Miracle-dz/UniFAR-FTUs huggingface dataset:
The impact of database restriction on pharmacovigilance signal detection of selected cancer therapies

Background: The aim of this study was to investigate whether database restriction can improve oncology drug pharmacovigilance signal detection performance. Methods: We used spontaneous adverse event (AE) reports in the United States (US) Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database. Positive control (PC) drug medical concept (DMC) pairs were selected from safety information not included in the product’s first label but subsequently added as label changes. These medical concepts (MCs) were mapped to the Medical Dictionary for Regulatory Activities (MedDRA) preferred terms (PTs) used in FAERS to code AEs. Negative controls (NC) were MCs with circumscribed PTs not included in the corresponding US package insert (USPI). We calculated shrinkage-adjusted observed-to-expected (O/E) reporting frequencies for the aforementioned drug–PT pairs. We also formulated an adjudication framework to calculate performance at the MC level. Performance metrics [sensitivity, specificity, positive and negative predictive value (PPV, NPV), signal/noise (S/N), F and Matthews correlation coefficient (MCC)] were calculated for each analysis and compared. Results: The PC reference set consisted of 11 drugs, 487 PTs, 27 MCs, 37 drug–MC combinations and 638 drug–event combinations (DECs). The NC reference set consisted of 11 drugs, 9 PTs, 5 MCs, 40 drug–MC combinations and 67 DECs. Most drug–event pairs were not highlighted by either analysis. A small percentage of signals of disproportionate reporting were lost, more noise than signal, with no gains. Specificity and PPV improved whereas sensitivity, NPV, F and MCC decreased, but all changes were small relative to the decrease in sensitivity. The overall S/N improved. Conclusion: This oncology drug restricted analysis improved the S/N ratio, removing proportionately more noise than signal, but with significant credible signal loss. Without broader experience and a calculus of costs and utilities of correct versus incorrect classifications in oncology pharmacovigilance such restricted analyses should be optional rather than a default analysis.
Lipid peroxidation and parathyroid hormone influence the cytosolic calcium levels of erythrocytes in peritoneal dialysis patients.

BACKGROUND The aim of this study was to examine the alterations in calcium and lipid peroxidation in red blood cells (RBCs) and serum samples of continuous ambulatory peritoneal dialysis (CAPD) patients. We also investigated the relationship between parathyroid hormone (PTH) and calcium homeostasis in this study. METHODS For this purpose, routine blood counts and blood chemistry were analyzed by standard laboratory procedures in serum samples. The concentration of TBARS was measured in erythrocytes and serum samples. RBC calcium was measured by Fura-2AM in a spectrofluorometer. RESULTS In CAPD patients, hemoglobin, albumin, and high density lipoprotein cholesterol levels were lower, but glucose, very low density lipoprotein cholesterol, triglyceride, magnesium, PTH, sensitive C-reactive protein, and uric acid levels were higher than the controls. Thiobarbituric acid-reactive substance (TBARS) levels in RBCs and serum samples and cytosolic calcium in RBCs were all found to be significantly increased in CAPD patients compared to control subjects. Multiple regression analysis showed that RBC TBARS and serum PTH were the independent predictors of RBC calcium in our study. CONCLUSIONS Our results confirm that oxidative stress is an important risk factor for CAPD. The results of multiple regression analysis suggest that RBC calcium was affected by both increased levels of TBARS and PTH.
High-intensity focused ultrasound ablation of thyroid nodules: first human feasibility study.

