Role of ion channels in gastrointestinal cancer Anderson, Kyle J; Cormier, Robert T; Scott, Patricia M
World journal of gastroenterology : WJG,
2019-Oct-14, 2019-10-14, 20191014, Letnik:
25, Številka:
38
Journal Article
Odprti dostop
In their seminal papers Hanahan and Weinberg described oncogenic processes a normal cell undergoes to be transformed into a cancer cell. The functions of ion channels in the gastrointestinal (GI) ...tract influence a variety of cellular processes, many of which overlap with these hallmarks of cancer. In this review we focus on the roles of the calcium (Ca
), sodium (Na
), potassium (K
), chloride (Cl
) and zinc (Zn
) transporters in GI cancer, with a special emphasis on the roles of the KCNQ1 K
channel and CFTR Cl
channel in colorectal cancer (CRC). Ca
is a ubiquitous second messenger, serving as a signaling molecule for a variety of cellular processes such as control of the cell cycle, apoptosis, and migration. Various members of the TRP superfamily, including TRPM8, TRPM7, TRPM6 and TRPM2, have been implicated in GI cancers, especially through overexpression in pancreatic adenocarcinomas and down-regulation in colon cancer. Voltage-gated sodium channels (VGSCs) are classically associated with the initiation and conduction of action potentials in electrically excitable cells such as neurons and muscle cells. The VGSC Na
1.5 is abundantly expressed in human colorectal CRC cell lines as well as being highly expressed in primary CRC samples. Studies have demonstrated that conductance through Na
1.5 contributes significantly to CRC cell invasiveness and cancer progression. Zn
transporters of the ZIP/SLC39A and ZnT/SLC30A families are dysregulated in all major GI organ cancers, in particular, ZIP4 up-regulation in pancreatic cancer (PC). More than 70 K
channel genes, clustered in four families, are found expressed in the GI tract, where they regulate a range of cellular processes, including gastrin secretion in the stomach and anion secretion and fluid balance in the intestinal tract. Several distinct types of K
channels are found dysregulated in the GI tract. Notable are hERG1 upregulation in PC, gastric cancer (GC) and CRC, leading to enhanced cancer angiogenesis and invasion, and KCNQ1 down-regulation in CRC, where KCNQ1 expression is associated with enhanced disease-free survival in stage II, III, and IV disease. Cl
channels are critical for a range of cellular and tissue processes in the GI tract, especially fluid balance in the colon. Most notable is CFTR, whose deficiency leads to mucus blockage, microbial dysbiosis and inflammation in the intestinal tract. CFTR is a tumor suppressor in several GI cancers. Cystic fibrosis patients are at a significant risk for CRC and low levels of CFTR expression are associated with poor overall disease-free survival in sporadic CRC. Two other classes of chloride channels that are dysregulated in GI cancers are the chloride intracellular channels (CLIC1, 3 & 4) and the chloride channel accessory proteins (CLCA1,2,4). CLIC1 & 4 are upregulated in PC, GC, gallbladder cancer, and CRC, while the CLCA proteins have been reported to be down-regulated in CRC. In summary, it is clear, from the diverse influences of ion channels, that their aberrant expression and/or activity can contribute to malignant transformation and tumor progression. Further, because ion channels are often localized to the plasma membrane and subject to multiple layers of regulation, they represent promising clinical targets for therapeutic intervention including the repurposing of current drugs.
The objective of this study was to evaluate the relationship between three distinct spinal manipulative therapy dose groups and escalated spine care by analyzing insurance claims from a cohort of ...patients with low back pain.
We compared three distinct spinal manipulative therapy dose groups (low = 1 SMT visits, moderate = 2-12 SMT visits, high = 13+ SMT visits), to a control group (no spinal manipulative therapy) regarding the outcome of escalated spine care. Escalated spine care procedures include imaging studies, injection procedures, emergency department visits, surgery, and opioid medication use. Propensity score matching was performed to address treatment selection bias. Modified Poisson regression modeling was used to estimate the relative risk of spine care escalation among three spinal manipulative therapy doses, adjusting for age, sex, retrospective risk score and claim count.
