Miracle-dz/UniFAR-FTUs huggingface dataset:
A call for action: Increasing enrollment of untreated patients with higher‐risk myelodysplastic syndromes in first‐line clinical trials

Hypomethylating agents (HMAs) have changed the landscape of the management of patients with higher‐risk myelodysplastic syndromes (HR‐MDS). HMAs have improved hematopoiesis and quality of life and, in the case of azacitidine, prolonged survival in a large randomized trial. However, multiple real‐life and registry analyses have demonstrated minimal survival gains at the population level after the approval of HMAs. Furthermore, the 24‐month median survival observed with azacitidine in the landmark AZA‐001 trial has not been replicated in population‐based studies or in other clinical trials using azacitidine monotherapy arms. Herein, we critically review the accumulating data suggesting that the actual survival impact of HMAs, especially azacitidine, in patients with HR‐MDS is significantly lower than what was observed in the AZA‐001 trial and what often is quoted to patients, and discuss the potential explanations for this discrepancy. We also present the rationale for why front‐line clinical trial enrollment should be always considered and discussed with every newly diagnosed patient with HR‐MDS rather than defaulting to the routine use of HMAs. Finally, we review the challenges to wider‐scale enrollment in front‐line HR‐MDS clinical trials and suggest solutions to accelerate this process with the ultimate goal of achieving a real and substantial change in the natural history of this aggressive malignancy. Cancer 2017;123:3662–3672. © 2017 American Cancer Society
Clostridium botulinum C2 Toxin Delays Entry into Mitosis and Activation of p34cdc2Kinase and cdc25-C Phosphatase in HeLa cells

ABSTRACT The Clostridium botulinum C2 toxin ADP-ribosylates monomeric actin, thereby inducing disassembly of actin filaments, alteration of focal adhesions, and rounding of cells. After treatment with C2 toxin, cells stop to proliferate but remain viable for about 2 days. In view of reported correlations between the structure of the actin cytoskeleton and cell cycle transition, the effects of C2 toxin on the G2/M phase transition of the cell division cycle were studied. Since C2 toxin delayed entry into mitosis in HeLa cells, those enzymes which control entry into mitosis, the cyclin-dependent protein kinase mitosis-promoting factor (MPF) and the phosphatase cdc25-C were examined after treatment of synchronized cells with C2 toxin. MPF is composed of the regulatory cyclin B and the enzymatic p34cdc2 kinase subunits. For its activation at the G2/M border, p34cdc2 needs to be associated with cyclin B and additionally dephosphorylated at Tyr-15 by the specific phosphatase cdc25-C. Treatment of synchronized cells in S or G2 phase with C. botulinum C2 toxin prevented p34cdc2 protein kinase activation by inhibiting its tyrosine dephosphorylation at the G2/M border. Furthermore, the activity of cdc25-C phosphatase was decreased after treatment of cells with C2 toxin. Our results suggest that the prevented activation of the mitotic inducers p34cdc2 kinase and cdc25-C phosphatase represents the final downstream events in the action of C2 toxin resulting in a G2 phase cell cycle delay in synchronized HeLa cells.
Genetically determined low maternal serum dopamine beta-hydroxylase levels and the etiology of autism spectrum disorders.