BACKGROUND Thyroid surgery is common, but complications may occur. High-intensity focused ultrasound (HIFU) is a minimally invasive alternative to surgery. We hypothesized that an optimized HIFU device could be safe and effective for ablating benign thyroid nodules without affecting neighboring structures. METHODS In this open, single-center feasibility study, 25 patients were treated with HIFU with real-time ultrasound imaging 2 weeks before a scheduled thyroidectomy for multinodular goiter. Thyroid ultrasonography imaging, thyroid function, were evaluated before and after treatment. Adverse events were carefully recorded. Each patient received HIFU for one thyroid nodule, solid or mixed, with mean diameter ≥8 mm, and no suspicion of malignancy. The HIFU device was progressively adjusted with stepwise testing. The energy level for ablation ranged from 35 to 94 J/pulse for different groups of patients. One pathologist examined all removed thyroids. RESULTS Three patients discontinued treatment due to pain or skin microblister. Among the remaining 22 patients, 16 showed significant changes by ultrasound. Macroscopic and histological examinations showed that all lesions were confined to the targeted nodule without affecting neighboring structures. At pathological analysis, the extent of nodule destruction ranged from 2% to 80%. Five out of 22 patients had over 20% pathological lesions unmistakably attributed to HIFU. Seventeen cases had putative lesions including nonspecific necrosis, hemorrhage, nodule detachment, cavitations, and cysts. Among these 17 cases, 12 had both ultrasound changes and cavitation at histology that may be expected for an HIFU effect. In the last three patients ablated at the highest energy level, significant ultrasound changes and complete coagulative necrosis were observed in 80%, 78%, and 58% of the targeted area, respectively. There were no major complications of ablation. CONCLUSION This study showed the potential efficacy of HIFU for human thyroid nodule ablation. Lesions were clearly visible by histology and ultrasound after high energy treatments, and safety and tolerability were good. We identified a power threshold for optimal necrosis of the target thyroid tissue. Further studies are ongoing to assess nodule changes at longer follow-up times.
Bladder afferent sensitivity in wild‐type and TRPV1 knockout mice

Understanding bladder afferent pathways may reveal novel targets for therapy of lower urinary tract disorders such as overactive bladder syndrome and cystitis. Several potential candidate molecules have been postulated as playing a significant role in bladder function. One such candidate is the transient receptor potential vanilloid 1 (TRPV1) ion channel. Mice lacking the TRPV1 channel have altered micturition thresholds suggesting that TRPV1 channels may play a role in the detection of bladder filling. The aim of this study was therefore to investigate the role of TRPV1 receptors in controlling bladder afferent sensitivity in the mouse using pharmacological receptor blockade and genetic deletion of the channel. Multiunit afferent activity was recorded in vitro from bladder afferents taken from wild‐type (TRPV+/+) mice and knockout (TRPV1−/−) mice. In wild‐type preparations, ramp distension of the bladder to a maximal pressure of 40 mmHg produced a graded increase in afferent activity. Bath application of the TRPV1 antagonist capsazepine (10 μm) caused a significant attenuation of afferent discharge in TRPV1+/+ mice. Afferent responses to distension were significantly attenuated in TRPV1−/− mice in which sensitivity to intravesical hydrochloric acid (50 mm) and capsaicin (10 μm) were also blunted. Altered mechanosensitivity occurred in the absence of any changes in the pressure–volume relationship during filling indicating that this was not secondary to a change in bladder compliance. Single‐unit analysis was used to classify individual afferents into low‐threshold and high‐threshold fibres. Low threshold afferent responses were attenuated in TRPV1−/− mice compared to the TRPV1+/+ littermates while surprisingly high threshold afferent sensitivity was unchanged. While TRPV1 channels are not considered to be mechanically gated, the present study demonstrates a clear role for TRPV1 in the excitability of particularly low threshold bladder afferents. This suggests that TRPV1 may play an important role in normal bladder function.
Bullying and symptoms of depression in chilean middle school students.

BACKGROUND The goal of this study was to assess the association between bullying and symptoms of depression among middle school students in Chile. METHODS Secondary data analysis of Chile's 2004 Global School-Based Health Survey. RESULTS A total of 8131 middle school students participated in the study. Forty-seven percent of students reported having been bullied in the past month and 30% reported having been sad and hopeless for 2 or more weeks in the past year. Students in the seventh and eighth grades were more likely to report having been bullied in the past month than students in ninth grade. Ninth grade students reported higher levels of loneliness, difficulty sleeping, and suicidal thoughts than students in the seventh and eighth grades. Boys were more likely than girls to report being bullied in the past month, but girls were more likely than boys to report symptoms of depression, such as prolonged feelings of sadness and hopelessness, loneliness, difficulty sleeping, and suicidal thoughts. Students who reported being bullied in the past month were more likely than nonbullied students to report symptoms of depression. A higher number of days of being bullied in the past month was associated with a statistically significant increase in reported rates of sadness and hopelessness (p < .001). CONCLUSIONS Bullying is common among middle school children in Chile, and bullying and symptoms of depression are strongly linked. This finding is consistent with studies of bullying and depression in adolescents from other parts of the world.
Molecular Cloning and Characterization of a New Multispecific Organic Anion Transporter from Rat Brain*

