Miracle-dz/UniFAR-FTUs huggingface dataset:
A phase I clinical trial with monoclonal antibody ch806 targeting transitional state and mutant epidermal growth factor receptors

An array of cell-surface antigens expressed by human cancers have been identified as targets for antibody-based therapies. The great majority of these antibodies do not have specificity for cancer but recognize antigens expressed on a range of normal cell types (differentiation antigens). Over the past two decades, our group has analyzed thousands of mouse monoclonal antibodies for cancer specificity and identified a battery of antibodies with limited representation on normal human cells. The most tumor-specific of these antibodies is 806, an antibody that detects a unique epitope on the epidermal growth factor receptor (EGFR) that is exposed only on overexpressed, mutant, or ligand-activated forms of the receptor in cancer. In vitro immunohistochemical specificity analysis shows little or no detectable 806 reactivity with normal tissues, even those with high levels of wild-type (wt)EGFR expression. Preclinical studies have demonstrated that 806 specifically targets a subset of EGFR expressed on tumor cells, and has significant anti-tumor effects on human tumor xenografts, primarily through abrogation of signaling pathways. The present clinical study was designed to examine the in vivo specificity of a chimeric form of mAb 806 (ch806) in a tumor targeting/biodistribution/pharmacokinetic analysis in patients with diverse tumor types. ch806 showed excellent targeting of tumor sites in all patients, no evidence of normal tissue uptake, and no significant toxicity. These in vitro and in vivo characteristics of ch806 distinguish it from all other antibodies targeting EGFR.
Thrombotic thrombocytopenic purpura plasma enhances platelet–leucocyte interaction in vitro

In thrombotic thrombocytopenic purpura (TTP), intravascular platelet aggregation and formation of platelet‐rich thrombi impair the microcirculation. TTP plasma has been shown to induce aggregation of normal platelets in vitro. The present study investigates the formation of activated platelet aggregates (aPAg) induced by TTP plasma, with particular attention to their binding to leucocytes (LPAg). Results were compared with the effects of plasmas from normal controls (CTL) and from patients with immune thrombocytopenic purpura (ITP) or thrombosis (THR). Following addition of test plasma to normal whole blood (WB), aPAg and LPAg were assayed by flow cytometry using mAbs against CD41 (platelet marker), CD62p (platelet activation marker) and CD45 (pan‐leucocyte marker). Compared to control plasma, TTP plasma was more potent than ITP or THR plasma in increasing aPAg; only TTP plasma significantly promoted leucocyte binding to give increased LPAg. Prior removal of neutrophils (PMN) from WB by beads coated with anti‐CD15 mAb largely prevented formation of aPAg and LPAg. However, TTP plasma added to normal platelet‐rich plasma significantly increased aPAg, which suggested possible hindrance of aPAg formation by erythrocytes and other leucocytes in PMN‐depleted blood. We concluded that TTP plasma was most potent in the induction of aPAg and unique in promoting LPAg formation in WB. Neutrophils, and not other leucocytes, appear to be essential for LPAg formation. Enhanced PMN–platelet interaction in the microcirculation may facilitate platelet adhesion to vessel walls and promote the formation of platelet‐rich microthrombi in TTP.
Newspaper Policies on the Potential Merging of Advertising and News Content

Newspaper readers more readily trust news than advertising content. Therefore, journalists and media scholars consider it important that audiences can distinguish between news stories and advertisements. The authors collected survey responses from 321 daily newspapers on their standards for acceptable advertising for publication. The responses were analyzed to discover if advertising acceptance policies and practices reflect publications’ willingness to blur the lines between news and advertising sections. The data indicate that most newspapers are careful about letting advertisers pretend their messages are really news stories. In general, newspapers’ journalistic priorities for honesty influence their advertising policies. A few newspapers may use the editorial content to help sell advertising space and otherwise blur the lines between news and advertising content, but it is not a common and widespread problem.
Atomic insight into the CD4 binding‐induced conformational changes in HIV‐1 gp120

