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Phenotypic screen of sixty-eight colorectal cancer cell lines identifies CEACAM6 and CEACAM5 as markers of acid resistance.
Elevated cancer metabolism releases lactic acid and CO2 into the under-perfused tumor microenvironment, resulting in extracellular acidosis. The surviving cancer cells must adapt to this selection pressure; thus, targeting tumor acidosis is a rational therapeutic strategy to manage tumor growth. However, none of the major approved treatments are based explicitly on disrupting acid handling, signaling, or adaptations, possibly because the distinction between acid-sensitive and acid-resistant phenotypes is not clear. Here, we report pH-related phenotypes of sixty-eight colorectal cancer (CRC) cell lines by measuring i) extracellular acidification as a readout of acid production by fermentative metabolism and ii) growth of cell biomass over a range of extracellular pH (pHe) levels as a measure of the acid sensitivity of proliferation. Based on these measurements, CRC cell lines were grouped along two dimensions as "acid-sensitive"/"acid-resistant" versus "low metabolic acid production"/"high metabolic acid production." Strikingly, acid resistance was associated with the expression of CEACAM6 and CEACAM5 genes coding for two related cell-adhesion molecules, and among pH-regulating genes, of CA12. CEACAM5/6 protein levels were strongly induced by acidity, with a further induction under hypoxia in a subset of CRC lines. Lack of CEACAM6 (but not of CEACAM5) reduced cell growth and their ability to differentiate. Finally, CEACAM6 levels were strongly increased in human colorectal cancers from stage II and III patients, compared to matched samples from adjacent normal tissues. Thus, CEACAM6 is a marker of acid-resistant clones in colorectal cancer and a potential motif for targeting therapies to acidic regions within the tumors.
Alternate day versus consecutive day oral iron supplementation in iron-depleted women: a randomized double-blind placebo-controlled study.
BACKGROUND: Guidelines to treat iron deficiency recommend daily provision of oral iron, but this may decrease fractional iron absorption and increase side effects. Our objective was to compare consecutive-day versus alternate-day iron supplementation. METHODS: In a double-masked, randomized, placebo-controlled trial, young Swiss women (n = 150; serum ferritin ≤30 μg/L) were assigned to: daily 100 mg iron for 90 d, followed by daily placebo for another 90 d (consecutive-day group) or the same daily dose of iron and placebo on alternate days for 180 d (alternate-day group). The study period was 24/11/2021-10/8/2022. Co-primary outcomes, at equal total iron doses, were serum ferritin and gastrointestinal side effects; secondary outcomes were iron deficiency and serum hepcidin. Compliance and side effects were recorded daily using a mobile application. Data were analysed using mixed models and longitudinal prevalence ratios (LPR). The trial was registered at ClinicalTrials.gov (NCT05105438). FINDINGS: 75 women were assigned to each group and included in the intention-to-treat analysis. Capsule adherence and side effect reporting was >97% in both groups. At equal total iron doses, comparing consecutive-day and alternate-day groups, median serum ferritin was 43.8 μg/L (31.7-58.2) versus 44.8 μg/L (33.8-53.6) (P = 0.98), the LPR for gastrointestinal side effects on days of iron intake was 1.56 (95% CI: 1.38, 1.77; P
Biofortified Yellow-Fleshed Potatoes Provide More Absorbable Zinc than a Commonly Consumed Variety: A Randomized Trial Using Stable Isotopes in Women in the Peruvian Highlands.
BACKGROUND: Zinc-biofortified potatoes have considerable potential to reduce zinc deficiency because of their low levels of phytate, an inhibitor of zinc absorption, and their high consumption, especially in the Andean region of Peru. OBJECTIVES: The purpose of this study was to measure fractional and total zinc absorption from a test meal of biofortified compared with regular potatoes. METHODS: We undertook a single-blinded randomized crossover study (using 67Zn and 70Zn stable isotopes) in which 37 women consumed 500-g biofortified or regular potatoes twice a day. Urine samples were collected to determine fractional and total zinc absorption. RESULTS: The zinc content of the biofortified potato and regular potato was 0.48 (standard deviation [SD]: 0.02) and 0.32 (SD: 0.03) mg/100 g fresh weight, respectively. Mean fractional zinc absorption (FZA) from the biofortified potatoes was lower than from the regular potatoes, 20.8% (SD: 5.4%) and 25.5% (SD: 7.0%), respectively (P < 0.01). However, total zinc absorbed was significantly higher (0.49; SD: 0.13 and 0.40; SD: 0.11 mg/500 g, P < 0.01, respectively). CONCLUSIONS: The results of this study demonstrate that biofortified potatoes provide more absorbable zinc than regular potatoes. Zinc-biofortified potatoes could contribute toward reducing zinc deficiency in populations where potatoes are a staple food. This trial was registered at clinicaltrials.gov as NCT05154500.
