Miracle-dz/UniFAR-FTUs huggingface dataset:
Development and characterization of a differentiated thyroid cancer cell line resistant to VEGFR-targeted kinase inhibitors.

BACKGROUND Vascular endothelial growth factor-targeted kinase inhibitors have emerged as highly promising therapies for radioiodine-refractory metastatic differentiated thyroid cancer. Unfortunately, drug resistance uniformly develops, limiting their therapeutic efficacies and thereby constituting a major clinical problem. APPROACH AND METHODS To study acquired drug resistance and elucidate underlying mechanisms in this setting, BHP2-7 human differentiated thyroid cancer cells were subjected to prolonged continuous in vitro selection with 18 μM pazopanib, a clinically relevant concentration; acquisition of pazopanib resistance was serially assessed, with the resulting resistant cells thereafter subcloned and characterized to assess potential mechanisms of acquired pazopanib resistance. RESULTS Stable 2- to 4-fold in vitro pazopanib resistance emerged in response to pazopanib selection associated with similar in vitro growth characteristics but with markedly more aggressive in vivo xenograft growth. Selected cells were cross-resistant to sunitinib and to a lesser extent sorafenib but not to MAPK kinase (MEK1/2) inhibition by GSK1120212. Genotyping demonstrated acquisition of a novel activating KRAS codon 13 GGC to GTT (glycine to valine) mutation, consistent with the observed resistance to upstream vascular endothelial growth factor receptor inhibition yet sensitivity to downstream MAPK kinase (MEK1/2) inhibition. CONCLUSIONS Selection of thyroid cancer cells with clinically utilized therapeutics can lead to acquired drug resistance and altered in vivo xenograft behavior that can recapitulate analogous drug resistance observed in patients. This approach has the potential to lead to insights into acquired treatment-related drug resistance in thyroid cancers that can be subjected to subsequent validation in serially collected patient samples and that has the potential to yield preemptive and responsive approaches to dealing with this important clinical problem.
ATLANTIC-DIP: excessive gestational weight gain and pregnancy outcomes in women with gestational or pregestational diabetes mellitus.

CONTEXT Women who have diabetes mellitus during pregnancy are at higher risk of adverse outcomes. Excessive gestational weight gain (GWG) is also emerging as a risk factor for maternofetal complications, and in 2009, the Institute of Medicine published recommendations for appropriate GWG. It is unclear whether excessive GWG confers additional risk to women with diabetes in pregnancy and whether Institute of Medicine recommendations are applicable to this population. OBJECTIVE The objective of this study was to examine whether excessive GWG in pregnancies complicated by diabetes mellitus is associated with higher adverse obstetric outcomes. DESIGN This was an observational study. SETTING The study was conducted at five antenatal centers along the Irish Atlantic seaboard. PARTICIPANTS 802 women with diabetes in pregnancy participated in the study. MAIN OUTCOME MEASURE Maternal outcomes examined included preeclampsia, gestational hypertension, and cesarean delivery. Fetal outcomes included large for gestational age (LGA), macrosomia, and small for gestational age. RESULTS Excessive GWG was noted in 59% of women. In all women, excessive GWG resulted in higher odds for LGA [adjusted odds ratio (aOR) 2.01, 95% confidence intervals 1.24-3.25 in GDM; aOR 3.97, CI 1.85-8.53 in pregestational diabetes mellitus (PGDM)] and macrosomia (aOR 2.17, CI 1.32-3.55 in GDM; aOR 3.58, CI 1.77-7.24 in PGDM). Excessive GWG was also associated with an increased odds for gestational hypertension (aOR 1.72, CI 1.04-2.85) in women with GDM, and treatment with insulin further increased the odds for LGA (aOR 2.80, CI 1.23-6.38) and macrosomia (aOR 5.63, CI 2.16-14.69) in this group. CONCLUSION We show that in the already high-risk settings of both GDM and PGDM, excessive GWG confers an additive risk for LGA birth weight, macrosomia, and gestational hypertension.
Cinacalcet monotherapy in neonatal severe hyperparathyroidism: a case study and review.