The entry of HIV‐1 into a target cell requires gp120 and receptor CD4 as well as coreceptor CCR5/CXCR4 recognition events associated with conformational changes of the involved proteins. The binding of CD4 to gp120 is the initiation step of the whole process involving structural rearrangements that are crucial for subsequent pathways. Despite the wealth of knowledge about the gp120/CD4 interactions, details of the conformational changes occurring at this stage remain elusive. We have performed molecular dynamics simulations in explicit solvent based on the gp120/CD4/CD4i crystal structure in conjunction with modeled V3 and V4 loops to gain insight into the dynamics of the binding process. Three differentiated interaction modes between CD4 and gp120 were found, which involve electrostatics, hydrogen bond and van der Waals networks. A “binding funnel” model is proposed based on the dynamical nature of the binding interface together with a CD4‐attraction gradient centered in gp120 at the CD4‐Phe43‐binding cavity. Distinct dynamical behaviors of free and CD4‐bound gp120 were monitored, which likely represent the ground and pre‐fusogenic states, respectively. The transition between these states revealed concerted motions in gp120 leading to: i) loop contractions around the CD4‐Phe43‐insertion cavity; ii) stabilization of the four‐stranded “bridging sheet” structure; and iii) translocation and clustering of the V3 loop and the bridging sheet leading to the formation of the coreceptor binding site. Our results provide new insight into the dynamic of the underlying molecular recognition mechanism that complements the biochemical and structural studies. Proteins 2004. © 2004 Wiley‐Liss, Inc.
The role of gamification in activating primary school students' intrinsic and extrinsic motivation at a museum

Internationally, the increased use of digital media by museums has turned them into dynamic learning centers, as far as culture, science, and learning are concerned. Despite the promise, gamification has not yet been strongly established in the educational arena, and its relationship with learning at museums is not yet clear. The purpose of this study was to investigate the impact of a gamified mobile learning environment on primary school students' motivation and learning. The participants of the study were 35 students, ages 10-11 years old, who visited a local archaeological museum. A pre-test post-test quasi-experimental research design was adopted, with two cohorts of students. The first cohort (n=18), which served as the control group, engaged in mobile learning at the museum without gamification, whereas the second cohort (n=17) was exposed to the same content using mobile devices, but following a gamified approach. A pre-test was given to both groups to assess initial knowledge and motivation prior to the visit to the museum; students' discourse and interactions during the visit were videotaped and analyzed; at the end of the visit, students completed a post-test. The analysis of the data examined the relation between gamification and students' learning gains and motivation in each condition. Results showed that the gamified approach contributed to the increase of students' extrinsic motivation, as well as to the improvement of their historical knowledge, but did not modify their intrinsic motivation with the exception of their interest. Implications of the study are discussed.
Skeletal Muscle Mitochondrial Functions, Mitochondrial DNA Copy Numbers, and Gene Transcript Profiles in Type 2 Diabetic and Nondiabetic Subjects at Equal Levels of Low or High Insulin and Euglycemia

We investigated whether previously reported muscle mitochondrial dysfunction and altered gene transcript levels in type 2 diabetes might be secondary to abnormal blood glucose and insulin levels rather than an intrinsic defect of type 2 diabetes. A total of 13 type 2 diabetic and 17 nondiabetic subjects were studied on two separate occasions while maintaining similar insulin and glucose levels in both groups by 7-h infusions of somatostatin, low- or high-dose insulin (0.25 and 1.5 mU/kg of fat-free mass per min, respectively), and glucose. Muscle mitochondrial DNA abundance was not different between type 2 diabetic and nondiabetic subjects at both insulin levels, but the majority of transcripts in muscle that are involved mitochondrial functions were expressed at lower levels in type 2 diabetes at low levels of insulin. However, several gene transcripts that are specifically involved in the electron transport chain were expressed at higher levels in type 2 diabetic patients. After the low-dose insulin infusion, which achieved postabsorptive insulin levels, the muscle mitochondrial ATP production rate (MAPR) was not different between type 2 diabetic and nondiabetic subjects. However, increasing insulin to postprandial levels increased the MAPR in nondiabetic subjects but not in type 2 diabetic patients. The lack of MAPR increment in response to high-dose insulin in type 2 diabetic patients occurred in association with reduced glucose disposal and expression of peroxisome proliferator–activated receptor-γ coactivator 1α, citrate synthase, and cytochrome c oxidase I. In conclusion, the current data supports that muscle mitochondrial dysfunction in type 2 diabetes is not an intrinsic defect, but instead a functional defect related to impaired response to insulin.
Activation of Mitogen-activated Protein Kinase by Membrane-targeted Raf Chimeras Is Independent of Raft Localization*

