Miracle-dz/UniFAR-FTUs huggingface dataset:
Randomized phase III study of pegylated liposomal doxorubicin plus bortezomib compared with bortezomib alone in relapsed or refractory multiple myeloma: combination therapy improves time to progression.

PURPOSE This phase III international study compared the efficacy and safety of a combination of pegylated liposomal doxorubicin (PLD) plus bortezomib with bortezomib monotherapy in patients with relapsed or refractory multiple myeloma. PATIENTS AND METHODS Six hundred forty-six patients were randomly assigned to receive either intravenous bortezomib 1.3 mg/m(2) on days 1, 4, 8, and 11 of an every 21-days cycle, or the same bortezomib regimen with PLD 30 mg/m(2) on day 4. RESULTS Median time to progression was increased from 6.5 months for bortezomib to 9.3 months with the PLD + bortezomib combination (P = .000004; hazard ratio, 1.82 [monotherapy v combination therapy]; 95% CI, 1.41 to 2.35). The 15-month survival rate for PLD + bortezomib was 76% compared with 65% for bortezomib alone (P = .03). The complete plus partial response rate was 41% for bortezomib and 44% for PLD + bortezomib, a difference that was not statistically significant. Median duration of response was increased from 7.0 to 10.2 months (P = .0008) with PLD + bortezomib. Grade 3/4 adverse events were more frequent in the combination group (80% v 64%), with safety profiles consistent with the known toxicities of the two agents. An increased incidence in the combination group was seen of grade 3/4 neutropenia, thrombocytopenia, asthenia, fatigue, diarrhea, and hand-foot syndrome. CONCLUSION PLD with bortezomib is superior to bortezomib monotherapy for the treatment of patients with relapsed or refractory multiple myeloma. The combination therapy is associated with a higher incidence of grade 3/4 myelosuppression, constitutional symptoms, and GI and dermatologic toxicities.
Tagging Complex Non-Verbal German Chunks with Conditional Random Fields

We report on chunk tagging methods for German that recognize complex non-verbal phrases using structural chunk tags with Conditional Random Fields (CRFs). This state-of-the-art method for sequence classification achieves 93.5% accuracy on newspaper text. For the same task, a classical trigram tagger approach based on Hidden Markov Models reaches a baseline of 88.1%. CRFs allow for a clean and principled integration of linguistic knowledge such as part-of-speech tags, morphological constraints and lemmas. The structural chunk tags encode phrase structures up to a depth of 3 syntactic nodes. They include complex prenominal and postnominal modifiers that occur frequently in German noun phrases.
Prevalence , hematology and serum biochemistry in stray dogs naturally infected by Hepatozoon canis in São Paulo [

The clinical signs observed in H. canis-infected dogs in Brazil were anorexia, pale mucous membranes, weight loss, diarrhoea, gait abnormalities, fever, polyuria and polydipsia. The laboratory findings were anemia, leucocytosis with neutrophilia, lymphopenia, monocytosis, and elevated alkaline phosphatase (Gondim et al., 1998; Paludo et al., 2003; Aguiar et al., 2004). All the animals in these studies had concurrent diseases and the findings could not be exclusively attributed to H. canis. The few studies on H. canis infection in Brazil show the lack of information about the epidemiology, pathogenicity and genetic characterization of H. canis in this country.
Dynamics transitions at the outer vestibule of the KcsA potassium channel during gating