CONTEXT Neonatal severe hyperparathyroidism (NSHPT) is a severe form of familial hypocalciuric hypercalcemia characterized by severe hypercalcemia and skeletal demineralization. In most cases, NSHPT is due to biallelic loss-of-function mutations in the CASR gene encoding the calcium-sensing receptor (CaSR), but some patients have heterozygous mutations. Conventional treatment consists of iv saline, bisphosphonates, and parathyroidectomy. OBJECTIVE The aim of this project was to characterize the molecular basis for NSHPT in an affected newborn and to describe the response to monotherapy with cinacalcet. METHODS Clinical and biochemical features were monitored as cinacalcet therapy was initiated and maintained. Genomic DNA was obtained from the proband and parents. The CASR gene was amplified by PCR and sequenced directly. RESULTS The patient was a full-term male who developed hypotonia and respiratory failure soon after birth. He was found to have multiple fractures and diffuse bone demineralization, with a marked elevation in serum ionized calcium (1.99 mmol/L) and elevated serum levels of intact PTH (1154 pg/mL); serum 25-hydroxyvitamin D was low, and fractional excretion of calcium was reduced. The serum calcium level was not reduced by iv saline infusion. Based on an extensive family history of autosomal dominant hypercalcemia, a diagnosis of NSHPT was made, and cinacalcet therapy was initiated with a robust and durable effect. Molecular studies revealed a heterozygous R185Q missense mutation in the CASR in the patient and his father, whereas normal sequences for the CASR gene were present in the patient's mother. CONCLUSIONS We describe the first use of cinacalcet as monotherapy for severe hypercalcemia in a newborn with NSHPT. The rapid and durable response to cinacalcet suggests that a trial of calcimimetic therapy should be considered early in the course of NSHPT.
Effects of pioglitazone on visceral fat metabolic activity in impaired glucose tolerance or type 2 diabetes mellitus.

CONTEXT Excess visceral fat is associated with chronic systemic inflammation and cardiovascular complications. Pioglitazone has been reported to variably influence visceral fat volume; however, its effect on metabolic activity of the visceral fat remains uncharacterized. OBJECTIVE The aim of this study was to assess the effects of pioglitazone on glucose metabolism of fat tissue by using (18)F-fluorodeoxyglucose (FDG)-positron emission tomography (PET) and computed tomography imaging. DESIGN, SETTING, AND PARTICIPANTS FDG-PET and computed tomography imaging were performed in 56 patients with impaired glucose tolerance or type 2 diabetes mellitus; lipid and glycemic profiles and inflammatory biomarkers were obtained in all patients. These patients were randomized to treatment with either pioglitazone or glimepiride for 16 weeks. MAIN OUTCOME MEASURES The metabolic activity of the visceral fat tissues as assessed by FDG uptake was expressed as a target-to-background ratio (TBR) of blood-normalized standardized uptake value. RESULTS The study was completed in 32 pioglitazone-treated and 21 glimepiride-treated patients (40 men and 13 women; mean age, 67.7 ± 8.1 y; body mass index, 25.0 ± 3.6 kg/m(2); glycated hemoglobin, 6.78 ± 0.70%). Both treatments were well-tolerated and comparably improved glycemic control. At baseline, visceral fat exhibited a higher TBR value than subcutaneous fat (0.55 ± 0.14 vs 0.30 ± 0.07, P < .001). Pioglitazone, but not glimepiride, significantly decreased the visceral fat volume (130.5 ± 53.0 to 122.1 ± 51.0 cm(2), P = . 013) and TBR values (0.57 ± 0.16 to 0.50 ± 0.11, P = .007). Neither pioglitazone nor glimepiride treatment showed any effect on the volume or TBR values of subcutaneous fat. After 16 weeks of treatment with pioglitazone, reduction in visceral fat TBR was correlated to the increase in high-density lipoprotein cholesterol levels. CONCLUSIONS Our study indicated that pioglitazone decreased the visceral fat volume and its metabolic activity in patients with impaired glucose tolerance or type 2 diabetes mellitus. The beneficial effects of pioglitazone on visceral fat may be independent of its glucose-lowering effect.
Medroxyprogesterone acetate enhances monocyte-endothelial interaction under flow conditions by stimulating the expression of cell adhesion molecules.

