Background
There is a considerable need to incorporate biomarkers of resistance to new antiandrogen agents in the management of castration‐resistant prostate cancer (CRPC).
Methods
We conducted a ...phase II trial of enzalutamide in first‐line chemo‐naïve asymptomatic or minimally symptomatic mCRPC and analyzed the prognostic value of TMPRSS2‐ERG and other biomarkers, including circulating tumor cells (CTCs), androgen receptor splice variant (AR‐V7) in CTCs and plasma Androgen Receptor copy number gain (AR‐gain). These biomarkers were correlated with treatment response and survival outcomes and developed a clinical–molecular prognostic model using penalized cox‐proportional hazard model. This model was validated in an independent cohort.
Results
Ninety‐eight patients were included. TMPRSS2‐ERG fusion gene was detected in 32 patients with no differences observed in efficacy outcomes. CTC detection was associated with worse outcome and AR‐V7 in CTCs was associated with increased rate of progression as best response. Plasma AR gain was strongly associated with an adverse outcome, with worse median prostate specific antigen (PSA)‐PFS (4.2 vs. 14.7 m; p < 0.0001), rad‐PFS (4.5 vs. 27.6 m; p < 0.0001), and OS (12.7 vs. 38.1 m; p < 0.0001). The clinical prognostic model developed in PREVAIL was validated (C‐Index 0.70) and the addition of plasma AR (C‐Index 0.79; p < 0.001) increased its prognostic ability. We generated a parsimonious model including alkaline phosphatase (ALP); PSA and AR gain (C‐index 0.78) that was validated in an independent cohort.
Conclusions
TMPRSS2‐ERG detection did not correlate with differential activity of enzalutamide in first‐line mCRPC. However, we observed that CTCs and plasma AR gain were the most relevant biomarkers.
Status of folate in healthy children in Almeria Gómez-Bueno, Sara; Vázquez-López, Maria A.; García-Escobar, Iciar ...
European journal of pediatrics,
06/2021, Letnik:
180, Številka:
6
Journal Article
Recenzirano
The objective of this study is to establish reference values for folic acid in a healthy population of children aged 4–11 years and to examine related epidemiological, dietary and analytical factors. ...A cross-sectional study of 658 healthy children aged 4–11 years was made. Epidemiological, socioeconomic and dietary variables were analysed, the BMI Z-score was obtained, levels of serum folate and serum vitamin B
12
were determined and haematological, iron status and erythropoietic activity parameters were examined. The study data were analysed by non-parametric tests and linear multiple regression. The mean folate value was 8.6 ± 4.6 ng/mL (95% reference interval: 2.8–20 ng/mL). A level < 3 ng/mL (5th percentile) was considered as folate deficiency (4.6% of subjects). No child reported symptoms related to this deficiency. Folate values were significantly lower with age (
p
< 0.01), low NSE and low parental educational level (
p
: 0.0001). No relationship was found between folates and the analytical variables. According to multivariate linear regression, the variables significantly associated with serum folate were age, socioeconomic level and vitamin B
12
.
Conclusions:
Serum folate levels in healthy school children are described. Age, socioeconomic level and serum vitamin B
12
are factors associated with folate status. Specific cut-off values for a paediatric population should be defined.
What is Known:
•
Folic acid is an essential micronutrient for optimal growth and development; its deficit is associated with adverse health effects.
•
The studies on their status and deficit are not comparable due to a lack of agreement on appropriate indicators and reference values.
What is New:
•
This study reports the levels of serum folate in a large population of healthy schoolchildren, with strict inclusion criteria in a developed country and identifies the associated sociodemographic, dietary and analytical (vitamin B12, iron parameters and erythropoietic activity) factors, avoiding potential confusion.
OBJECTIVE:To assess the usefulness of the “Candida score” (CS) for discriminating between Candida species colonization and invasive candidiasis (IC) in non-neutropenic critically ill patients. A rate ...of IC <5% in patients with CS <3 was the primary end point.
DESIGN:Prospective, cohort, observational study.
SETTING:Thirty-six medical-surgical intensive care units of Spain, Argentina, and France.