Significance C-type inactivation gating in K+ channels plays an important role in controlling the firing patterns of excitable cells and is fundamental in determining the length and frequency of the cardiac action potential. At a molecular level, toxins, blockers, and metal ions bind to the outer vestibule and modulate the functional behavior of K+ channels. Using KcsA, we show that the shuttling between the inactivated and conductive states of K+ channels is accompanied by changes in local outer vestibule dynamics, in the absence of large conformational changes. The altered structural and hydration dynamics of the outer vestibule appear to be likely and important modulators of selectivity filter gating transitions in K+ channels. In K+ channels, the selectivity filter, pore helix, and outer vestibule play a crucial role in gating mechanisms. The outer vestibule is an important structurally extended region of KcsA in which toxins, blockers, and metal ions bind and modulate the gating behavior of K+ channels. Despite its functional significance, the gating-related structural dynamics at the outer vestibule are not well understood. Under steady-state conditions, inactivating WT and noninactivating E71A KcsA stabilize the nonconductive and conductive filter conformations upon opening the activation gate. Site-directed fluorescence polarization of 7-nitrobenz-2-oxa-1,3-diazol-4-yl (NBD)-labeled outer vestibule residues shows that the outer vestibule of open/conductive conformation is highly dynamic compared with the motional restriction experienced by the outer vestibule during inactivation gating. A wavelength-selective fluorescence approach shows a change in hydration dynamics in inactivated and noninactivated conformations, and supports a possible role of restricted/bound water molecules in C-type inactivation gating. Using a unique restrained ensemble simulation method, along with distance measurements by EPR, we show that, on average, the outer vestibule undergoes a modest backbone conformational change during its transition to various functional states, although the structural dynamics of the outer vestibule are significantly altered during activation and inactivation gating. Taken together, our results support the role of a hydrogen bond network behind the selectivity filter, side-chain conformational dynamics, and water molecules in the gating mechanisms of K+ channels.
An Experiment on Node Size in a Hypermedia System

The node size that should be used in a hypermedia system is an important design issue. Three interpretations of node size are identified: storage (physical size), window size (presentation size), and length (logical size). An experiment in which presentation size and text length are varied in a HyperCard application is described. The experiment involves student subjects performing a fact retrieval task from a reference handbook. No interaction is found between these two independent variables. Performance is significantly better for the longer texts, but no significant difference is found for the two different window sizes.
Targeting Natural Killer Cells to Acute Myeloid Leukemia In Vitro with a CD16 × 33 Bispecific Killer Cell Engager and ADAM17 Inhibition

Purpose: The graft versus leukemia effect by natural killer (NK) cells prevents relapse following hematopoietic stem cell transplantation. We determined whether a novel bispecific killer cell engager (BiKE) signaling through CD16 and targeting CD33 could activate NK cells at high potency against acute myelogenous leukemia (AML) targets. Experimental Design: We investigated the ability of our fully humanized CD16 × CD33 (CD16 × 33) BiKE to trigger in vitro NK cell activation against HL60 (CD33+), RAJI (CD33−), and primary AML targets (de novo and refractory) to determine whether treatment with CD16 × 33 BiKE in combination with an ADAM17 inhibitor could prevent CD16 shedding (a novel inhibitory mechanism induced by NK cell activation) and overcome inhibition of class I MHC recognizing inhibitory receptors. Results: NK cell cytotoxicity and cytokine release were specifically triggered by the CD16 × 33 BiKE when cells were cultured with HL60 targets, CD33+ de novo and refractory AML targets. Combination treatment with CD16 × 33 BiKE and ADAM17 inhibitor resulted in inhibition of CD16 shedding in NK cells, and enhanced NK cell activation. Treatment of NK cells from double umbilical cord blood transplant (UCBT) recipients with the CD16 × 33 BiKE resulted in activation, especially in those recipients with cytomegalovirus reactivation. Conclusion: CD16 × 33 BiKE can overcome self-inhibitory signals and effectively elicit NK cell effector activity against AML. These in vitro studies highlight the potential of CD16 × 33 BiKE ± ADAM17 inhibition to enhance NK cell activation and specificity against CD33+ AML, which optimally could be applied in patients with relapsed AML or for adjuvant antileukemic therapy posttransplantation. Clin Cancer Res; 19(14); 3844–55. ©2013 AACR.
The reduction of HIV transfusion risk in southern Brazil in the 1990s

A retrospective study of blood donor records was undertaken to obtain risk estimates for transfusing HIV‐contaminated blood due to an infectious window period in a large blood bank in the south of Brazil in the 1990s. An incidence/window period model was used to estimate HIV incidence and risk of seroconversion among 11 286 repeat donors with 8917 person‐years of follow‐up. Separate estimates were calculated for the periods of 1991–94, 1995–96 and 1997–99. Although the residual risk of HIV‐positive transfusion decreased from 1 : 5000 in 1991–94 and 1 : 3794 in 1995–96 to 1 : 48 777 in 1997–99, this is still almost 10 times higher than in developed countries. The risk reduction is likely to have resulted from improved donor selection. Despite a 10‐fold reduction in the risk of transfusing HIV‐contaminated blood because of the screening test's failure to detect the virus during the infectious window period in the 1990s, additional measures are urgently needed to reduce the risk further. To this end, PCR screening of pooled blood donations might be considered in areas of high HIV prevalence when justified by cost‐effectiveness calculations.
Individual differences in susceptibility to false memories: The effect of memory specificity

