cardiac Na
1.5 isoform. However, this has not previously been studied. Here, we investigated the electrophysiological effects of ESL and S-Lic on Na
1.5 using whole-cell patch clamp recording. We interrogated two model systems: (1) MDA-MB-231 metastatic breast carcinoma cells, which endogenously express the "neonatal" Na
1.5 splice variant, and (2) HEK-293 cells stably over-expressing the "adult" Na
1.5 splice variant. We show that both ESL and S-Lic inhibit transient and persistent Na
current, hyperpolarise the voltage-dependence of fast inactivation, and slow the recovery from channel inactivation. These findings highlight, for the first time, the potent inhibitory effects of ESL and S-Lic on the Na
1.5 isoform, suggesting a possible explanation for the prolonged PR interval observed in patients on ESL treatment. Given that numerous cancer cells have also been shown to express Na
1.5, and that VGSCs potentiate invasion and metastasis, this study also paves the way for future investigations into ESL and S-Lic as potential invasion inhibitors.
After soybean rust was confirmed in soybean in the USA, sentinel plots were established in 26 states to monitor its spread. Funding for establishing, sampling, and monitoring the plots came from the ...USDA, national, regional, and state soybean commodity boards, and state departments of agriculture, extension services, and universities. The presence of sentinel plots for soybean rust monitoring provided the potential for reducing the time and expense of extensive statewide travel for collection of soybean leaf samples for monitoring the incidence of other foliar diseases of soybean in Illinois.
Accepted for publication 27 July 2010. Published 27 August 2010.
PDF