Autism, a neurodevelopmental disability characterized by repetitive stereopathies and deficits in reciprocal social interaction and communication, has a strong genetic basis. Since previous findings showed that some families with autistic children have a low level of serum dopamine beta-hydroxylase (DbetaH), which catalyzes the conversion of dopamine to norepinephrine, we examined the DBH gene as a candidate locus in families with two or more children with autism spectrum disorder using the affected sib-pair method. DBH alleles are defined by a polymorphic AC repeat and the presence/absence (DBH+/DBH-) of a 19-bp sequence 118 bp downstream in the 5' flanking region of the gene. There was no increased concordance for DBH alleles in affected siblings, but the mothers had a higher frequency of alleles containing the 19-bp deletion (DBH-), compared to an ethnically similar Canadian comparison group (chi(2) = 4.20, df = 1, P = 0.02 for all multiplex mothers; chi(2) = 4.71, df = 1, P < 0.02 for mothers with only affected sons). Although the odds ratios suggested only a moderate relevance for the DBH- allele as a risk allele, the attributable risk was high (42%), indicating that this allele is an important factor in determining the risk for having a child with autism. DBH genotypes also differed significantly among mothers and controls, with 37% of mothers with two affected sons having two DBH- alleles, compared to 19% of controls (chi(2) = 5.81, df = 2, P = 0.03). DbetaH enzyme activity was lower in mothers of autistic children than in controls (mean was 23.20 +/- 15.35 iU/liter for mothers vs. 33.14 +/- 21.39 iU/liter for controls; t = - 1.749, df = 46, P = 0.044). The DBH- allele was associated with lower mean serum DbetaH enzyme activity (nondeletion homozygotes: 41.02 +/- 24.34 iU/liter; heterozygotes: 32.07 +/- 18.10 iU/liter; and deletion homozygotes: 22.31 +/- 13.48 iU/liter; F = 5.217, df = 2, P = 0.007) in a pooled sample of mothers and controls. Taken together, these findings suggest that lowered maternal serum DbetaH activity results in a suboptimal uterine environment (decreased norepinephrine relative to dopamine), which, in conjunction with genotypic susceptibility of the fetus, results in autism spectrum disorder in some families.
Intracochlear Perfusion of Pneumolysin, a Pneumococcal Protein, Rapidly Abolishes Auditory Potentials in the Guinea Pig Cochlea

Objective —Bacterial meningitis and chronic suppurative otitis media caused by Streptococcus pneumoniae are associated with considerable otological morbidity. Specifically, sensorineural hearing loss is a permanent sequela in a third of those who contract pneumococcal meningitis. Pneumolysin, a pneumococcal protein, has been implicated as one of the main virulence/cytotoxic factors. Its pathogenicity is intimately dependent on an ability to form transmembrane pores on binding with cholesterol in target tissues. Material and Methods —We perfused wild-type pneumolysin, at a number of different concentrations, into the guinea pig cochlea and used electrocochleography to characterize the effects of this cytolytic exotoxin in the organ of Corti. Results —Intracochlear perfusion of pneumolysin (10 μg/50 μl) reduced the compound action potential of the auditory nerve within seconds. The cochlear microphonics (f1=8 kHz, f2=9.68 kHz) and their distortion product (2f1–f2) were also reduced, albeit in a slightly less dramatic fashion. At lower concentrations (1 μg/50 μl), a selective and earlier effect on inner hair cells was observed. Conclusions —These results clearly show that significant ototoxicity ensues when sensory cells of the organ of Corti are exposed to pneumolysin (and complete cochlear death when the concentration is high enough). Toxicity is dose-dependent and appears to be site-sensitive. This may have implications for any possible future protective strategies against pneumococcal disease in the ear.
Sexual divergence in activity‐dependent neuroprotective protein impacting autism, schizophrenia, and Alzheimer's disease

Discovered in our laboratory, activity‐dependent neuroprotective protein (ADNP) interacts with key regulatory proteins, including the chromatin remodeling complex SWI/SNF, proteins associated with RNA splicing, RNA translation, microtubule dynamics, and autophagy. ADNP regulates > 400 genes during mouse embryonic development and is essential for neural tube closure. ADNP key functions extend from mice to men, with mutations causing ADNP‐related ID/autism syndrome, also known as the Helsmoortel‐Van der Aa syndrome. ADNP mRNA increases in lymphocytes derived from schizophrenia patients and in patients suffering from mild cognitive impairment (MCI) and further increases in Alzheimer's disease patients compared with controls. Serum ADNP levels correlate with IQ. NAP (davunetide), an ADNP snippet drug candidate, protects cognition in patients suffering from amnestic MCI preceding Alzheimer's disease and significantly enhances functional daily activities in schizophrenia patients toward future development. It is important to note that ADNP is sexually regulated in the brains of birds, mice, and men and in lymphocytes of patients suffering from schizophrenia. ADNP haploinsufficiency in mice results in significantly decreased axonal transport (with male–female differences) changes in gene expression in a sex‐dependent manner, including key regulatory mechanisms during brain and heart development and function and behavioral outcomes. These findings pave the path for better understanding of brain function through the prism of sex differences. © 2016 Wiley Periodicals, Inc.
Transforming Primary Care in the New Orleans Safety-net: The Patient Experience