Previous research has highlighted the wide individual variability in susceptibility to the false memories produced by the Deese/Roediger–McDermott (DRM) procedure. This study investigated whether susceptibility to false memories is influenced by individual differences in the specificity of autobiographical memory retrieval. Memory specificity was measured using the Sentence Completion for Events from the Past Test (SCEPT). Memory specificity did not correlate with correct recognition, but a specific retrieval style was positively correlated with levels of false recognition. It is proposed that the contextual details that frequently accompany false memories of non-studied lures are more accessible in individuals with specific retrieval styles.
Can exaggerated response to a GH provocative test identify patients with partial GH insensitivity syndrome?

OBJECTIVES In the majority of children with short stature, the etiology is unknown. Mutations of the GH receptor (GHR) have been reported in a few children with apparent idiopathic short stature (ISS). These patients had low IGF-I, IGF-binding protein-3 (IGFBP-3) and GH-binding protein (GHBP), but a normal or exaggerated GH response to provocative stimuli, suggestive of partial GH insensitivity (GHI). We attempted to identify children with partial GHI syndrome, based on their response to GH provocative stimuli and other parameters of the GH-IGF-I axis. SUBJECTS AND METHODS One hundred and sixty-four pre-pubertal children (97 boys, 67 girls) aged 7.2 (0.5-16.75) years were studied. All had short stature with height <3rd centile. The weight, bone age (BA) and body mass index (BMI) of the subjects, as well as the parents' heights and mid parental height (MPH) were assessed. Basal blood samples were taken for IGF-I, IGFBP-3 and GHBP. All subjects underwent a GH provocative test with either clonidine, arginine or insulin. The subjects were divided into three groups: (A) patients with peak GH concentration <18 mIU/l in two different provocative tests (GH deficiency - GHD, n=33); (B) patients with peak GH between 18.2 and 39.8 mIU/l (normal response, n=78); (C) patients with peak GH >40 mIU/l (exaggerated GH response, n=53). RESULTS No significant differences were found in age, height (standard deviation score (SDS)), parental height (SDS) and the difference between chronological age and bone age (DeltaBA) between the groups. Patients with GHD were heavier (P=0.039) and had significantly higher BMI (SDS) (P=0.001) than the other groups. MPH (SDS) was lower in the group of exaggerated responders (P=0.04) compared with the other groups. No significant differences were found between the groups for the biochemical parameters when expressed nominally or in SDS, except for IGFBP-3 (SDS), which was lower in the GHD group (P=0.005). The GHBP levels were not lower in the group of exaggerated GH response to provocative stimuli. Height (SDS) correlated negatively with basal GH values in pooled data of all the subjects (r=-0.358, P<0.0001), in normal responders (r=-0.45, P<0.0001) and in the exaggerated responders (r=-0.341, P<0.0001), but not in the GHD group. CONCLUSION Exaggerated GH response to provocative tests alone does not appear to be useful in identifying children with GHI.
Rapid decay of averaged single-channel NMDA receptor activations recorded at low agonist concentration

The NMDA class of glutamate receptors have the unique property of binding some agonists, including glutamate, for a very long period of time. One manifestation of this is that brief (1 ms) application of glutamate (1 mM) produces a slowly decaying current, the major component of which has a time constant of approximately 200 ms. Application of glutamate at low concentrations allows identification of groups (‘superclusters’) of openings in the data record that probably correspond to a single period during which one or more molecules of glutamate are bound to the receptor, i. e. a single activation of the channel. The length of such superclusters is long on average (74 ms); the longest component of the distribution has a duration of approximately 300 ms, and comprises about 25% of the area. However, aligning many superclusters to obtain an average current reveals that the decay is mainly fast; the major component has a time constant of around only 5 ms. It is shown that incorporation of a distribution of first latencies (from the time of the jump to the first opening) can explain at least part of this discrepancy.
The nuclear receptor RORα exerts a bi-directional regulation of IL-6 in resting and reactive astrocytes