A cDNA encoding the new member of the multispecific organic anion transporter family, OAT3, was isolated by the reverse transcription-polymerase chain reaction cloning method. Degenerate primers were designed based on the sequences conserved among OAT1, OAT2, and organic cation transporter 1 (OCT1), and reverse transcription-polymerase chain reaction was performed using rat brain poly(A)+ RNA. The 536-amino acid protein sequence encoded by OAT3 showed 49, 39, and 36% identity to those of OAT1, OAT2, and OCT1, respectively. Northern blot analysis revealed that rat OAT3 mRNA is expressed in the liver, brain, kidney, and eye. When expressed in Xenopus laevis oocytes, OAT3 mediated the uptake of organic anions, such as p-aminohippurate (K m = 65 μm), ochratoxin A (K m = 0.74 μm), and estrone sulfate (K m = 2.3 μm) and a cationic compound, cimetidine. OAT3-mediated uptake of [3H]estrone sulfate was sodium-independent. para-Aminohippuric acid, estrone sulfate or ochratoxin A did not show anytrans-stimulatory effect on either influx or efflux of [3H]estrone sulfate via OAT3. Organic anions such as sulfobromophthalein, probenecid, indocyanine green, bumetanide, piroxicam, furosemide, azidodeoxythymidine, 4,4′-diisothiocyanostilbene-3,3′-disulfonic acid, and benzylpenicillin inhibited OAT3-mediated estrone sulfate uptake, while ouabain and digoxin did not. Organic cations such as tetraethylammonium, guanidine, verapamil, and quinidine did not interact with OAT3. Acidic metabolites of neurotransmitters derived from dopamine, epinephrine, norepinephrine, and serotonin inhibited the uptake of estrone sulfate via OAT3. These results suggest an important role of OAT3 in the excretion/detoxification of endogenous and exogenous organic anions, especially from the brain.
Copper toxicosis and tolerance in the rat. I‐changes in copper content of the liver and kidney

Rats can tolerate toxic copper diets; the extent of this adaptation and the changes that take place in the liver and kidney with respect to copper are studied. Rats were fed diets containing 3000–6000 mg/kg copper for 15 weeks and groups were killed at regular intervals. Their livers and kidneys were examined for pathological changes and for their copper content. Liver copper rose rapidly in the 3000 mg/kg trial to 4780 £ 636 μg/g copper between 4 and 5 weeks with marked liver damage. Stainable copper protein was present at 2 weeks in the hepatocytes but had disappeared by 5 weeks. Liver copper subsequently fell with recovery by 15 weeks. Kidney copper rose to plateau from 4 weeks. Stainable copper protein was present from 2 weeks in the cells of the proximal tubules and was apparently excreted. Tubular necrosis occurred at 4–5 weeks followed by regeneration. In the 6000 mg/kg trial the toxicosis was prolonged. Copper toxicosis in the rat can be a temporary phenomenon during the transformation of copper protein synthesis in the liver from a stainable to a non stainable form. Adaptation occurs after the removal of excess liver copper, facilitated probably by renal excretion, and the animals become tolerant.
Anti-IgE Therapy with Omalizumab Decreases Endothelin-1 in Exhaled Breath Condensate of Patients with Severe Persistent Allergic Asthma

Background: Omalizumab is a humanized monoclonal anti-IgE antibody, especially useful for the treatment of severe persistent allergic asthma, inadequately controlled despite regular therapy. Objectives: The aim of the study was to determine the effect of omalizumab treatment on changes in endothelin-1 (ET-1), which plays an important role in the development of airway inflammation and remodeling in exhaled breath condensate (EBC) in patients with severe asthma. Methods: The study was conducted in a group of 19 patients with severe persistent allergic asthma treated with conventional therapy (according to the Global Initiative for Asthma, 2006) and with or without omalizumab (9 vs. 10 patients). Changes in ET-1 in EBC compared with other inflammatory parameters [exhaled nitric oxide – (FENO), blood eosinophil count, and serum eosinophil cationic protein (ECP)] were measured after 16 and 52 weeks of therapy. Results: Omalizumab-treated patients demonstrated a statistically significant decrease in the concentrations of ET-1 in EBC, FENO, serum ECP, and blood eosinophil count and an increase in spirometry parameters compared to patients with conventional therapy. In the group of omalizumab-treated patients, statistically significant correlations between the decrease in ET-1 in EBC and a decrease in FENO, ECP, and blood eosinophil count as well as the increase in forced expiratory volume in 1 s after omalizumab therapy were revealed. Conclusions: Our results confirmed that anti-IgE therapy with omalizumab in patients with severe persistent allergic asthma results in decreased expression of ET-1 in the airways. This could be very important in limiting airway inflammation and bronchial structural changes caused by such treatment in asthmatic patients.
Association Between C4d Staining in Renal Transplant Biopsies, Production of Donor-Specific HLA Antibodies, and Graft Outcome