The Effect of Zinc Biofortified Wheat Produced via Foliar Application on Zinc Status: A Randomized, Controlled Trial in Indian Children.
BACKGROUND: Agronomic zinc biofortification of wheat by foliar application increases wheat zinc content and total zinc absorption in humans. OBJECTIVES: To assess the effect of agronomically biofortified whole wheat flour (BFW) on plasma zinc (PZC) compared with a postharvest fortified wheat (PHFW) and unfortified control wheat (CW) when integrated in a midday school meal scheme. METHODS: We conducted a 20-wk double-blind intervention trial in children (4-12 y, n = 273) individually randomly assigned to 3 groups to receive a daily school lunch consisting of 3 chapattis prepared with the 3 different wheat flour types. Measurements of anthropometry, blood biochemistry, and leukocyte DNA strand breaks were conducted. We applied sparse serial sampling to monitor PZC over time, and analysis was performed using linear mixed-effects models. RESULTS: Mean zinc content in BFW, PHFW, and CW were 48.0, 45.1, and 21.2 ppm, respectively (P < 0.001). Mean (standard deviation) daily zinc intakes in the study intervention in BFW, PHFW, and CW groups were 4.4 (1.6), 5.9 (1.9) and 2.6 (0.6) mg Zn/d, respectively, with intake in groups PHFW and BFW differing from CW (P < 0.001) but no difference between BFW and PHFW. There were no time effect, group difference, or group × time interaction in PZC. Prevalence of zinc deficiency decreased in the BFW (from 14.1%-11.2%), PHFW (from 8.9%-2.3%), and CW (9.8%-8.8%) groups, but there was no time × treatment interaction in the prevalence of zinc deficiency (P = 0.191). Compliance with consuming the study school meals was associated with PZC (P = 0.006). DNA strand breaks were not significantly associated with PZC (n = 51; r = 0.004, P = 0.945). CONCLUSIONS: Consumption of either PHFW or BFW provided an additional ∼1.8 to 3.3 mg Zn/d, but it did not affect PZC or zinc deficiency, growth, or DNA strand breaks. This trial was registered on clinicaltrials.gov as NCT02241330 and ctri.nic.in as CTRI/2015/06/005913.
The remarkable impact of iodisation programmes on global public health.
The objective of this paper is to review the global effort to eliminate iodine deficiency and its impact on public health. Iodine is an essential component of hormones produced by the thyroid gland. Iodine deficiency has multiple adverse effects in humans due to inadequate thyroid hormone production that are termed the iodine deficiency disorders. The major adverse effect is impaired cognition in children. The WHO's first estimate of the global prevalence of goitre in 1960 suggested that 20-60 % of the world's population was affected, with most of the burden in low- and middle-income countries. Iodine deficiency was identified as a key global risk factor for impaired child development where the need for intervention was urgent. This spurred a worldwide effort to eliminate iodine deficiency led by a coalition of international organisations working closely with national governments and the salt industry. In most countries, the best strategy to control iodine deficiency is carefully monitored iodisation of salt. The reach of current iodised salt programmes is remarkable: in 2018, 88 % of the global population used iodised salt. The number of countries with adequate iodine intake has nearly doubled over the past 20 years from 67 in 2003 to 118 in 2020. The resulting improvement in cognitive development and future earnings suggests a potential global economic benefit of nearly $33 billion. Iodine programmes are appealing for national governments because the health and economic consequences are high and can be easily averted by salt iodisation, a low-cost and sustainable intervention.