83,025 claims were categorized into 11,114 unique low back pain episodes; 8,137 claims had 0 spinal manipulative therapy visits, with the remaining episodes classified as low dose (n = 404), moderate dose (n = 1,763) or high dose (n = 810). After propensity score matching, 5,348 episodes remained; 2,454 had 0 spinal manipulative therapy visits with the remaining episodes classified as low dose (n = 404), moderate dose (n = 1,761), or high dose (n = 729). The estimated relative risk (vs no spinal manipulative therapy) for any escalated spine care was 0.45 (95% confidence interval 0.38, 0.55, p <0.001), 0.58 (95% confidence interval 0.53, 0.63, p <0.001), and 1.03 (95% confidence interval 0.95, 1.13, p = 0.461) for low, moderate, and high dose spinal manipulative therapy groups, respectively.
For claims associated with initial episodes of low back pain, low and moderate dose spinal manipulative therapy groups were associated with a 55% and 42% reduction, respectively, in the relative risk of any escalated spine care.
The reliability of Arctic climate predictions is currently hampered by insufficient knowledge of natural climate variability in the past. A sediment core from Lake El'gygytgyn in northeastern (NE) ...Russia provides a continuous, high-resolution record from the Arctic, spanning the past 2.8 million years. This core reveals numerous "super interglacials" during the Quaternary; for marine benthic isotope stages (MIS) 11c and 31, maximum summer temperatures and annual precipitation values are ∼4° to 5°C and ∼300 millimeters higher than those of MIS 1 and 5e. Climate simulations show that these extreme warm conditions are difficult to explain with greenhouse gas and astronomical forcing alone, implying the importance of amplifying feedbacks and far field influences. The timing of Arctic warming relative to West Antarctic Ice Sheet retreats implies strong interhemispheric climate connectivity.
Single domain antibodies are the small recombinant variable domains derived from camelid heavy-chain-only antibodies. They are renowned for their stability, in large part due to their ability to ...refold following thermal or chemical denaturation. In addition to refolding after heat denaturation, A3, a high affinity anti-Staphylococcal Enterotoxin B single domain antibody, possesses a melting temperature of ∼84°C, among the highest reported for a single domain antibody. In this work we utilized the recently described crystal structure of A3 to select locations for the insertion of a second disulfide bond and evaluated the impact that the addition of this second bond had on the melting temperature. Four double-disulfide versions of A3 were constructed and each was found to improve the melting temperature relative to the native structure without reducing affinity. Placement of the disulfide bond at a previously published position between framework regions 2 and 3 yielded the largest improvement (>6°C), suggesting this location is optimal, and seemingly provides a universal route to raise the melting temperature of single domain antibodies. This study further demonstrates that even single domain antibodies with extremely high melting points can be further stabilized by addition of disulfide bonds.
•Childhood obesity has grown from 5% in 1978 to 18.5% in 2016.•The rate of increase in childhood obesity has slowed from 2004 to 2016.•Cohort-level obesity increases through age 10 and is steady ...through age 18.•5 year olds in 2010 were 2 percentage points more likely to be obese than in 1997.•The rate of obesity growth from kindergarten to 3rd grade has recently declined.
The prevalence of childhood obesity in the United States has more than tripled over the last four decades from 5 percent in 1978 to 18.5 percent in 2016. There is evidence for a break in trend in recent years: after growing from 0.4 to 0.7 percentage point per year between 1978 and 2004, the rate of increase has slowed to 0.1 percentage point per year from 2004 to 2016. To better understand these trends, in this paper we analyze a range of datasets that collect information on childhood obesity. We analyze the data overall, across the age distribution, across birth cohorts, and for subgroups of interest. We find steady increases in cohort-level obesity prevalence through approximately age 10, with levels unchanged thereafter, suggesting a need for additional interventions at early ages. We find that the prevalence of obesity has diverged by race and gender in recent years, especially among children entering kindergarten. Compared with 5-year-olds in 1997, 5-year-olds in 2010 were 2 percentage points more likely to be obese overall. Black and Hispanic 5-year-olds were 5 and 3 percentage points more likely to be obese, respectively, while whites had a 1 percentage point increase in obesity. However, overall and among all subgroups the rate of growth in obesity from kindergarten through 3rd grade has declined in recent years. Together, these findings can inform a future research literature that aims to target obesity interventions where they will be most impactful.