CONTEXT Monocyte adhesion to endothelial cells is an important initial event in atherosclerosis and is partially mediated by adhesion molecule expression on the cell surface. Although estrogens inhibit atherosclerosis development, effects of coadministered progestogen remain controversial. OBJECTIVE We examined the effects of progestogen on cytokine-stimulated human umbilical venous endothelial cell (HUVEC) expression of adhesion molecules. DESIGN In HUVECs, adhesion molecule mRNA levels were measured by real-time PCR. Protein expression was quantified by immunocytochemistry and ELISAs. To mimic the monocyte adherence to endothelial cells, we used a flow chamber system to assess progestogen effects on U937 monocytoid cell adherence to HUVEC monolayers. We also examined the suppression effects of adhesion molecules with small interference RNAs. RESULTS mRNA levels of adhesion molecules in HUVECs treated with medroxyprogesterone acetate (MPA) or 17β-estradiol + MPA were 1.7- to 2.5-fold higher than those in the control. MPA increased the protein expression of E-selectin, P-selectin, and intercellular adhesion molecule-1 compared with that for the control (83.0 ± 0.7, 34.8 ± 1.2, and 5.4 ± 0.0 ng/mL, respectively), whereas other progestogens or 17β-estradiol additive to progestogens did not significantly change expression. MPA significantly increased U937 monocytoid cell adherence compared with the control (56.0 ± 1.5 vs 46.5 ± 3.5 adherent cells per 10 fields) but did not increase adherence to HUVECs with knocked down intercellular adhesion molecule-1. CONCLUSIONS MPA increases cell adhesion molecule expression on HUVECs, causing increased numbers of monocytoid cells to adhere to HUVECs. These MPA effects may be a risk factor for atherogenesis on endothelial cells in postmenopausal women receiving hormone replacement therapy.
The impact of gestational thyroid hormone concentrations on ADHD symptoms of the child.

CONTEXT Maternal hypothyroidism during pregnancy is associated with adverse neuropsychological development in the offspring. OBJECTIVE The objective of the study was to evaluate the effect of maternal thyroid dysfunction during pregnancy on a child's attention-deficit/hyperactivity disorder (ADHD) symptoms. DESIGN, SETTINGS, AND PARTICIPANTS The prospective, population-based Northern Finland Birth Cohort 1986 (9362 pregnancies; 9479 infants) included analysis of maternal TSH, free T4, and thyroid-peroxidase antibodies (TPO-Abs) from early pregnancy samples (5791 women). Teachers evaluated the children's ADHD symptoms at 8 years using the Rutter B2 scale (5131 mother-child pairs), in which a high score indicated probable psychiatric disorders and three questions focused directly on ADHD. MAIN OUTCOME MEASURES The odds ratios (ORs) and 95% confidence intervals (95% CIs) of child having ADHD symptoms and/or a high Rutter B2 score after exposure to increases in maternal TSH levels (after logarithmic transformation), low free T4 levels, and TPO-Ab positivity was tested with logistic regression, adjusting for maternal/family covariates. Data were stratified by the child's gender due to interaction. RESULTS Among girls the odds of inattention (OR 1.18, 95% CI 1.02-1.37), high Rutter B2 total score (OR 1.23, 95% CI 1.03-1.48), and combined ADHD symptoms (OR 1.39, 95% CI 1.07-1.80) significantly increased with every natural log increase in maternal TSH concentrations. Such findings were not evident in boys. No associations were seen between ADHD symptoms and low maternal free T4 levels or TPO-Ab positivity. CONCLUSIONS Increases in maternal TSH in early pregnancy showed weak but significant association with girls' ADHD symptoms.
Treadmill running reduces parathyroid hormone concentrations during recovery compared with a nonexercising control group.

