Miracle-dz/UniFAR-FTUs huggingface dataset:
Predictive Value of Phase I Trials for Safety in Later Trials and Final Approved Dose: Analysis of 61 Approved Cancer Drugs

Phase I trials use a small number of patients to define a maximum tolerated dose (MTD) and the safety of new agents. We compared data from phase I and registration trials to determine whether early trials predicted later safety and final dose. We searched the U.S. Food and Drug Administration (FDA) website for drugs approved in nonpediatric cancers (January 1990–October 2012). The recommended phase II dose (R2PD) and toxicities from phase I were compared with doses and safety in later trials. In 62 of 85 (73%) matched trials, the dose from the later trial was within 20% of the RP2D. In a multivariable analysis, phase I trials of targeted agents were less predictive of the final approved dose (OR, 0.2 for adopting ± 20% of the RP2D for targeted vs. other classes; P = 0.025). Of the 530 clinically relevant toxicities in later trials, 70% (n = 374) were described in phase I. A significant relationship (P = 0.0032) between increasing the number of patients in phase I (up to 60) and the ability to describe future clinically relevant toxicities was observed. Among 28,505 patients in later trials, the death rate that was related to drug was 1.41%. In conclusion, dosing based on phase I trials was associated with a low toxicity-related death rate in later trials. The ability to predict relevant toxicities correlates with the number of patients on the initial phase I trial. The final dose approved was within 20% of the RP2D in 73% of assessed trials. Clin Cancer Res; 20(2); 281–8. ©2013 AACR.
A prospective study of venous thromboembolism after major trauma.

BACKGROUND Although deep-vein thrombosis and pulmonary embolism are considered common complications after major trauma, their frequency and the associated risk factors have not been carefully quantified. METHODS We performed serial impedance plethysmography and lower-extremity contrast venography to detect deep-vein thrombosis in a cohort of 716 patients admitted to a regional trauma unit. Prophylaxis against thromboembolism was not used. RESULTS Deep-vein thrombosis in the lower extremities was found in 201 of the 349 patients (58 percent) with adequate venographic studies, and proximal-vein thrombosis was found in 63 (18 percent). Three patients died of massive pulmonary embolism before venography could be performed. Before venography, only three of the patients with deep-vein thrombosis had clinical features suggestive of the condition. Deep-vein thrombosis was found in 65 of the 129 patients with major injuries involving the face, chest, or abdomen (50 percent); in 49 of the 91 patients with major head injuries (53.8 percent); in 41 of the 66 with spinal injuries (62 percent); and in 126 of the 182 with lower-extremity orthopedic injuries (69 percent). Thrombi were detected in 61 of the 100 patients with pelvic fractures (61 percent), in 59 of the 74 with femoral fractures (80 percent), and in 66 of the 86 with tibial fractures (77 percent). A multivariate analysis identified five independent risk factors for deep-vein thrombosis: older age (odds ratio, 1.05 per year of age; 95 percent confidence interval, 1.03 to 1.06), blood transfusion (odds ratio, 1.74; 95 percent confidence interval, 1.03 to 2.93), surgery (odds ratio, 2.30; 95 percent confidence interval, 1.08 to 4.89), fracture of the femur or tibia (odds ratio, 4.82; 95 percent confidence interval, 2.79 to 8.33), and spinal cord injury (odds ratio, 8.59; 95 percent confidence interval, 2.92 to 25.28). CONCLUSIONS Venous thromboembolism is a common complication in patients with major trauma, and effective, safe prophylactic regimens are needed.
Challenges faced by skilled birth attendants in providing antenatal and intrapartum care in selected rural areas of Myanmar