Binding of proteins to the plasma membrane can be achieved with various membrane targeting motifs, including combinations of fatty acids, isoprenoids, and basic domains. In this study, we investigate whether attachment of different membrane targeting motifs influences the signaling capacity of membrane-bound signal transduction proteins by directing the proteins to different membrane microdomains. We used c-Raf-1 as a model for a signaling protein that is activated when membrane-bound. Three different membrane targeting motifs from K-Ras, Fyn, and Src proteins were fused to the N or C terminus of Raf-1. The ability of the modified Rafs to initiate MAPK signaling was then investigated. All three modified Raf-1 constructs activated MAPK to nearly equivalent levels. The extent of localization of the Raf-1 constructs to membrane microdomains known as rafts did not correlate with the level of MAPK activation. Moreover, treatment of cells with the raft disrupting drug methyl-β-cyclodextrin (MβCD) caused activation of MAPK to levels equivalent to those achieved with membrane-targeted Raf constructs. The use of pharmacological agents as well as dominant negative mutants revealed that MAPK activation by MβCD proceeds via a phosphoinositide 3-kinase-dependent mechanism that is Ras/Raf-independent. We conclude that cholesterol depletion from the plasma membrane by MβCD constitutes an alternative pathway for activating MAPK.
Olivocochlear innervation in the mouse: Immunocytochemical maps, crossed versus uncrossed contributions, and transmitter colocalization

To further understand the roles and origins of γ‐aminobutyric acid (GABA) and calcitonin gene‐related peptide (CGRP) in the efferent innervation of the cochlea, we first produced in the mouse an immunocytochemical map of the efferent terminals that contain acetylcholine (ACh), CGRP, and GABA. Olivocochlear (OC) terminals in inner and outer hair cell (IHC and OHC) regions were analyzed quantitatively along the cochlear spiral via light‐microscopic observation of cochlear wholemounts immunostained with antibodies to glutamic acid decarboxylase (GAD), vesicular acetylcholine transporter (VAT), or the peptide CGRP. Further immunochemical characterization was performed in mice with chronic OC transection at the floor of the fourth ventricle to distinguish crossed from uncrossed contributions and, indirectly, the contributions of lateral versus medial components of the OC system. The results in mouse showed that (1) there are prominent GABAergic, cholinergic, and CGRPergic innervations in the OHC and IHC regions, (2) GABA and CGRP are extensively colocalized with ACh in all OC terminals in the IHC and OHC areas, (3) the longitudinal gradient of OC innervation peaks roughly at the 10‐kHz region in the OHC area and is more uniform along the cochlear spiral in the IHC area, (4) in contrast to other mammalian species there is no radial gradient of OC innervation of the OHCs, and (5) all OHC efferent terminals arise from the medial OC system and terminals in the IHC area arise from the lateral OC system. J. Comp. Neurol. 455:406–416, 2003. © 2002 Wiley‐Liss, Inc.
Regional electric field induced by electroconvulsive therapy: A finite element simulation study

The goal of this study is to investigate the regional distribution of the electric field (E-field) strength induced by electroconvulsive therapy (ECT), and to contrast clinically relevant electrode configurations through finite element (FE) analysis. An FE human head model incorporating tissue heterogeneity and white matter anisotropy was generated based on structural magnetic resonance imaging (MRI) and diffusion tensor MRI (DT-MRI) data. We simulated the E-field spatial distributions of three standard ECT electrode placements [bilateral (BL), bifrontal (BF), and right unilateral (RUL)] and an investigational electrode configuration [focal electrically administered seizure therapy (FEAST)]. A quantitative comparison of the E-field strength was subsequently carried out in various brain regions of interests (ROIs) that have putative role in the therapeutic action and/or adverse side effects of ECT. This study illustrates how the realistic FE head model provides quantitative insight in the biophysics of ECT, which may shed light on the differential clinical outcomes seen with various forms of ECT, and may guide the development of novel stimulation paradigms with improved risk/benefit ratio.
Brief communication: Cineradiographic analysis of the chimpanzee (Pan troglodytes) talonavicular and calcaneocuboid joints.