Astrocytes and one of their products, IL-6, not only support neurons but also mediate inflammation in the brain. Retinoid-related orphan receptor-α (RORα) transcription factor has related roles, being neuro-protective and, in peripheral tissues, anti-inflammatory. We examined the relation of RORα to astrocytes and IL-6 using normal and RORα loss-of-function mutant mice. We have shown RORα expression in astrocytes and its up-regulation by pro-inflammatory cytokines. We have also demonstrated that RORα directly trans-activates the Il-6 gene. We suggest that this direct control is necessary to maintain IL-6 basal level in the brain and may be a link between the neuro-supportive roles of RORα, IL-6, and astrocytes. Furthermore, after inflammatory stimulation, the absence of RORα results in excessive IL-6 up-regulation, indicating that RORα exerts an indirect repression probably via the inhibition of the NF-κB signaling. Thus, our findings indicate that RORα is a pluripotent molecular player in constitutive and adaptive astrocyte physiology.
Establishment and hormonal regulation of a conditionally transformed preosteocytic cell line from adult human bone.

Osteocytes are differentiated forms of osteoblasts that arise upon entrapment within the bone matrix. In this report, we describe the establishment and hormonal regulation of the first conditionally transformed human preosteocytic cell line. Primary adult bone cells were obtained from protease cell line. Primary adult bone cells were obtained from protease digestion of cancellous chips. The cells were infected with adenovirus-ori- SV40 tsA 209, which encodes for a temperature-sensitive large T-antigen. After immortalization, we isolated a clone designated HOB-01-C1. This cell line expressed the mutant T-antigen and proliferated at the permissive temperature (34 C) but stopped dividing at the nonpermissive temperature (39-40 C). Electron microscopy of cells incubated at 39 C demonstrated the presence of preosteocytic cellular processes, some of which appeared to form gap junctions or were rich in microfilaments. The clone expressed alpha 1 type (I) procollagen messenger RNA (mRNA) and secreted type I procollagen C peptide at both temperatures, and this expression was elevated 1.6-fold to 1.8-fold at 40 degrees C. The cells expressed very low basal levels of alkaline phosphatase activity (approximately 0.02 nmol/min.mg), which was increased 2- to 5-fold in a dose-dependent manner by 0.1-100 nM 1 alpha,25-dihydroxyvitamin D3 (vitamin D3) at both temperatures. Vitamin D3 also increased osteocalcin secretion in a dose-dependent manner when the clone was maintained at 34 C (approximately 6-fold), and this stimulation was enhanced > 5 fold at 40 C. In contrast to the low expression of alkaline phosphatase, the cells secreted high amounts of osteocalcin in response to vitamin D3 (approximately 15 ng/mg cell protein); this biochemical profile also resembled that of preosteocytes. Alizarin red-S histochemical staining demonstrated that these cells rapidly produced mineralized nodules at both temperatures. PTH (10 and 100 nM) had no effect on the intracellular accumulation of cAMP at 34 C but stimulated a 14- to 18-fold increase in the production of this second messenger at 40 C. In contrast, 100 nM prostaglandin E2 and 1 microM forskolin stimulated cAMP synthesis better at 34 C. Western blot analysis indicated that the cells expressed CD44, a putative osteocytic marker, at both temperatures. Finally, interleukin-1 beta and tumor necrosis factor-alpha (1-1000 pM) stimulated dose-dependent increases in the secretion of interleukin-6 and monocyte chemoattractant protein-1 at 34 C and 40C. We conclude that the HOB-01-C1 cell line has a preosteocytic phenotype. Moreover, these cells respond to calcitropic hormones and bone resorbing cytokines.
Social and Legal Control in China: A Comparative Perspective

This article exposes the reader to a different social and legal control system and a different way of thinking about crime—that of China. Chinese think positively about the nature of humans and their potential, and China’s social control system weaves together a unique combination of formal and informal mechanisms with a strong emphasis on the latter. The criminal justice system constitutes a key element of the social control system, but it appears to be more of a last resort. It is hoped that through a comparative analysis, the reader can develop a deeper understanding of different social and legal systems.
Mode of Delivery Determines Neonatal Pharyngeal Bacterial Composition and Early Intestinal Colonization