Context:
Cytotoxic treatment may accelerate depletion of the primordial follicle pool, leading to impaired fertility and premature menopause. Assessment of ovarian damage in prepubertal girls is not ...currently possible, but Anti-Müllerian Hormone (AMH) is a useful marker of ovarian reserve in adults.
Objective:
The objective of the study was to prospectively evaluate AMH measurement in children as a marker of ovarian toxicity during cancer treatment.
Design and Setting:
This was a prospective, longitudinal study at a University Hospital.
Patients:
Twenty-two females (17 prepubertal), median age 4.4 yr (range 0.3–15 yr), were recruited before treatment for cancer.
Main Outcome Measures:
AMH, inhibin B, and FSH at diagnosis, after each chemotherapy course and during follow-up, were measured. Risk of gonadotoxicity was classified as low/medium (n = 13) or high (n = 9) based on chemotherapy agent, cumulative dose, and radiotherapy involving the ovaries.
Results:
Pretreatment AMH was detectable across the age range studied. AMH decreased progressively during chemotherapy (P < 0.0001) in both prepubertal and pubertal girls, becoming undetectable in 50% of patients, with recovery in the low/medium risk groups after completion of treatment. In the high-risk group, AMH became undetectable in all patients and showed no recovery. Inhibin B was undetectable in most patients before treatment and, with FSH, showed no clear relationship to treatment.
Conclusion:
AMH is detectable in girls of all ages and falls rapidly during cancer treatment in both prepubertal and pubertal girls. Both the fall during treatment and recovery thereafter varied with risk of gonadotoxicity. AMH is therefore a clinically useful marker of damage to the ovarian reserve in girls receiving treatment for cancer.
Coastal waters of the United States (U.S.) are subject to many of the major harmful algal bloom (HAB) poisoning syndromes and impacts. These include paralytic shellfish poisoning (PSP), neurotoxic ...shellfish poisoning (NSP), amnesic shellfish poisoning (ASP), ciguatera fish poisoning (CFP) and various other HAB phenomena such as fish kills, loss of submerged vegetation, shellfish mortalities, and widespread marine mammal mortalities. Here, the occurrences of selected HABs in a selected set of regions are described in terms of their relationship to eutrophication, illustrating a range of responses. Evidence suggestive of changes in the frequency, extent or magnitude of HABs in these areas is explored in the context of the nutrient sources underlying those blooms, both natural and anthropogenic. In some regions of the U.S., the linkages between HABs and eutrophication are clear and well documented, whereas in others, information is limited, thereby highlighting important areas for further research.
Although algal blooms, including those considered toxic or harmful, can be natural phenomena, the nature of the global problem of harmful algal blooms (HABs) has expanded both in extent and its ...public perception over the last several decades. Of concern, especially for resource managers, is the potential relationship between HABs and the accelerated eutrophication of coastal waters from human activities. We address current insights into the relationships between HABs and eutrophication, focusing on sources of nutrients, known effects of nutrient loading and reduction, new understanding of pathways of nutrient acquisition among HAB species, and relationships between nutrients and toxic algae. Through specific, regional, and global examples of these various relationships, we offer both an assessment of the state of understanding, and the uncertainties that require future research efforts. The sources of nutrients potentially stimulating algal blooms include sewage, atmospheric deposition, groundwater flow, as well as agricultural and aquaculture runoff and discharge. On a global basis, strong correlations have been demonstrated between total phosphorus inputs and phytoplankton production in freshwaters, and between total nitrogen input and phytoplankton production in estuarine and marine waters. There are also numerous examples in geographic regions ranging from the largest and second largest U. S. mainland estuaries (Chesapeake Bay and the Albemarle-Pamlico Estuarine System), to the Inland Sea of Japan, the Black Sea, and Chinese coastal waters, where increases in nutrient loading have been linked with the development of large biomass blooms, leading to anoxia and even toxic or harmful impacts on fisheries resources, ecosystems, and human health or recreation. Many of these regions have witnessed reductions in phytoplankton biomass (as chlorophyll a) or HAB incidence when nutrient controls were put in place. Shifts in species composition have often been attributed to changes in nutrient supply ratios, primarily N:P or N:Si. Recently this concept has been extended to include organic forms of nutrients, and an elevation in the ratio of dissolved organic carbon to dissolved