Regulation of iron absorption in infants.
BACKGROUND: Iron programs in low- and middle-income countries often target infants and young children. Limited data from human infants and mouse models suggest that homeostatic control of iron absorption is incomplete in early infancy. Excess iron absorption during infancy may have detrimental effects. OBJECTIVES: Our aims were to 1) investigate determinants of iron absorption in infants aged 3-15 mo and assess whether regulation of iron absorption is fully mature during this period and 2) define the threshold ferritin and hepcidin concentrations in infancy that trigger upregulation of iron absorption. METHODS: We performed a pooled analysis of standardized, stable iron isotope absorption studies performed by our laboratory in infants and toddlers. We used generalized additive mixed modeling (GAMM) to examine relationships between ferritin, hepcidin, and fractional iron absorption (FIA). RESULTS: Kenyan and Thai infants aged 2.9-15.1 mo (n = 269) were included; 66.8% were iron deficient and 50.4% were anemic. In regression models, hepcidin, ferritin, and serum transferrin receptor were significant predictors of FIA, whereas C-reactive protein was not. In the model including hepcidin, hepcidin was the strongest predictor of FIA (β = -0.435). In all models, interaction terms, including age, were not significant predictors of FIA or hepcidin. The fitted GAMM trend of ferritin versus FIA showed a significant negative slope until ferritin of 46.3 μg/L (95% CI: 42.1, 50.5 μg/L), which corresponded to an FIA decrease from 26.5% to 8.3%; above this ferritin value, FIA remained stable. The fitted GAMM trend of hepcidin versus FIA showed a significant negative slope until hepcidin of 3.15 nmol/L (95% CI: 2.67, 3.63 nmol/L), above which FIA remained stable. CONCLUSIONS: Our findings suggest that the regulatory pathways of iron absorption are intact in infancy. In infants, iron absorption begins to increase at threshold ferritin and hepcidin values of ∼46 μg/L and ∼3 nmol/L, respectively, similar to adult values.
Prebiotics increase iron absorption and reduce the adverse effects of iron on the gut microbiome and inflammation: a randomized controlled trial using iron stable isotopes in Kenyan infants.
BACKGROUND: Iron fortificants tend to be poorly absorbed and may adversely affect the gut, especially in African children. OBJECTIVE: We assessed the effects of prebiotic galacto-oligosaccharides/fructo-oligosaccharides (GOS/FOS) on iron absorption and gut health when added to iron-fortified infant cereal. METHODS: We randomly assigned Kenyan infants (n = 191) to receive daily for 3 wk a cereal containing iron and 7.5 g GOS/FOS (7.5 g+iron group), 3 g (3-g+iron group) GOS/FOS, or no prebiotics (iron group). A subset of infants in the 2 prebiotic+iron groups (n = 66) consumed 4 stable iron isotope-labeled test meals without and with prebiotics, both before and after the intervention. Primary outcome was fractional iron absorption (FIA) from the cereal with or without prebiotics regardless of dose, before and after 3 wk of consumption. Secondary outcomes included fecal gut microbiota, iron and inflammation status, and effects of prebiotic dose. RESULTS: Median (25th-75th percentiles) FIAs from meals before intervention were as follows: 16.3% (8.0%-27.6%) without prebiotics compared with 20.5% (10.4%-33.4%) with prebiotics (Cohen d = 0.53; P < 0.001). FIA from the meal consumed without prebiotics after intervention was 22.9% (8.5%-32.4%), 41% higher than from the meal without prebiotics before intervention (Cohen d = 0.36; P = 0.002). FIA from the meal consumed with prebiotics after intervention was 26.0% (12.2%-36.1%), 60% higher than from the meal without prebiotics before intervention (Cohen d = 0.45; P = 0.007). After 3 wk, compared with the iron group, the following results were observed: 1) Lactobacillus sp. abundances were higher in both prebiotic+iron groups (P < 0.05); 2) Enterobacteriaceae sp. abundances (P = 0.022) and the sum of pathogens (P < 0.001) were lower in the 7.5-g+iron group; 3) the abundance of bacterial toxin-encoding genes was lower in the 3-g+iron group (false discovery rate < 0.05); 4) fecal pH (P < 0.001) and calprotectin (P = 0.033) were lower in the 7.5-g+iron group. CONCLUSIONS: Adding prebiotics to iron-fortified infant cereal increases iron absorption and reduces the adverse effects of iron on the gut microbiome and inflammation in Kenyan infants. This trial was registered at clinicaltrials.gov as NCT03894358.