Background. We carried out a retrospective study of C4d staining in paraffin sections from renal transplant biopsies to determine the association between C4d staining, donor-specific antibodies (DSA), histological features, and graft outcome. Methods. We studied 92 patients who had been biopsied for graft dysfunction. Biopsies were classified using Banff 97 criteria and features suggestive of antibody-mediated rejection were noted. Paraffin sections were stained with a polyclonal antibody using an immunoperoxidase technique. The presence of DSA in concurrent sera was determined by enzyme-linked immunosorbent assay and clinical data were reviewed. Results. Of the 92 cases, 15% showed diffuse and 24% showed focal C4d positivity. The grafts failed in 36% of the diffuse (P<0.025), 23% of the focal, and 7% of the negative group at between one month and 15 years posttransplantation. Only patients in the group with diffuse C4d positivity had concurrent DSA (five cases, P<0.001). Of the five DSA-positive patients, three had type II acute rejection and two of these transplants subsequently failed. The remaining two had chronic allograft nephropathy with features of alloimmune injury. Only two of the nine DSA-negative/C4d-positive transplants had failed at the time of writing, in one case due to recurrent disease. Conclusion. We demonstrated a significant association between diffuse C4d staining, production of DSA, and graft failure. Although the concurrent detection of DSA and C4d positivity is uncommon in our patients, these results indicate that outcome in this group is poor and they may benefit from therapies directed at the humoral response.
Conserved residues in the N‐domain of the AAA+ chaperone ClpA regulate substrate recognition and unfolding

Protein degradation in the cytosol of Escherichia coli is carried out by a variety of different proteolytic machines, including ClpAP. The ClpA component is a hexameric AAA+ (ATPase associated with various cellular activities) chaperone that utilizes the energy of ATP to control substrate recognition and unfolding. The precise role of the N‐domains of ClpA in this process, however, remains elusive. Here, we have analysed the role of five highly conserved basic residues in the N‐domain of ClpA by monitoring the binding, unfolding and degradation of several different substrates, including short unstructured peptides, tagged and untagged proteins. Interestingly, mutation of three of these basic residues within the N‐domain of ClpA (H94, R86 and R100) did not alter substrate degradation. In contrast mutation of two conserved arginine residues (R90 and R131), flanking a putative peptide‐binding groove within the N‐domain of ClpA, specifically compromised the ability of ClpA to unfold and degrade selected substrates but did not prevent substrate recognition, ClpS‐mediated substrate delivery or ClpP binding. In contrast, a highly conserved tyrosine residue lining the central pore of the ClpA hexamer was essential for the degradation of all substrate types analysed, including both folded and unstructured proteins. Taken together, these data suggest that ClpA utilizes two structural elements, one in the N‐domain and the other in the pore of the hexamer, both of which are required for efficient unfolding of some protein substrates.
In vivo biosynthesis of clathrin and other coated vesicle proteins from rat liver