Background: In Myanmar a large proportion of antenatal and intrapartum care in rural areas is provided by skilled birth attendants (SBAs), this study assessed the coverage by these health workers of all births, their adherence to service guidelines, and community opinion on the antenatal and delivery care they give in two rural health centres in Pathein Township, Ayeyarwaddy Region to identify the challenges and improve antenatal and intrapartum service delivery provided by the SBAs. Method: A structured questionnaire was used to interview 304 women who had infants under one year of age, and in-depth interviews were held with 12 SBAs and 10 community members. Results: Of the 304 pregnancies, 93% had received antenatal care (ANC); 97% of these were covered by SBAs at an average 15 weeks’ gestation. The average frequency of ANC visits was 9. Rates of home and hospital deliveries were 84.5% and 13.8% respectively. Among home deliveries, use rate of SBA was 51.4%, while for postnatal care, 31.3% was given by unskilled providers (traditional birth attendants (TBAs) 17.5%, auxiliary midwives (AMWs),13.8%). Multivariate analysis showed that interviewees aged 30 years and below (OR=0.468, P=0.046), with an education at primary level and below that of husband (OR=0.391, P=0.007) or not residing in the village of the rural/station health centre (OR=0.457, P=0.011) were significantly less likely to use SBAs. The categories of supervision, referral, and health education activities of SBAs were not in line with service guidelines. The main reasons were lack of access and community acceptance of TBAs. Conclusion: Heavy workload, geographical location, transportation and financial concerns were major challenges for SBAs, along with community compliance and mutual coordination. Good communication and service management skills were important to overcome these challenges.
Budesonide/Formoterol Pressurized Metered-Dose Inhaler versus Budesonide: A Randomized Controlled Trial in Black Patients with Asthma

Objective. Concerns exist that responses to long-acting β2-adrenergic agonists in black patients may differ from the general population. The efficacy and safety of budesonide/formoterol (BUD/FM) pressurized metered-dose inhaler (pMDI) versus budesonide dry powder inhaler (BUD DPI) were evaluated in adolescent and adult black asthma patients. Methods. This 12-week, randomized, double-blind, multicenter, phase IV US study was conducted in 311 self-reported black patients aged ≥12 years with moderate to severe persistent asthma, previously receiving medium- to high-dose inhaled corticosteroid. After 2 weeks on BUD 90 μg × 2 inhalations twice daily (bid), symptomatic patients were randomized to BUD/FM 160/4.5 μg × 2 inhalations bid or BUD 180 μg × 2 inhalations bid. Results. Improvement in predose forced expiratory volume in 1 second from baseline to the treatment mean (primary variable) was greater with BUD/FM versus BUD (0.16 vs. 0.07 L; p = .008); this effect was also observed at weeks 2, 6, and end of treatment (p ≤ .032). Greater improvements (p < .001) in peak expiratory flow with BUD/FM versus BUD were seen at first measurement and maintained during 12 weeks (morning: 25.34 vs. 7.53 L/minute, respectively; evening: 21.61 vs. 7.67 L/minute, respectively); greater improvements in daily asthma symptom score and rescue medication use were also observed (p ≤ .039). Both treatments were well tolerated, with similar safety profiles. Conclusions. In this population of black asthma patients, BUD/FM pMDI resulted in greater improvements in pulmonary function and asthma control versus BUD DPI, with similar safety profiles.
The PINT Service Protocol: Extensions to SIP and SDP for IP Access to Telephone Call Services

This document contains the specification of the PINT Service Protocol 1.0, which defines a protocol for invoking certain telephone services from an IP network. These services include placing basic calls, sending and receiving faxes, and receiving content over the telephone. The protocol is specified as a set of enhancements and additions to the SIP 2.0 and SDP protocols.
The Effect of the Moscow Theatre Siege on Expectations of Well-Being in the Future

We employ the Russia Longitudinal Monitoring Survey–Higher School of Economics (RLMS-HSE), a survey of 6,000 individuals, and a difference-in-differences estimation strategy to examine the effect of the 2002 Moscow theatre siege on the level of self-reported expectations of life in the future of the Russian population. The longitudinal nature of the data allows us to explore both the short- and long-term effects of terrorism on this population as well as contribute to the limited number of quasi-experimental studies in this area. By focusing on expectations of life in the future, we broaden our understanding of the social consequences of terrorism. Controlling for a range of sociodemographic variables including self-assessed relative income, our findings suggest that the well-being effects of terrorism are complex and the net effect of a terrorism incident on well-being may not necessarily be negative. This can be explained, at least in part, by the theory of posttraumatic growth—a theory that refers to the positive psychological change experienced as a result of adversity, with terrorism incidents inadvertently promoting more meaningful interpersonal relationships, new views of the self and new views of the world. That is not to suggest that terrorism is a positive phenomenon—rather, that individuals have a lifelong plasticity rendering them capable of recovery from adversity. The primary objectives of terrorists, therefore, are unlikely to be fully achieved. It is hoped that our research allows for the development of more refined policies that aim to encourage posttraumatic growth while simultaneously attempting to minimize posttraumatic stress disorder. This may involve engaging with the psychological community to devise policies and programs that target those in the population who are most vulnerable and for these groups devise strategies to enhance their psychological resilience following a terrorist (or other traumatic) event.
Competing Interactions between Micro-RNAs Determine Neural Progenitor Survival and Proliferation after Ethanol Exposure: Evidence from an Ex Vivo Model of the Fetal Cerebral Cortical Neuroepithelium