Background:The patient-centered medical home (PCMH) is a key service delivery innovation in health reform. However, there are growing questions about whether the changes in clinics promoted by the PCMH model lead to improvements in the patient experience. Objective:To test the hypothesis that PCMH improvements in safety-net primary care clinics are associated with a more positive patient experience. Research Design:Multilevel cross-sectional analysis of patients nested within the primary care clinics that serve them. Subjects:Primary care clinic leaders and patients throughout the City of New Orleans health care safety-net. Measures:Dependent variables included patient ratings of accessibility, coordination, and confidence in the quality/safety of care. The key independent variable was a score measuring PCMH structural and process improvements at the clinic level. Results:Approximately two thirds of patients in New Orleans gave positive ratings to their clinics on access and quality/safety, but only one third did for care coordination. In all but the largest clinics, patient experiences of care coordination were positively associated with the clinic’s use of PCMH structural and process changes. Results for patient ratings of access and quality/safety were mixed. Conclusions:Among primary care clinics in the New Orleans safety-net, use of more PCMH improvements at the clinic level led to more positive patient rating of care coordination, but not of accessibility or confidence in quality/safety. Ongoing efforts to pilot, demonstrate, implement, and evaluate the PCMH should consider how the impact of medical practice transformation could vary across different aspects of the patient experience.
Implicit prototypes predict risky sun behavior.

OBJECTIVE Despite the fact that skin cancer is highly avoidable, incidence and death rates in the United States continue to climb. The pattern is particularly problematic among young, White women, who sometimes overexpose themselves to harmful ultraviolet rays in hopes of being tan. Research has suggested that positivity toward prototypes of individuals who engage in unhealthy behavior, like tanning, influences the likelihood that an individual will personally engage in those behaviors. Although the prototype-to-behavior link is considered to operate automatically, researchers have typically relied on people's self-reported evaluations of prototypes, which are more controlled and susceptible to self-presentational concerns. METHOD In the present research, we developed a measure of implicit prototypes and compared it with measures of explicit prototypes in predicting the safe sun behavior of 731 women. RESULTS Meta-analysis of 5 different prototypes (i.e., cool, fun, healthy, intelligent, and attractive) suggested that implicit prototypes predicted more variance in women's current behavior, planned behavior, behavioral willingness, and tanning frequency than did explicit prototypes. CONCLUSION Although some models recognize that health behavior may be based on automatic processes, they exclusively use measures of self-reported attitudes and prototypes to predict behavior. The results suggest that measuring implicit prototypes may provide important explanatory power.
Prevalence and Correlates of Influenza Vaccination among Kidney Transplant Patients

Context Immunosuppressive regimens increase kidney transplant patients' risk of contracting life-threatening influenza. However, little information exists about the prevalence and correlates of influenza vaccinations in this population. Objective To determine the prevalence and explore correlates of influenza vaccination in kidney transplant recipients. Design, Sample, and Setting This cross-sectional study used data from the Supporting Medication Adherence in Renal Transplantation study. The convenience sample consisted of 356 adult kidney transplant recipients (58.1% male; mean age, 52.9 [SD 13.53] years) recruited from 2 Swiss transplant outpatient clinics. Influenza vaccination status was assessed by self-report (yes/no). Main Outcome Measure Known correlates of vaccination in chronically ill patients (older age, cohabitation, higher education, higher socioeconomic status, financial stability, more comorbid diseases, nonsmoking status, and clinical site where care is received) were entered into a multiple logistic regression model. Results Of the 356 patients, only 83 (23.3%) reported having been vaccinated against influenza in the previous year. Positive vaccination status was significantly related to older age (odds ratio, 1.04; 95% confidence interval, 1.02–1.06). Conclusion Despite national and international guidelines recommending influenza vaccination in kidney transplant recipients, the prevalence of influenza vaccination in this sample was low. This study's results suggest that transplant centers need to implement policies to maximize influenza vaccination of their patients.
Atrial Natriuretic Factor and Exocrine Pancreas: Effects on the Secretory Process