During terrestrial locomotion, chimpanzees exhibit dorsiflexion of the midfoot between midstance and toe-off of stance phase, a phenomenon that has been called the "midtarsal break. " This motion is generally absent during human bipedalism, and in chimpanzees is associated with more mobile foot joints than in humans. However, the contribution of individual foot joints to overall foot mobility in chimpanzees is poorly understood, particularly on the medial side of the foot. The talonavicular (TN) and calcaneocuboid (CC) joints have both been suggested to contribute significantly to midfoot mobility and to the midtarsal break in chimpanzees. To evaluate the relative magnitude of motion that can occur at these joints, we tracked skeletal motion of the hindfoot and midfoot during passive plantarflexion and dorsiflexion manipulations using cineradiography. The sagittal plane range of motion was 38 ± 10° at the TN joint and 14 ± 8° at the CC joint. This finding indicates that the TN joint is more mobile than the CC joint during ankle plantarflexion-dorsiflexion. We suggest that the larger range of motion at the TN joint during dorsiflexion is associated with a rotation (inversion-eversion) across the transverse tarsal joint, which may occur in addition to sagittal plane motion.
Coupling of the Dolichol-P-P-Oligosaccharide Pathway to Translation by Perturbation-sensitive Regulation of the Initiating Enzyme, GlcNAc-1-P Transferase*

In mammalian cells, inhibition of translation interferes with synthesis of the lipid-linked oligosaccharide (LLO) Glc3Man9GlcNAc2-P-P-dolichol as measured with radioactive sugar precursors. Conflicting hypotheses have been proposed, and the fundamental basis for this regulation has remained elusive. Here, fluorophore-assisted carbohydrate electrophoresis (FACE) was used to measure LLO concentrations directly in cells treated with translation blockers. Further, LLO biosynthetic enzymes were assayed in vitro with endogenous acceptor substrates using either cells gently permeabilized with streptolysin-O (SLO) or microsomes from homogenized cells. In Chinese hamster ovary (CHO)-K1 cells treated with translation blockers, FACE did not detect changes in concentrations of Glc3Man9GlcNAc2-P-P-dolichol or early LLO intermediates. These results do not support earlier proposals for feedback repression of LLO initiation by accumulated Glc3Man9GlcNAc2-P-P-dolichol, or inhibition of a GDP-mannose dependent transferase. With microsomes from cells treated with translation blockers, there was no interference with LLO initiation by GlcNAc-1-P transferase (GPT), mannose-P-dolichol synthase, glucose-P-dolichol synthase, or LLO synthesis in vitro, as reported previously. Surprisingly, inhibition of all of these was detected with the SLO in vitro system. Additional experiments with the SLO system showed that the three transferases shared a limited pool of dolichol-P that was trapped as Glc3Man9GlcNAc2-P-P-dolichol by translation arrest. Overexpression of GPT was unable to reverse the effects of translation arrest on LLO initiation, and experiments with FACE and the SLO system showed that overexpressed GPT was not functional in vivo, although it was highly active in microsomal assays. Thus, the combined use of the SLO in vitro system and FACE showed that LLO biosynthesis depends upon a limited primary pool of dolichol-P. Physical perturbation associated with microsome preparation appears to make available a secondary pool of dolichol-P, masking inhibition by translation arrest, as well as activating a nonfunctional fraction of GPT. The implications of these results for the organization of the LLO pathway are discussed.
Serum testosterone and gonadotropins levels in patients with premature ejaculation: A comparison with normal men

Background: To investigate the role of testosterone (T) in the pathogenesis of ejaculatory symptoms, particularly premature ejaculation (PE). Materials and Methods: A total of 41 male patients with PE as well as 41 controls with no sexual dysfunction were recruited in this cross-sectional study. We used the stopwatch measurement to monitor the intravaginal ejaculatory latency time (IELT). Patients with mean IELT values lower than 60 s were considered to have PE. Serum levels of follicle stimulating hormone (FSH), luteinizing hormone (LH), prolactin (PRL), total testosterone (TT) and free testosterone (FT) were measured in patients as well as controls. Patients with thyroid dysfunction, hypogonadism, hypertension and dyslipidemia were excluded from the study. Results: The serum levels of FT and FSH were significantly higher in cases (P = 0.036 and 0.003, respectively). There was no significant difference between TT, LH and PRL levels of the two groups. Conclusion: Patients with PE have higher FT and FSH levels compared with normal men. The causative relationship between these entities and also the clinical importance of this finding has to be determined by more comprehensive studies.
The addition of ceftriaxone to oral therapy does not improve outcome in febrile children with urinary tract infections.