The fetal brain is sensitive to a variety of teratogens, including ethanol. We showed previously that ethanol induced mitosis and stem cell maturation, but not death, in fetal cerebral cortex-derived progenitors. We tested the hypothesis that micro-RNAs (miRNAs) could mediate the teratogenic effects of ethanol in a fetal mouse cerebral cortex-derived neurosphere culture model. Ethanol, at a level attained by alcoholics, significantly suppressed the expression of four miRNAs, miR-21, -335, -9, and -153, whereas a lower ethanol concentration, attainable during social drinking, induced miR-335 expression. A GABAA receptor-dependent mechanism mediated miR-21, but not miR-335 suppression, suggesting that divergent mechanisms regulate ethanol-sensitive miRNAs. Antisense-mediated suppression of miR-21 expression resulted in apoptosis, suggesting that miR-21 is an antiapoptotic factor. miR-335 knockdown promoted cell proliferation and prevented death induced by concurrently suppressing miR-21, indicating that miR-335 is a proapoptotic, antimitogenic factor whose actions are antagonistic to miR-21. Computational analyses identified two genes, Jagged-1, a Notch-receptor ligand, and embryonic-lethal abnormal vision, Drosophila-like 2 (ELAVL2), a brain-specific regulator of RNA stability, as presumptive targets of three of four ethanol-sensitive micro-RNAs. Combined knockdown of miR-335, -21, and -153 significantly increased Jagged-1 mRNA. Furthermore, ethanol induced both Jagged-1 and ELAVL2 mRNA. The collective suppression of micro-RNAs is consistent with ethanol induction of cell cycle and neuroepithelial maturation in the absence of apoptosis. These data identify a role for micro-RNAs as epigenetic intermediaries, which permit teratogens to shape complex, divergent developmental processes, and additionally demonstrate that coordinately regulated miRNAs exhibit both functional synergy and antagonism toward each other.
Proteomic characterization of cytoskeletal and mitochondrial class III β-tubulin

Class III β-tubulin (TUBB3) has been discovered as a marker of drug resistance in human cancer. To get insights into the mechanisms by which this protein is involved in drug resistance, we analyzed TUBB3 in a panel of drug-sensitive and drug-resistant cell lines. We identified two main different isoforms of TUBB3 having a specific electrophoretic profile. We showed that the apparently higher molecular weight isoform is glycosylated and phosphorylated and it is localized in the cytoskeleton. The apparently lower molecular weight isoform is instead found exclusively in mitochondria. We observed that levels of phosphorylation and glycosylation of TUBB3 are associated with the resistant phenotype and compartmentalization into cytoskeleton. By two-dimensional nonreduced/reduced SDS-PAGE analysis, we also found that TUBB3 protein in vivo forms protein complexes through intermolecular disulfide bridges. Through TUBB3 immunoprecipitation, we isolated protein species able to interact with TUBB3. Following trypsin digestion, these proteins were characterized by mass spectrometry analysis. Functional analysis revealed that these proteins are involved in adaptation to oxidative stress and glucose deprivation, thereby suggesting that TUBB3 is a survival factor able to directly contribute to drug resistance. Moreover, glycosylation of TUBB3 could represent an attractive pathway whose inhibition could hamper cytoskeletal compartmentalization and TUBB3 function. [Mol Cancer Ther 2008;7(7):2070–9]
On the stability limits of long nonaxisymmetric cylindrical liquid bridges

There is a self-similar solution for the stability limits of long, almost cylindrical liquid bridges between equal disks subjected to both axial and lateral accelerations. The stability limits depend on only two variables; the so-called reduced axial, and lateral Bond numbers. A novel experimental setup that involved rotating a horizontal cylindrical liquid bridge about a vertical axis of rotation was designed to test the stability limits predicted by the self-similar solution. Analytical predictions compared well with both numerical and experimental results.
A Tick Vector Transmission Model of Monocytotropic Ehrlichiosis.