Immunoreactive atrial natriuretic factor (ANF) has recently been identified in pancreatic acinar cells. The current study therefore, was, designed to ascertain whether the atrial peptide exercises any biological effects on the exocrine pancreas. When isolated rat pancreatic acinar cells were incubated with rat ANF (8–33), a concentration-dependent increase in cGMP synthesis was observed (EC50 about 5 × 10−9 M) with the peak response occurring within 2.5 min of exposure of the cells to the peptide. ANF did not affect basal or secretagogue (carbachol ± DbcAMP, CCK-OP, or forskolin)-induced amylase secretion from acinar cells, nor did it affect [3H]thymidine incorporation into DNA or [3H]leucine incorporation into trichloroacetic acid-precipitable protein. ANF was also infused intravenously (0.01–0.25 μg/min) in rabbits with cannulated pancreatic ducts, and the peptide stimulated a dose-dependent secretion of cGMP into pancreatic juice. ANF, by itself, did not affect protein or fluid secretion from rabbit pancreas; when co-infused with secretin (0.1 CU/min), which is not an acinar cell secretagogue in rabbits, ANF increased fluid secretion in one of three animals tested. The data suggest that acinar cells possess functional ANF receptors, whose activation results in both synthesis and secretion of cGMP. Intra-acinar cell cGMP is not involved in the enzyme secretory process. Secreted nucleotide is not co-released with digestive hydrolases, and does not, by itself, appear to have an intraluminal effect on fluid secretion. The mechanism by which acinar cells secrete cGMP into pancreatic juice as well as the biological significance of intracellular (acinar), and extracellular (intraluminal) cGMP remain to be elucidated.
Dynamics of the Epithelium During Canalization of the Rat Ventral Prostate

Outgrowth and branching of solid cords are the initial events in postnatal prostatic morphogenesis. These processes involve cell proliferation and their projection into the stroma and precede epithelial canalization. The purpose of the present study was to examine the dynamics of the prostate epithelium during canalization of the rat ventral prostate in the first week of postnatal development using histological, stereological, and ultrastructural analyses. The terminal deoxynucleotidyltransferase [TdT]‐mediated deoxy‐UTP nick end labeling assay was used to investigate the occurrence of DNA fragmentation. Our results demonstrate that canalization of the prostate epithelium starts as early as on day 1 (24 hr after birth) and progresses thereafter. By the end of the first week (day 6), luminal volume density reached ∼3% (P < 0.05) of the organ. Canalization was the result of epithelial cell differentiation and apoptosis. The former involved organization of the epithelial cells into a single layer sitting on the basement membrane, polarization, enlargement of secretory organelles and accumulation of secretory vesicles, microvilli formation, and establishment of the adult pattern of cell junctions. The latter was observed to occur mostly to epithelial cells not in contact with the basement membrane. Structures of variable electron density were observed in the developing lumen. In conclusion, different phenomena seem to be involved in the canalization of the rat ventral prostate. However, it was evident from the present results that complex epithelial cell fate decisions take place during this process. Anat Rec, 290:1223–1232, 2007. © 2007 Wiley‐Liss, Inc.
Increased aryl hydrocarbon receptor expression in patients with allergic rhinitis.

BACKGROUND A predominant Th17 population is a marker of allergic rhinitis (AR). As a ligand-activated transcription factor, the aryl hydrocarbon receptor (AhR) plays a vital role in promoting or inhibiting the development of specific Th cells. However, its role in AR remains undefined. OBJECTIVE To analyze the potential role of AhR in the pathogenesis of AR. METHODS In total, 30 AR patients and 13 healthy controls were recruited for this study and AR patients had clinical features, as demonstrated by rhinoconjunctivitis quality of life questionnaires, total symptom scores and visual analog scale scores. The expression of AhR, IL-17 and IL-22 and the presence of Th17 cells in peripheral blood mononuclear cells were measured before and after treatment with the nontoxic AhR ligand 2-(1'H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE). RESULTS Pretreatment ITE studies revealed that all AR patients had a significant increase in AhR expression compared with controls and AhR expression positively correlated with clinical parameters. After ITE intervention, a severe reduction in the differentiation of Th17 cells and the production of IL-17 and IL-22 was noted in both AR patients and normal subjects. Simultaneously, a dramatic enhancement of AhR expression was also observed in all healthy controls, but not in AR patients. CONCLUSION The results suggested that the AhR may be one of the mechanisms underlying the Th17 response during the pathogenesis of AR and AhR levels were closely related to clinical severity in all AR patients. Additionally, ITE may represent a new drug candidate in the treatment of AR.
Effect of Propranolol on Circulatory Responses to Induction of Diazepam‐Nitrous Oxide Anesthesia and to Endotracheal Intubation