PATIENTS:A total of 1,107 non-neutropenic adult intensive care unit patients admitted for at least 7 days between April 2006 and June 2007.
MEASUREMENTS AND MAIN RESULTS:Clinical data, surveillance cultures for fungal growth, and serum levels of (1–3)-beta-d-glucan and anti-Candida antibodies (in a subset of patients) were recorded. The CS was calculated as follows (variables coded as absent = 0, present = 1)total parenteral nutrition ×1, plus surgery ×1, plus multifocal Candida colonization ×1, plus severe sepsis ×2. A CS ≥3 accurately selected patients at high risk for IC. The colonization index was registered if ≥0.5. The rate of IC was 2.3% (95% confidence interval CI 1.06–3.54) among patients with CS <3, with a linear association between increasing values of CS and IC rate (p ≤ 0.001). The area under the receiver operating characteristic curve for CS was 0.774 (95% CI 0.715–0.832) compared with 0.633 (95% CI 0.557–0.709) for CI. (1–3)-Beta-d-glucan was also an independent predictor of IC (odds ratio 1.004, 95% CI 1.0–1.007). The relative risk for developing IC in colonized patients without antifungal treatment was 6.83 (95% CI 3.81–12.45).
CONCLUSIONS:In this cohort of colonized patients staying >7 days, with a CS <3 and not receiving antifungal treatment, the rate of IC was <5%. Therefore, IC is highly improbable if a Candida-colonized non-neutropenic critically ill patient has a CS <3.
Alzheimer’s disease (AD) is one of the most frequent causes of death and disability worldwide and has a significant clinical and socioeconomic impact. In the search for novel therapeutic strategies, ...serotonin 5-HT6 receptor (5-HT6R) has been proposed as a promising drug target for cognition enhancement in AD. This manuscript reviews the compelling evidence for the implication of this receptor in learning and memory processes. We have summarized the current status of the medicinal chemistry of 5-HT6R antagonists and the encouraging preclinical findings that demonstrate their significant procognitive behavioral effects in a number of learning paradigms, probably acting through modulation of multiple neurotransmitter systems and signaling pathways. The results of the ongoing clinical trials are eagerly awaited to shed some light on the validation of 5-HT6R antagonists as a new drug class for the treatment of symptomatic cognitive impairment in AD, either as stand-alone therapy or in combination with established agents.
Hypocalcemia is one of the most common complications after total thyroidectomy. Recently, indocyanine green (ICG) angiography of the parathyroid glands (PGs) has been suggested as a reliable tool for ...predicting postoperative hypocalcemia. The aim of our study was to evaluate the performance of a simple quantitative score based on ICG angiography of the PGs (4-ICG score) for predicting postoperative hypocalcemia.
Thirty nine consecutive patients who underwent total thyroidectomy for multinodular goiter were included. For each patient, the 4-ICG score was calculated, adding the individual viability value of the four PGs. Discrimination and correlation analyses were performed.
In 32/39 patients, the four PGs were identified. Patients with postoperative hypocalcemia (n = 6, 19%) had a lower 4-ICG score (2.5 1.8–3.3 vs. 4.0 3.0–6.0; p = 0.003). The 4-ICG score showed good discrimination in terms of predicting postoperative hypocalcemia (AUC = 0.875 (0.710–0.965); p = 0.001) and a good correlation with postoperative parathyroid function.
The 4-ICG score predicts postoperative hypocalcemia and correlates well with postoperative parathyroid function in patients undergoing total thyroidectomy for multinodular goiter.
•The 4-ICG score had good discrimination in predicting postoperative hypocalcemia.•A 4-ICG score > 3 had high negative predictive value for postoperative hypocalcemia.•This score may be useful in identifying patients eligible for early discharge.