CONTEXT Lower PTH concentrations reported in the hours after acute, endurance exercise compared with preexercise levels might be influenced by factors such as circadian fluctuations. OBJECTIVE The objective of the study was to compare postexercise PTH concentrations with a nonexercising control group. DESIGN AND SETTING A laboratory-based study with a crossover design, comparing a 60-minute (at 10:30 am) bout of treadmill running at 65% of the maximal rate of oxygen uptake (exercise) with semirecumbent rest (CON). Blood samples were obtained immediately before (baseline 10:15 am) and after (11:30 am) exercise and during recovery (12:30 am, 1:30 pm, and 2:15 pm). PARTICIPANTS Ten physically active men (mean ± 1 SD, age 26 ± 5 y; body mass 78.3 ± 5.8 kg; maximal rate of oxygen uptake 57.3 ± 6.9 mL/kg(-1) · min(-1)) participated in the study. MAIN OUTCOME MEASURES PTH, albumin-adjusted calcium, and phosphate concentrations were measured. RESULTS PTH concentrations increased (+85%, P < .01) during exercise and were higher than in CON immediately at the end of exercise (4.5 ± 1.9 vs 2.6 ± 0.9 pmol/L(-1), P < . 05). In the postexercise period (12:30-2:15 pm), PTH was not different compared with baseline but was lower compared with CON at 1:30 pm (-22%; P < .01) and tended to be lower at both 12:30 pm (-12%; P = .063) and 2:15 pm (-13%; P = .057). Exercise did not significantly affect the albumin-adjusted calcium concentrations, whereas phosphate was higher than CON immediately after exercise (1.47 ± 0.17 vs 1.03 ± 0.17 pmol/L(-1), P < . 001) and was lower at 1:30 pm (-16%: P < .05). CONCLUSIONS Lower PTH concentrations after acute endurance running compared with a rested control condition suggest a true effect of exercise.
Treatment of Drug Addiction in Traumatised Refugees

The comorbidity of post-traumatic stress disorder (PTSD) and drug addiction is quite often overlooked in refugees. However, the simultaneous treatment of both disorders is of elemental importance for a positive outcome in addicted and traumatised refugees. Furthermore, mutual misinterpretations of habits, behaviours and reactions through negligence of the distinct sociocultural context of patient and clinician often leads to unfavourable developments. These observations are exemplified in this case report.
Feeling like a group after a natural disaster: Common ingroup identity and relations with outgroup victims among majority and minority young children.

We conducted a field study to test whether the common ingroup identity model (Gaertner & Dovidio, 2000, reducing intergroup bias: The common ingroup identity model. Philadelphia, PA: Psychology Press) could be a useful tool to improve intergroup relations in the aftermath of a natural disaster. Participants were majority (Italian) and minority (immigrant) elementary school children (N = 517) living in the area struck by powerful earthquakes in May 2012. Results revealed that, among majority children, the perceived external threat represented by the earthquake was associated with greater perceptions of belonging to a common ingroup including both ingroup and outgroup. In turn, heightened one-group perceptions were associated with greater willingness to meet and help outgroup victims, both directly and indirectly via more positive outgroup attitudes. Among immigrant children, perceived disaster threat was not associated with any of the dependent variables; one-group perceptions were positively associated with outgroup attitudes, helping and contact intentions towards outgroup victims. Thus, one-group perceptions after a natural disaster may promote more positive and supporting relations between the majority and the minority group. We discuss the theoretical and practical implications of the findings.
Testosterone, dihydrotestosterone, and incident cardiovascular disease and mortality in the cardiovascular health study.

CONTEXT Low testosterone (T) is associated with prevalent cardiovascular disease (CVD) and mortality. DHT, a more potent androgen, may also be associated with CVD and mortality, but few studies have examined this. OBJECTIVE The study objective was to examine whether T and DHT are risk factors for incident CVD and mortality. DESIGN In a longitudinal cohort study, we evaluated whether total T, calculated free T (cFT), DHT, and calculated free DHT were associated with incident CVD and mortality in men in the Cardiovascular Health Study (mean age 76, range 66-97 years) who were free of CVD at the time of blood collection. MAIN OUTCOME The main outcomes were incident CVD and all-cause mortality. RESULTS Among 1032 men followed for a median of 9 years, 436 incident CVD events and 777 deaths occurred. In models adjusted for cardiovascular risk factors, total T and cFT were not associated with incident CVD or all-cause mortality, whereas DHT and calculated free DHT had curvilinear associations with incident CVD (P < .002 and P = .04, respectively) and all-cause mortality (P < .001 for both). CONCLUSIONS In a cohort of elderly men, DHT and calculated free DHT were associated with incident CVD and all-cause mortality. Further studies are needed to confirm these results and to clarify the underlying physiologic mechanisms.
Can Patients with Unilateral Neglect following Stroke Drive Electrically Powered Wheelchairs?