Iron status in Swiss adolescents with paediatric major depressive disorder and healthy controls: a matched case-control study.
PURPOSE: Depression is associated with low-grade systemic inflammation and impaired intestinal function, both of which may reduce dietary iron absorption. Low iron status has been associated with depression in adults and adolescents. In Swiss adolescents, we determined the associations between paediatric major depressive disorder (pMDD), inflammation, intestinal permeability and iron status. METHODS: This is a matched case-control study in 95 adolescents with diagnosed pMDD and 95 healthy controls aged 13-17 years. We assessed depression severity using the Children's Depression Rating Scale-Revised. We measured iron status (serum ferritin (SF) and soluble transferrin receptor (sTfR)), inflammation (C-reactive protein (CRP) and alpha-1-acid-glycoprotein (AGP)), and intestinal permeability (intestinal fatty acid binding protein (I-FABP)). We assessed history of ID diagnosis and treatment with a self-reported questionnaire. RESULTS: SF concentrations did not differ between adolescents with pMDD (median (IQR) SF: 31.2 (20.2, 57.0) μg/L) and controls (32.5 (22.6, 48.3) μg/L, p = 0.4). sTfR was lower among cases than controls (4.50 (4.00, 5.50) mg/L vs 5.20 (4.75, 6.10) mg/L, p
Associations of n-3 polyunsaturated fatty acid status and intake with paediatric major depressive disorder in Swiss adolescents: A case-control study.
BACKGROUND: Observational studies suggest a link between n-3 polyunsaturated fatty acid (PUFA) intake, n-3 PUFA status, and depression in adults, but studies in adolescents are scarce. This study aimed to determine associations of n-3 PUFA status and intake with paediatric major depressive disorder (pMDD) in Swiss adolescents. METHODS: We conducted a matched case-control study in 95 adolescents diagnosed with pMDD and 95 healthy controls aged 13 to <18 years. We analysed red blood cell (RBC) fatty acid (FA) composition (% of total FA). n-3 PUFA intake was assessed using a focused food frequency questionnaire and depression severity was assessed by the Children's Depression Rating Scale-Revised (CDRS-R). RESULTS: Mean RBC eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) were lower in cases than controls (EPA: 0.41 ± 0.11 vs 0.46 ± 0.12, p
Register-based information on thyroid diseases in Europe: lessons and results from the EUthyroid collaboration.
OBJECTIVE: Registers of diagnoses and treatments exist in different forms in the European countries and are potential sources to answer important research questions. Prevalence and incidence of thyroid diseases are highly dependent on iodine intake and, thus, iodine deficiency disease prevention programs. We aimed to collect European register data on thyroid outcomes to compare the rates between countries/regions with different iodine status and prevention programs. DESIGN: Register-based cross-sectional study. METHODS: National register data on thyroid diagnoses and treatments were requested from 23 European countries/regions. The provided data were critically assessed for suitability for comparison between countries/regions. Sex- and age-standardized rates were calculated. RESULTS: Register data on ≥1 thyroid diagnoses or treatments were available from 22 countries/regions. After critical assessment, data on medication, surgery, and cancer were found suitable for comparison between 9, 10, and 13 countries/regions, respectively. Higher rates of antithyroid medication and thyroid surgery for benign disease and lower rates of thyroid hormone therapy were found for countries with iodine insufficiency before approx. 2001, and no relationship was observed with recent iodine intake or prevention programs. CONCLUSIONS: The collation of register data on thyroid outcomes from European countries is impeded by a high degree of heterogeneity in the availability and quality of data between countries. Nevertheless, a relationship between historic iodine intake and rates of treatments for hyper- and hypothyroid disorders is indicated. This study illustrates both the challenges and the potential for the application of register data of thyroid outcomes across Europe.
Another iron in C. difficile's fire.