The prevalence of type 2 diabetes mellitus (T2DM) is rising in the general population. This increase leads to higher cardiovascular risk, with cardiovascular diseases being the main cause of death in ...diabetic patients. New therapeutic weapons for diabetes mellitus are now available. Sodium-glucose cotransporter type 2 (SGLT2) inhibitors are novel drugs that are widely used due to their strong benefit in preventing hospitalization for decompensated heart failure and renal protection, limiting the deterioration of the glomerular filtration rate, independently of the presence of diabetes mellitus. These drugs have also shown benefit in the prevention of atherosclerotic cardiovascular events and cardiovascular mortality in diabetic patients with established cardiovascular disease. On the other hand, patients with T2DM usually present a high burden of associated comorbidities. Some of these entities are arterial hypertension, dyslipidemia, hyperuricemia, obesity, non-alcoholic fatty liver disease (NAFLD), polycystic ovary syndrome (PCOS), vascular aging, respiratory diseases, or osteoporosis and fractures. Healthcare professionals should treat these patients from an integral point of view, and not manage each pathology separately. Therefore, as potential mechanisms of SGLT2 inhibitors in metabolic diseases have not been fully reviewed, we conducted this review to know the current evidence of the use and effect of SGLT2 inhibitors on these metabolic diseases.The prevalence of type 2 diabetes mellitus (T2DM) is rising in the general population. This increase leads to higher cardiovascular risk, with cardiovascular diseases being the main cause of death in diabetic patients. New therapeutic weapons for diabetes mellitus are now available. Sodium-glucose cotransporter type 2 (SGLT2) inhibitors are novel drugs that are widely used due to their strong benefit in preventing hospitalization for decompensated heart failure and renal protection, limiting the deterioration of the glomerular filtration rate, independently of the presence of diabetes mellitus. These drugs have also shown benefit in the prevention of atherosclerotic cardiovascular events and cardiovascular mortality in diabetic patients with established cardiovascular disease. On the other hand, patients with T2DM usually present a high burden of associated comorbidities. Some of these entities are arterial hypertension, dyslipidemia, hyperuricemia, obesity, non-alcoholic fatty liver disease (NAFLD), polycystic ovary syndrome (PCOS), vascular aging, respiratory diseases, or osteoporosis and fractures. Healthcare professionals should treat these patients from an integral point of view, and not manage each pathology separately. Therefore, as potential mechanisms of SGLT2 inhibitors in metabolic diseases have not been fully reviewed, we conducted this review to know the current evidence of the use and effect of SGLT2 inhibitors on these metabolic diseases.
Current antidiabetic drugs have severe side effects, which may be minimized by new selective molecules that strongly inhibit α-glucosidase and weakly inhibit α-amylase. We have synthesized novel ...alkoxy-substituted xanthones and imidazole-substituted xanthones and have evaluated them for their in silico and in vitro α-glucosidase and α-amylase inhibition activity. Compounds
, and
promoted higher α-glucosidase inhibition (IC
= 16.0, 12.8, and 4.0 µM, respectively) and lower α-amylase inhibition (IC
= 76.7, 68.1, and >200 µM, respectively) compared to acarbose (IC
= 306.7 µM for α-glucosidase and 20.0 µM for α-amylase). Contrarily, derivatives
and
showed higher α-amylase inhibition (IC
= 5.4 and 8.7 µM, respectively) and lower α-glucosidase inhibition (IC
= 232.7 and 145.2 µM, respectively). According to the structure-activity relationship, attaching 4-bromobutoxy or 4'-chlorophenylacetophenone moieties to the 2-hydroxy group of xanthone provides higher α-glucosidase inhibition and lower α-amylase inhibition. In silico studies suggest that these scaffolds are key in the activity and interaction of xanthone derivatives. Enzymatic kinetics studies showed that
,
, and
are mainly mixed inhibitors on α-glucosidase and α-amylase. In addition, drug prediction and ADMET studies support that compounds
,
, and
are candidates with antidiabetic potential.