OBJECTIVE To determine whether the addition of a single dose of ceftriaxone sodium to a 10-day course of trimethoprim and sulfamethoxazole hastens urine sterilization or resolution of clinical symptoms in febrile children with urinary tract infections. DESIGN Prospective, single-blind, randomized study. SETTING Tertiary care children's hospital emergency department. PATIENTS Febrile children aged 6 months to 12 years with a presumptive urinary tract infection based on history, physical examination, and urinalysis findings. INTERVENTIONS A history was taken, a physical examination and urinalysis and culture were performed, and a white blood cell count and erythrocyte sedimentation rate were obtained. Children were randomized to receive an intramuscular dose of ceftriaxone then 10 days of trimethoprim-sulfamethoxazole (IM + PO group) or oral trimethoprim-sulfamethoxazole alone (PO group). After receiving study medication, patients were discharged from the hospital to return in 48 hours for a follow-up evaluation and urine culture. Treatment failure was defined as the persistence of a positive culture at 48 hours or the need for hospital admission for intravenous rehydration or antibiotic therapy. RESULTS Sixty-nine children were enrolled, 34 in the IM + PO group and 35 in the PO group. The 2 groups were similar at the initial visit with respect to age, sex, clinical degrees of illness, white blood cell count, and erythrocyte sedimentation rate (P>.05). At the 48-hour follow-up visit, there were no differences between the 2 treatment groups in resolution of vomiting, fever, general appearance, abdominal tenderness, and hydration state (P>.05). There were 9 treatment failures, 4 in the IM + PO group and 5 in the PO group (P =.93). CONCLUSION The addition of a single dose of intramuscular ceftriaxone to a 10-day course of oral trimethoprim-sulfamethoxazole for urinary tract infection with fever resulted in no difference at 48 hours in the urine sterilization rate, degree of clinical improvement, or subsequent hospital admission rate.
Left Ventricular Hypertrophy Determines the Severity of Diastolic Dysfunction in Patients with Nonvalvular Atrial Fibrillation and Preserved Left Ventricular Systolic Function

Regression of left ventricular (LV) hypertrophy (LVH) is known to be related to a lower incidence of stroke in hypertensive patients with nonvalvular atrial fibrillation (NV-AF). However, its mechanism remains controversial. Recently, diastolic dysfunction (DD) was reported to be correlated with ischemic stroke in NV-AF. We hypothesized that hypertension (HTN) and resultant LVH might be associated with the severity of DD in NV-AF. Two hundred and ninety-four patients (204 males, age 66 ± 12 y) with NV-AF with preserved LV systolic function were included. Clinical and echocardiographic data were compared between patients with enlarged left atrial (LA) volume (n == 237) and patients with normal LA. Age (60 ± 12 vs. 67 ± 11 years), sex (male; 81 vs. 62%%), duration of NV-AF (4.1 ± 7.8 vs. 45.7 ± 49.0 months), brain natriuretic peptide (108.3 ± 129.3 vs. 236.1 ± 197.0 pg//mL), right ventricular systolic pressure (24.5 ± 5.5 vs. 33.1 ± 11.1 mmHg), mitral inflow velocity (E [77.4 ± 22.2 vs. 88.3 ± 22.0 cm//s]), LV mass index (LVMI [87.6 ± 22.2 vs. 105.1 ± 23.2 g//m2]), peak systolic mitral annular velocity (S' [7.2 ± 2.0 vs. 5.8 ± 1.8 cm//s]), and mitral inflow velocity to diastolic mitral annular velocity (E//E' [9.8 ± 3.4 vs. 12.1 ± 4.4]) were significantly different between the two groups, respectively (P < 0.05). In multivariate analysis, LVMI was independently correlated with increased LA volume (OR: 1.037 [95%% CI: 1.011–1.063], P < 0.05), whereas HTN was not. LA enlargement, which reflects the severity and chronicity of DD, is independently associated with LVH in patients with NV-AF. Therefore, regression of LVH with anti-hypertensive treatment may lead to improvement of diastolic function and favorable clinical outcomes in hypertensive patients with NV-AF.