A biosynthetic study of rat liver coated vesicle (CV) proteins was undertaken by using in vivo labeling with L‐[35S]methionine. CVs were isolated and purified by using standard procedures and characterized by electron microscopy, sedimentation, and sodium dodecyl sulfate polyacrylamide gel electrophoresis followed by fluorography, or by gel slicing and liquid scintillation counting. After 51/2 min of labeling (the earliest time examined), incorporation of radioactive clathrin heavy‐chain (180‐kD (kilodalton)) subunits as well as a 90‐kD CV‐associated protein into purified CVs was demonstrated. The level of labeled 180‐kD clathrin in coated vesicles increased rapidly during the First 2 hr of labeling and then continued to rise at a slower rate between 4 and 16 hr. This slow accumulation of labeled clathrin heavy chains in the CV pool may reflect early compartmental sequestration of a fraction of newly synthesized clathrin with delayed assembly into free CVs. By 16 hr of labeling, clathrin 180‐kD chains and the 90‐kD CV‐associated protein accounted for approximately 48 and 26%, respectively, of the radioactivity in all CV proteins. Two proteins of MWa 68 kD and 53 kD showed marked declines in cpm/unit protein between 30 min and 4 hr, raising the possibility that these species may, be transferred out of CVs during or after transport without loss of the other CV proteins. The possibility is also raised that clathrin heavy chains may be recycled during CV formation. Possible heterogeneity within individual CV preparations with respect to protein composition and derivation from both plasma membrane and Golgi regions are proposed.
Estradiol Metabolites Attenuate Monocrotaline-Induced Pulmonary Hypertension in Rats

Pulmonary arterial hypertension (PH) is a deadly disease characterized by pulmonary arterial vasoconstriction and hypertension, pulmonary vasculature remodeling, and right ventricular hypertrophy. Our previous in vivo studies, performed in several models of cardiac, vascular, and/or renal injury, suggest that the metabolites of 17β-estradiol may inhibit vascular and cardiac remodeling. The goal of this study was to determine whether 2-methoxyestradiol (2ME), major non-estrogenic estradiol metabolite, prevents the development and/or retards the progression of monocrotaline (MCT)-induced PH. First, a total of 27 male Sprague Dawley rats were injected with distillated water (Cont, n = 6) or monocrotaline (MCT; 60 mg/kg, i.p.; n = 21). Subsets of MCT animals (n = 7 per group) received 2ME or its metabolic precursor 2-hydroxyestradiol (2HE; 10 μg/kg/h via osmotic minipumps) for 21 days. Next, an additional set (n = 24) of control and MCT rats was monitored for 28 days, before right ventricular peak systolic pressure (RVPSP) was measured. Some pulmonary hypertensive animals (n = 8) were treated with 2ME (10 μg/kg/h) beginning from day 14 after MCT administration. MCT caused pulmonary hypertension (ie, increased right ventricle/left ventricle + septum [RV/LV+S] ratio and wall thickness of small-sized pulmonary arteries, and elevated RVPSP) and produced high and late (days 22 to 27) mortality. Pulmonary hypertension was associated with strong proliferative response (PCNA staining) and marked inflammation (ED1 + cells) in lungs. Both metabolites significantly attenuated the RV/LV+S ratio and pulmonary arteries media hypertrophy and reduced proliferative and inflammatory responses in the lungs. Furthermore, in diseased animals, 2ME (given from day 14 to 28) significantly decreased RVPSP, RV/LV+S ratio and wall thickness, and reduced mortality by 80% (mortality rate: 62.5% vs. 12.5%, MCT vs. MCT+2ME day 14 to 28). This study provides the first evidence that 2ME, a major non-estrogenic, non-carcinogenic metabolite of estradiol, prevents the development and retards the progression of monocrotaline-induced pulmonary hypertension. Further evaluation of 2ME for management of pulmonary arterial hypertension is warranted.
Polarized Distribution of Glycine Transporter Isoforms in Epithelial and Neuronal Cells

Asymmetrical distribution of Na(+)- and Cl(-)-dependent neurotransmitter transporters on the cell surface of polarized cells seems to be a generalized feature in this gene family. In the present study we analyzed the subcellular distribution of the various isoforms of the glycine transporters GLYT1 and GLYT2 after heterologous expression in polarized MDCK cells and in hippocampal neurons. Our results indicate that glycine transporters are asymmetrically distributed in an isoform- and cell-type-specific manner. GLYT1b is localized in the basolateral and somatodendritic domains of MDCK cells and neurons, respectively. However, GLYT1a is somatodendritic in neurons but is predominantly expressed in the apical surface of MDCK cells. The two isoforms of GLYT2 (GLYT2a and GLYT2b) are found at the apical surface in epithelial cells but are uniformly distributed in neurons. By using site-directed mutagenesis we have been able to identify signals for basolateral/somatodendritic localization in the amino-terminal region of GLYT1 and in two dileucine motifs located in the carboxyl tail of this protein. These results contribute to defining the mechanisms of asymmetrical distribution of transporters on the cell surface of polarized cells.