organic nitrogen (DOC:DON) has been observed during several recent blooms. The physiological strategies by which different groups of species acquire their nutrients have become better understood, and alternate modes of nutrition such as heterotrophy and mixotrophy are now recognized as common among HAB species. Despite our increased understanding of the pathways by which nutrients are delivered to ecosystems and the pathways by which they are assimilated differentially by different groups of species, the relationships between nutrient delivery and the development of blooms and their potential toxicity or harmfulness remain poorly understood. Many factors such as algal species presence/abundance, degree of flushing or water exchange, weather conditions, and presence and abundance of grazers contribute to the success of a given species at a given point in time. Similar nutrient loads do not have the same impact in different environments or in the same environment at different points in time. Eutrophication is one of several mechanisms by which harmful algae appear to be increasing in extent and duration in many locations. Although important, it is not the only explanation for blooms or toxic outbreaks. Nutrient enrichment has been strongly linked to stimulation of some harmful species, but for others it has not been an apparent contributing factor. The overall effect of nutrient over-enrichment on harmful algal species is clearly species specific.
► I use the Early Childhood Longitudinal Survey-Kindergarten Class of 1998–1999 (ECLS-K) to investigate the relationships among maternal employment, family routines and obesity. ► I find that family ...routines do vary significantly with maternal employment intensity. ► I find that the impact of family routines and of maternal employment on children's obesity are similar whether included in the regression alone or together. ► I conclude that family routines cannot explain the deleterious effect maternal employment intensity has on children's obesity.
Using the Early Childhood Longitudinal Survey-Kindergarten Class of 1998–1999 (ECLS-K) data from kindergarten through eighth grade, this paper investigate the relationships among maternal employment, family routines and obesity. More hours worked by the mother tend to be negatively related to positive routines like eating meals as a family or at regular times, or having family rules about hours of television watched. Many of these same routines are significantly related to the probability of being obese, implying that family routines may be a mechanism by which maternal employment intensity affects children's obesity. However, inclusion of family routines in the obesity regression does not appreciably change the estimated effect of maternal employment hours. Thus, the commonly estimated deleterious effect of maternal employment on children's obesity cannot be explained by family routines, leaving the exact mechanisms an open question for further exploration.
The increase in childhood obesity over the past several decades, together with the associated health problems and costs, is raising grave concern among health care professionals, policy experts, ...children's advocates, and parents. Patricia Anderson and Kristin Butcher document trends in children's obesity and examine the possible underlying causes of the obesity epidemic. They begin by reviewing research on energy intake, energy expenditure, and "energy balance," noting that children who eat more "empty calories" and expend fewer calories through physical activity are more likely to be obese than other children. Next they ask what has changed in children's environment over the past three decades to upset this energy balance equation. In particular, they examine changes in the food market, in the built environment, in schools and child care settings, and in the role of parents-paying attention to the timing of these changes. Among the changes that affect children's energy intake are the increasing availability of energy-dense, high-calorie foods and drinks through schools. Changes in the family, particularly an increase in dual-career or single-parent working families, may also have increased demand for food away from home or pre-prepared foods. A host of factors have also contributed to reductions in energy expenditure. In particular, children today seem less likely to walk to school and to be traveling more in cars than they were during the early 1970s, perhaps because of changes in the built environment. Finally, children spend more time viewing television and using computers. Anderson and Butcher find no one factor that has led to increases in children's obesity. Rather, many complementary changes have simultaneously increased children's energy intake and decreased their energy expenditure. The challenge in formulating policies to address children's obesity is to learn how best to change the environment that affects children's energy balance.
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