Reticulocyte hemoglobin content (CHr) is considered an indicator of functional iron deficiency, but is understudied in children. The goals of this study are to determine the reference intervals for ...CHr in healthy children, and their relation with iron parameters, erythropoiesis, and individual conditions. A total of 902 children without iron deficiency, aged 1 to 11 years were analyzed in a cross-sectional study. Besides a physical examination of the subjects and a questionnaire completed by their parents, the complete blood count, serum transferrin receptor, ferritin, transferrin saturation, erythrocyte protoporphyrin, serum erythropoietin, C-reactive protein, and CHr levels were measured. Changes in CHr, iron status, and erythropoiesis at different age intervals were analyzed and linear multiple regression was used to identify the factors that determine CHr variability. Mean value obtained for CHr was 30.9±1.8 pg (P2.5-P97.5: 26.9 to 34.3 pg), but the influence of age on CHr (the values increased with age) and on the iron parameters justified the establishment of different reference ranges. In addition to age, nutritional status, hematologic measurements, reticulocytes, transferrin saturation, and erythrocyte protoporphyrin accounted for 39% of CHr variability.
Total fruit consumption is important for cardiovascular disease prevention, but also the variety and form in which is consumed. The aim of the study was to assess the associations between total ...fruit, subgroups of fruits based on their color and fruit juices consumption with different cardiometabolic parameters.
A total of 6633 elderly participants (aged 55–75 years) with metabolic syndrome from the PREDIMED-Plus study were included in this analysis. Fruit and fruit juice consumption was assessed using a food frequency questionnaire. Linear regression models were fitted to evaluate the association between exposure variables (total fruit, subgroups based on the color, and fruit juices) and different cardiometabolic risk factors. Individuals in the highest category of total fruit consumption (≥3 servings/d) had lower waist circumference (WC) (β = −1.04 cm; 95%CI:-1.81, −0.26), fasting glucose levels (β = −2.41 mg/dL; 95%CI(-4.19, −0.63) and LDL-cholesterol (β = −4.11 mg/dL; 95%CI:-6.93, −1.36), but, unexpectedly, higher systolic blood pressure (BP) (β = 1.84 mmHg; 95%CI: 0.37, 3.30) and diastolic BP (β = 1.69 mmHg; 95%CI:0.83, 2.56) when compared to those in the lowest category of consumption (<1 servings/d). Participants consuming ≥1 serving/day of total fruit juice had lower WC (β = −0.92 cm; 95%CI:-1.56, −0.27) and glucose levels (β = −1.59 mg/dL; 95%CI:-2.95, −0.23) than those consuming <1 serving/month. The associations with cardiometabolic risk factors differed according to the color of fruits.
Fruit consumption is associated with several cardiometabolic risk factors in Mediterranean elders with metabolic syndrome. The associations regarding BP levels could be attributed, at least partially, to reverse causality bias inherent to the cross-sectional design of the study.
•Total fruit consumption is inversely associated with cardiometabolic risk factors.•At least 1 serving/day of fruit juice is associated with low waist circumference.•At least 1 serving/day of fruit juice is associated with low glucose levels.•Cardiometabolic risk factors differed according to the color of fruits.
Summary
Transcriptional regulators based on CRISPR architecture expand our ability to reprogramme endogenous gene expression in plants. One of their potential applications is the customization of ...plant metabolome through the activation of selected enzymes in a given metabolic pathway. Using the previously described multiplexable CRISPR activator dCasEV2.1, we assayed the selective enrichment in Nicotiana benthamiana leaves of four different flavonoids, namely, naringenin, eriodictyol, kaempferol, and quercetin. After careful selection of target genes and guide RNAs combinations, we created successful activation programmes for each of the four metabolites, each programme activating between three and seven genes, and with individual gene activation levels ranging from 4‐ to 1500‐fold. Metabolic analysis of the flavonoid profiles of each multigene activation programme showed a sharp and selective enrichment of the intended metabolites and their glycosylated derivatives. Remarkably, principal component analysis of untargeted metabolic profiles clearly separated samples according to their activation treatment, and hierarchical clustering separated the samples into five groups, corresponding to the expected four highly enriched metabolite groups, plus an un‐activated control. These results demonstrate that dCasEV2.1 is a powerful tool for re‐routing metabolic fluxes towards the accumulation of metabolites of interest, opening the door for the custom‐made design of metabolic contents in plants.