People with unilateral neglect tend to have persisting disabilities and an increased probability of dependence following stroke. This preliminary research was designed to evaluate the potential use of an indoor electrically powered wheelchair with two people with unilateral neglect. Two male participants with a single-incident right hemisphere lesion were recruited; they were 32 days and 20 days post-stroke. Both had evidence of unilateral neglect on the Behavioural Inattention Test. An ABA single-subject experimental design was used, with a battery of measures administered every weekday for 6 weeks. The measures were the left collisions made and the time taken when negotiating an obstacle course in a powered wheelchair, and two tabletop tasks: the Star Cancellation Test and the Baking Tray Task. During the intervention phase (B), the participants were given 30 minutes of powered wheelchair training every weekday for 2 weeks. Both participants made marked improvements in driving accuracy by driving the wheelchair through an obstacle course for about 5 minutes each weekday for 2 weeks during phase A1. This improvement in driving accuracy unexpectedly occurred before the intervention phase (B), when the powered wheelchair training was introduced. Negligible changes in driving accuracy were seen during and after training had commenced. This suggests that negotiating the obstacle course, which was used as a measure, was acting as a form of treatment. The changes seen in the measures of unilateral neglect suggested that the participants learned to drive the powered wheelchair despite persisting neglect. Many patients with unilateral neglect are not given the chance to drive an electrically powered wheelchair owing to concerns about safety. This preliminary study suggests not only that this patient group can learn to drive indoors safely but also that this may be achieved with minimal therapeutic intervention. Further work needs to be carried out in this area.
Only one small sin: How self‐construal affects self‐control

Past research has shown that self-construal can influence self-control by reducing interdependent people's impulsivity in the presence of peers. We broaden these findings by examining the hypothesis that an interdependent (vs. independent) self-construal fosters self-control even in the absence of peers and for non-impulsive decisions. We further explore whether this effect could be mediated by the more interrelated (vs. isolated) processing style of interdependent (vs. independent) people. Such an interrelated (vs. isolated) processing style of temptations makes the impact of a single temptation more salient and can thereby increase self-control. Study 1 demonstrated that more interdependent participants show more self-control behaviour by refraining from chocolate consumption to secure a monetary benefit. Studies 2a and 2b highlighted a link between self-construal and trait self-control via the processing of temptations. Study 3 suggested that an interrelated (vs. isolated) perspective on temptations could mediate the effect of (primed) self-construal on self-control. Taken together, self-construal shapes self-control across various decision contexts.
Serum 25-hydroxyvitamin D and incidence of diabetes in elderly people: the PRO.V.A. study.

CONTEXT Increasing research has shown that low levels of serum 25-hydroxyvitamin (25OHD) predict the onset of diabetes, but no research is available on this issue in elderly people. OBJECTIVE Our objective was to examine whether low serum levels of 25OHD are associated with a higher risk of incident type 2 diabetes over a lengthy follow-up in a representative group of elderly people. DESIGN AND SETTING This was a population-based cohort study as part of the Progetto Veneto Anziani (Pro.V.A.) Study over a follow-up of 4.4 years in the general community. PARTICIPANTS PARTICIPANTS included 2227 participants (1728 with follow-up visits and 499 died during the follow-up) over 65 years of age without diabetes at baseline, of 2352 initially included. MAIN OUTCOME MEASURE The main outcome measure was incident diabetes. RESULTS There were no baseline differences in known factors for the onset of diabetes (body mass index, waist circumference, total cholesterol, renal function, and hemoglobin A1c levels) between the groups with different serum 25OHD levels (≤ 25, 25-50, 50-75, and ≥ 75 nmol/L). Over a 4.4-year follow-up, 291 individuals developed diabetes, with an incidence of 28 events per 1000 person-years. No significant difference in the incidence of diabetes emerged between the baseline 25OHD groups. Cox's regression analysis, adjusted for potential confounders, revealed no relationship between low vitamin D levels and incident diabetes during the follow-up (hazard ratio [HR] = 1.05, 95% confidence interval [CI] = 0.76-1.45, P = .77; HR = 1.44, 95% CI = 0.95-1.98, P = .12; and HR = 1.37, 95% CI = 0.87-2.16, P = .17 for those with 25OHD ≤25, 25-50, and 50-75 nmol/L, respectively). CONCLUSION Baseline serum concentrations of 25OHD were not associated with the incidence of diabetes in community-dwelling elderly people over a follow-up of 4.4 years.