BACKGROUND Ehrlichioses are emerging, tick-borne diseases distributed worldwide. Previously established animal models use needle inoculation as a mode of infection; however, there is limited representation of natural transmission in artificially inoculated models compared with transmission by the tick vector. The objective of this study was to develop a tick vector transmission animal model of ehrlichial infection using a human pathogen, Ehrlichia muris-like agent (EMLA). METHODS Ixodes scapularis larvae were fed on EMLA-infected mice, and after molting, infected nymphs were used to infest naive animals. RESULTS Ehrlichiae were acquired by 90%-100% of feeding larvae. The majority of animals fed upon by infected nymphs developed sublethal infection with 27% lethality. Bacteria disseminated to all tissues tested with greatest bacterial loads in lungs, but also spleen, lymph nodes, liver, kidneys, brain, and bone marrow. Numerous foci of cellular infiltration, mitoses, and hepatocellular death were observed in liver. Mice infected by tick transmission developed higher antiehrlichial antibody levels than needle-inoculated animals. Tick-feeding-site reactions were observed, but there was no observed difference between animals infested with infected or uninfected ticks. CONCLUSIONS For the first time we were able to develop a tick transmission model with an Ehrlichia that is pathogenic for humans.
Physical training prevents oxidative stress in L‐NAME‐induced hypertension rats

The present study investigated the effects of a 6‐week swimming training on blood pressure, nitric oxide (NO) levels and oxidative stress parameters such as protein and lipid oxidation, antioxidant enzyme activity and endogenous non‐enzymatic antioxidant content in kidney and circulating fluids, as well as on serum biochemical parameters (cholesterol, triglycerides, urea and creatinine) from Nω‐nitro‐L‐arginine methyl ester hydrochloride (L‐NAME)‐induced hypertension treated rats. Animals were divided into four groups (n = 10): Control, Exercise, L‐NAME and Exercise L‐NAME. Results showed that exercise prevented a decrease in NO levels in hypertensive rats (P < 0·05). An increase in protein and lipid oxidation observed in the L‐NAME‐treated group was reverted by physical training in serum from the Exercise L‐NAME group (P < 0·05). A decrease in the catalase (CAT) and superoxide dismutase (SOD) activities in the L‐NAME group was observed when compared with normotensive groups (P < 0·05). In kidney, exercise significantly augmented the CAT and SOD activities in the Exercise L‐NAME group when compared with the L‐NAME group (P < 0·05). There was a decrease in the non‐protein thiols (NPSH) levels in the L‐NAME‐treated group when compared with the normotensive groups (P < 0·05). In the Exercise L‐NAME group, there was an increase in NPSH levels when compared with the L‐NAME group (P < 0·05). The elevation in serum cholesterol, triglycerides, urea and creatinine levels observed in the L‐NAME group were reverted to levels close to normal by exercise in the Exercise L‐NAME group (P < 0·05). Exercise training had hypotensive effect, reducing blood pressure in the Exercise L‐NAME group (P < 0·05). These findings suggest that physical training could have a protector effect against oxidative damage and renal injury caused by hypertension. Copyright © 2012 John Wiley & Sons, Ltd.
Clinical Characteristics of Human Bocavirus Infections Compared With Other Respiratory Viruses in Spanish Children