Iron is arguably the most important nutrient in the ongoing battle between hosts and bacteria. Recently in Nature, a unique iron storage organelle, the ferrosome, was discovered in the human pathogen Clostridioides difficile.1 But what is the role of ferrosomes and how do they affect bacterial behavior and infection?
Validation of a batch cultivation protocol for fecal microbiota of Kenyan infants.
BACKGROUND: The combination of cultivation studies with molecular analysis approaches allows characterization of the complex human gut microbiota in depth. In vitro cultivation studies of infants living in rural sub-Saharan Africa are scarce. In this study, a batch cultivation protocol for Kenyan infant fecal microbiota was validated. METHODS: Fresh fecal samples were collected from 10 infants living in a rural area of Kenya. Samples were transported under protective conditions and subsequently prepared for inoculation within less than 30 h for batch cultivation. A diet-adapted cultivation medium was used that mimicked the daily intake of human milk and maize porridge in Kenyan infants during weaning. 16 S rRNA gene amplicon sequencing and HPLC analyses were performed to assess the composition and metabolic activity, respectively, of the fecal microbiota after 24 h of batch cultivation. RESULTS: High abundance of Bifidobacterium (53.4 ± 11.1%) and high proportions of acetate (56 ± 11% of total metabolites) and lactate (24 ± 22% of total metabolites) were detected in the Kenyan infant fecal microbiota. After cultivation started at an initial pH 7.6, the fraction of top bacterial genera (≥ 1% abundant) shared between fermentation and fecal samples was high at 97 ± 5%. However, Escherichia-Shigella, Clostridium sensu stricto 1, Bacteroides and Enterococcus were enriched concomitant with decreased Bifidobacterium abundance. Decreasing the initial pH to 6.9 lead to higher abundance of Bifidobacterium after incubation and increased the compositional similarity of fermentation and fecal samples. Despite similar total metabolite production of all fecal microbiota after cultivation, inter-individual differences in metabolite profiles were apparent. CONCLUSIONS: Protected transport and batch cultivation in host and diet adapted conditions allowed regrowth of the top abundant genera and reproduction of the metabolic activity of fresh Kenyan infant fecal microbiota. The validated batch cultivation protocol can be used to study the composition and functional potential of Kenyan infant fecal microbiota in vitro.
Stable iron (58 Fe) isotopic measurements in Kenyan toddlers during 3 months of iron supplementation demonstrate that half of the iron absorbed is lost.
Increased iron loss may reduce the effectiveness of iron supplementation. The objective of this study was to determine if daily oral iron supplementation increases iron loss, measured using a stable isotope of iron (58 Fe). We enrolled and dewormed 24 iron-depleted Kenyan children, 24-27 months of age, whose body iron was enriched and equilibrated with 58 Fe given at least 1 year earlier. Over 3 months of supplementation (6 mg iron/kg body weight [BW]/day), mean (±SD) iron absorption was 1.10 (±0.28) mg/day. During supplementation, 0.55 (±0.36) mg iron/day was lost, equal to half of the amount of absorbed iron. Supplementation did not increase faecal haem/porphyrin or biomarkers of enterocyte damage and gut or systemic inflammation. Using individual patient data, we examined iron dose, absorption and loss among all available long-term iron isotopic studies of supplementation. Expressed in terms of body weight, daily iron loss was correlated significantly with iron absorption (Pearson's r = 0.66 [95% confidence interval 0.48-0.78]) but not with iron dose (r = 0.16 [95% CI -0.10-0.40]). The results of this study indicate that iron loss is increased with daily oral iron supplementation and may blunt the efficacy of iron supplements in children. This study was registered at ClinicalTrials.gov as NCT04721964.
Iron Absorption in Highly Trained Male Runners: Does it Matter When and Where You Eat Your Iron?