The present study evaluated the hemodynamic effects produced by the intravenous infusion of diazepam (0.5 mg/kg over 10 minutes) and the simultaneous inhalation of 50% nitrous oxide in oxygen administered to 19 patients with coronary artery disease who were receiving chronic propranolol therapy (106 ± 67 mg/day). In addition, hemodynamic changes produced by direct laryngoscopy and intubation of the trachea were measured. Data during the induction of anesthesia were compared to measurements obtained in a previously reported group of similar patients anesthetized in the same manner but not receiving propranolol. In the present study, as in previously observed patients not receiving propranolol, induction of anesthesia with diazepam-nitrous oxide did not result in any significant change from awake measurements with respect to heart rate (HR), mean arterial pressure (MAP), or rate-pressure product (RPP). Cardiovascular responses were similar in patients with awake resting heart rates greater than 70 beats per minute (nine patients) and less than 70 beats per minute (10 patients). This suggests that propranolol does not alter the benign hemodynamic effects produced by this type of induction of anesthesia. Laryngoscopy and tracheal intubation significantly (p < 0.01) increased MAP at 1 minute and HR and RPP at 1 and 2 minutes after the start of laryngoscopy. These changes were transient, returning to control values within 3 minutes after intubation. Patients with awake resting HR less than 70 beats per minute had greater increases in HR and RPP at 1 minute than did patients with resting HR greater than 70 beats per minute (p < 0.05). This suggests that propranolol even in doses adequate to produce significant slowing of HR in awake Patients does not ensure protection against increases in HR and MAP associated with laryngoscopy and intubation of the trachea.
Analysis of magnetic resonance imaging-based blood and cerebrospinal fluid flow measurements in patients with Chiari I malformation: a system approach.

OBJECT A pilot study was performed to assess noninvasively the change in intracranial compliance (ICC) and intracranial pressure (ICP) in patients with Chiari I malformation who undergo foramen magnum decompression. The working hypothesis was that the main effect of the decompressive surgery is a change in ICP. Noninvasive cine phasecontrast magnetic resonance (MR) imaging is a motion-sensitive dynamic MR imaging technique that allows for visualization and quantitation of tissue motion and flow. The authors' group has used dynamic phase-contrast MR imaging to visualize and quantify pulsatile blood and cerebrospinal fluid (CSF) flow in the craniospinal system. METHODS A system approach has been used to characterize the hemodynamic-hydrodynamic coupling in the craniospinal system and to derive measures for ICC and ICP. Magnetic resonance imaging-based ICC and ICP values are derived from the ratio of the volume and pressure changes that occur naturally during each cardiac cycle. The authors conducted a prospective study of four patients, three of whom were studied before and after decompressive surgery; significant change in MR imaging-derived ICC and ICP values was documented in only one of the three surgically treated patients. A significant change in the dynamics of the intracranial volume change (ICVC) during the cardiac cycle, however, was observed in all three patients. In healthy individuals the ICVC waveform usually consists of the following sequence: monotonic increase in intracranial volume (ICV) during the systolic phase due to increased blood inflow, monotonic decrease in ICV caused by the onset of CSF outflow into the spinal canal, and increase in the venous outflow. A nonmonotonic decline in the ICVC waveform has been observed in all patients with headaches, and a relatively normal waveform was found in those without headaches or whose headaches were resolved or alleviated by the surgery. A "partial-valve" mechanism is proposed as an explanation for the abnormal ICVC dynamics. The monotonic decline in ICVC is interrupted by a "premature" reduction in the CSF outflow. This may be caused by a displacement of the hindbrain into the cervical spinal canal during the systolic phase. This obstructs the CSF flow at the later part of the systolic phase such that the ICV does not continue its gradual decline. Postsurgery, the ICVC waveforms presented a more normal-appearing ICVC dynamics profile. CONCLUSIONS Magnetic resonance imaging measurement of transcranial CSF and blood flow may lead to a better understanding of the pathophysiology of Chiari malformations and may prove to be an important diagnostic tool for guiding for the treatment of patients with Chiari I malformation.