Background: Human bocavirus (HBoV) can be found in a substantial proportion of children with respiratory tract diseases. The relative importance of HBoV in viral respiratory tract illnesses is not yet well known. Objective: In this study, we looked for HBoV in pediatric patients to determine the incidence of HBoV as single infection and compared it with other commonly found respiratory viruses to describe the clinical differences associated with HBoV infections in children. Patients and Methods: A prospective study was conducted on children less than 14 years old, admitted with respiratory infection from September 2005 to August 2007 to the Pediatrics Department of the Severo Ochoa Hospital, Madrid, Spain. We studied the frequency of HBoV and 15 other respiratory viruses in nasopharyngeal aspirates and compared the clinical course of the infections caused by HBoV with those caused by other common respiratory viruses. Results: Positive results were confirmed in 435 (61.2%) of the 710 children studied. A single virus was detected in 308 patients. HBoV was found in 99 (13.9%) samples, but it was recovered as a single virus in only 35. Most of patients with HBoV infection (75%) were aged ≤26 months. The most common clinical diagnosis was recurrent wheezing (53%), followed by bronchiolitis (32%). Clinical differences were observed between HBoV and respiratory syncytial virus (RSV) infections (children were older and bronchiolitis less frequent), adenovirus (fever less frequent in HBoV group), and rhinovirus-associated infections (less hypoxia in HBoV group). Conclusions: HBoV was the fourth most frequent single virus after RSV, rhinovirus, and adenovirus in children hospitalized because of respiratory infection. It was associated with recurrent wheezing and bronchiolitis showing a different clinical course from other virus in terms of diagnosis, fever, and age.
Percentage-Avoiding, Northwest Shapes and Peelable Tableaux

We prove three results for Specht and Schur modules associated tonorthwest shapesand the more general class of%-avoiding shapes. The first result (conjectured for northwest shapes in by the authors) is a generalization the Littlewood? Richardson rule, giving an explicit combinatorial description for the multiplicities of irreducibles in the Specht and Schur modules of a %-avoiding shapeD, in terms ofD-peelable tableaux. The second result gives three involutions on the set of peelable tableaux which exhibit the symmetries of these multiplicities corresponding to three natural involutive operations on the set of %-avoiding shapes. The third result gives branching rules for the Specht and Schur modules of northwest shapes. The proofs are all combinatorial, with the exception of a key step in the first result, which requires results of Magyar on configuration varieties and characters of flagged Schur modules.
Embryonic Stem Cell‐Derived Neuronally Committed Precursor Cells with Reduced Teratoma Formation After Transplantation into the Lesioned Adult Mouse Brain

The therapeutic potential of embryonic stem (ES) cells in neurodegenerative disorders has been widely recognized, and methods are being developed to optimize culture conditions for enriching the cells of interest and to improve graft stability and safety after transplantation. Whereas teratoma formation rarely occurs in xenogeneic transplantation paradigms of ES cell‐derived neural progeny, more than 70% of mice that received murine ES cell‐derived neural precursor cells develop teratomas, thus posing a major safety problem for allogeneic and syngeneic transplantation paradigms. Here we introduce a new differentiation protocol based on the generation of substrate‐adherent ES cell‐derived neural aggregates (SENAs) that consist predominantly of neuronally committed precursor cells. Purified SENAs that were differentiated into immature but postmitotic neurons did not form tumors up to four months after syngeneic transplantation into the acutely degenerated striatum and showed robust survival.
CpG methylation accounts for genome-wide C>T mutation variation and cancer driver formation across cancer types

Cytosine methylation (5mC) is vital for cellular function, and yet 5mC sites are also commonly mutated in the genome. In this study, we analyse the genomes of over 900 cancer samples, together with tissue type-specific methylation and replication timing data. We describe a strong mutation-methylation association in colorectal cancers with microsatellite instability (MSI) or with Polymerase epsilon (POLE) exonuclease domain mutation. We describe a potential role for mismatch repair in the correction of mismatches resulting from deamination of 5mC, and propose a mutator phenotype to exist in POLE-mutant cancers specifically at 5mC sites. We also associate POLE-mutant hotspot coding mutations in APC and TP53 with CpG methylation. Analysing mutations across additional cancer types, we identify nucleotide excision repair- and AID/APOBEC-induced processes to underlie differential mutation-methylation associations in certain cancer subtypes. This study reveals differential associations vital for accurately mapping regional variation in mutation density and pinpointing driver mutations in cancer.