PURPOSE: We examined iron absorption and its regulation during two common scenarios experienced by endurance athletes. Our aims were to: (i) compare the effects of preexercise versus postexercise iron intake on iron absorption; and (ii) compare the impact of training at altitude (1800 m) on iron absorption preexercise. METHODS: Male runners (n = 18) completed three exercise trials over a 5-wk period, each preceded by 24 h of standardized low-iron diets. First, athletes completed two 60-min treadmill running trials at 65% V̇O2max at near sea-level (580 m). In a randomized order, preexercise and postexercise test meals labeled with 4 mg of 57Fe or 58Fe were consumed 30 min before or 30 min after exercise. Then, the same exercise trial was performed after living and training at altitude (~1800 m) for 7 d, with the labeled test meal consumed 30 min preexercise. We collected venous blood samples preexercise and postexercise for markers of iron status and regulation, and 14 d later to measure erythrocyte isotope incorporation. RESULTS: No differences in fractional iron absorption were evident when test meals were consumed preexercise (7.3% [4.4, 12.1]) or postexercise (6.2% [3.1, 12.5]) (n = 18; P = 0.058). Iron absorption preexercise was greater at altitude (18.4% [10.6, 32.0]) than at near sea-level (n = 17; P < 0.001) and hepcidin concentrations at altitude were lower at rest and 3 h postexercise compared with near sea level (P < 0.001). CONCLUSIONS: In an acute setting, preexercise and postexercise iron absorption is comparable if consumed within 30 min of exercise. Preexercise iron absorption increases 2.6-fold at altitude compared with near sea-level, likely due to the homeostatic response to provide iron for enhanced erythropoiesis and maintain iron stores.
Use of genome sequencing to hunt for cryptic second-hit variants: analysis of 31 cases recruited to the 100 000 Genomes Project.
BACKGROUND: Current clinical testing methods used to uncover the genetic basis of rare disease have inherent limitations, which can lead to causative pathogenic variants being missed. Within the rare disease arm of the 100 000 Genomes Project (100kGP), families were recruited under the clinical indication 'single autosomal recessive mutation in rare disease'. These participants presented with strong clinical suspicion for a specific autosomal recessive disorder, but only one suspected pathogenic variant had been identified through standard-of-care testing. Whole genome sequencing (WGS) aimed to identify cryptic 'second-hit' variants. METHODS: To investigate the 31 families with available data that remained unsolved following formal review within the 100kGP, SVRare was used to aggregate structural variants present in <1% of 100kGP participants. Small variants were assessed using population allele frequency data and SpliceAI. Literature searches and publicly available online tools were used for further annotation of pathogenicity. RESULTS: Using these strategies, 8/31 cases were solved, increasing the overall diagnostic yield of this cohort from 10/41 (24.4%) to 18/41 (43.9%). Exemplar cases include a patient with cystic fibrosis harbouring a novel exonic LINE1 insertion in CFTR and a patient with generalised arterial calcification of infancy with complex interlinked duplications involving exons 2-6 of ENPP1. Although ambiguous by short-read WGS, the ENPP1 variant structure was resolved using optical genome mapping and RNA analysis. CONCLUSION: Systematic examination of cryptic variants across a multi-disease cohort successfully identifies additional pathogenic variants. WGS data analysis in autosomal recessive rare disease should consider complex structural and small intronic variants as potentially pathogenic second hits.
Unraveling the molecular interactions between α7 nicotinic receptor and a RIC3 variant associated with backward speech.
Recent work putatively linked a rare genetic variant of the chaperone Resistant to Inhibitors of acetylcholinesterase (RIC3) (NM_024557.4:c.262G > A, NP_078833.3:p.G88R) to a unique ability to speak backwards, a language skill that is associated with exceptional working memory capacity. RIC3 is important for the folding, maturation, and functional expression of α7 nicotinic acetylcholine receptors (nAChR). We compared and contrasted the effects of RIC3G88R on assembly, cell surface expression, and function of human α7 receptors using fluorescent protein tagged α7 nAChR and Förster resonance energy transfer (FRET) microscopy imaging in combination with functional assays and 125I-α-bungarotoxin binding. As expected, the wild-type RIC3 protein was found to increase both cell surface and functional expression of α7 receptors. In contrast, the variant form of RIC3 decreased both. FRET analysis showed that RICG88R increased the interactions between RIC3 and α7 protein in the endoplasmic reticulum. These results provide interesting and novel data to show that a RIC3 variant alters the interaction of RIC3 and α7, which translates to decreased cell surface and functional expression of α7 nAChR.