Objectives: Bacterial colonization and succession of the human intestine shape development of immune function and risk for allergic disease, yet these processes remain poorly understood. We investigated the relations between delivery mode, initial bacterial inoculation of the infant oropharynx (OP), and intestinal colonization. Methods: We prospectively collected maternal rectal and vaginal swabs, infant OP aspirates, and infant stool from 23 healthy mother/infant pairs delivering by cesarean (CS) or vaginal delivery (VD) in an academic hospital. Bacterial abundance (16S rRNA sequencing) and community similarity between samples were compared by delivery mode. Shotgun DNA metagenomic sequencing of infant stool was performed. Results: VD infants had higher abundance of Firmicutes (mainly lactobacilli) in OP aspirates whereas CS OP aspirates were enriched in skin bacteria. OP aspirates were more similar to maternal vaginal and rectal microbiomes in VD compared with CS. Bacteroidetes were more abundant through 6 weeks in stool of VD infants. Infant fecal microbiomes in both delivery groups did not resemble maternal rectal or vaginal microbiomes. Differences in fecal bacterial gene potential between CS and VD at 6 weeks clustered in metabolic pathways and were mediated by abundance of Proteobacteria and Bacteroidetes. Conclusions: CS infants exhibited different microbiota in the oral inoculum, a chaotic pattern of bacterial succession, and a persistent deficit of intestinal Bacteroidetes. Pioneer OP bacteria transferred from maternal vaginal and intestinal communities were not prominent constituents of the early infant fecal microbiome. Oral inoculation at birth may impact the intestinal microenvironment, thereby modulating early succession of intestinal bacteria.
Improvement, Clinical Course, and Quality of Life After Palliative Radiotherapy for Recurrent Glioblastoma

The purpose of this review is to assess the palliative effect of re-irradiation in adult patients with recurrent supratentorial glioblastoma (GBM) previously treated with adjuvant or primary radiation therapy, with or without chemotherapy. From a comprehensive literature search, studies were identified reporting on survival, progression, and quality of life endpoints including, but not limited to, EORTC QLQ-C30 questionnaire, clinical symptoms, and ability to reduce dexamethasone. Data from more than 300 GBM patients (grade 3 anaplastic gliomas were excluded) demonstrate that re-irradiation yields 6-month PFS of 28% to 39% and 1-year overall survival of 18% to 48%, without additional chemotherapy (median value 26%). Patients with Karnofsky performance status <70 appeared to be at higher risk of early progression and apparently had lesser benefit from re-irradiation. Clinical improvement was observed in 24% to 45% of the patients. Most studies suggest that stabilization of the performance status is a realistic aim. In the studies reporting on corticosteroid usage during and after re-irradiation, 20% to 60% of the patients achieved a reduction in steroid dependency. Serious late toxicity was uncommon, especially after conventional treatment and fractionated stereotactic radiotherapy (FSRT). In light of recent technological advances such as FSRT and intensity modulated radiotherapy, which permit maximal sparing of normal brain, re-treatment seems attractive, and deserves scientific validation. Even fraction sizes of 3 to 5 Gy seem to be well tolerated in limited-volume recurrences as long as the total dose is limited to 30 to 35 Gy. Salvage chemotherapy or targeted agents should be prospectively tested against re-irradiation alone.
Inhibition of adhesion of enterotoxigenic Escherichia coli K88 by soya bean tempe

Aims: Tempe is a traditional fungal fermented food made from soaked and cooked soya beans. It has been associated with antidiarrhoeal characteristics. This study investigated potential inhibitory effects of tempe on enterotoxigenic Escherichia coli (ETEC) K88. Methods and Results: Soya beans were soaked, cooked and subsequently fermented using several Rhizopus spp. Water‐soluble filter‐sterile extracts were tested for their ability to inhibit growth of E. coli and several indicator microorganisms and to inhibit adhesion of ETEC K88. Antimicrobial activity was found against Bacillus stearothermophilus only. ETEC K88‐induced haemagglutination of hamster red blood cells was strongly inhibited by a number of tempe extracts and hardly by the cooked soya bean extract. Furthermore, several tempe extracts were able to inhibit adhesion of ETEC K88 to piglet small intestinal brush‐border membranes. Conclusions: Tempe appeared to interfere with ETEC K88 adhesion rather than showing growth inhibitory properties. Significance and Impact of the Study: The results indicate that tempe could exert an antagonistic effect against ETEC through inhibition of adhesion and might therefore have a protective effect against ETEC K88 infection in pigs. Hence, tempe could have potential to use as a feed supplement in the diet of weaned piglets.