Miracle-dz/UniFAR-FTUs huggingface dataset:
Effective lysis of lymphoma cells with a stabilised bispecific single‐chain Fv antibody against CD19 and FcγRIII (CD16)

A recombinant bispecific single‐chain fragment variable antibody (bsscFv), directed against the B‐cell antigen CD19 and the low affinity Fc‐receptor FcγRIII (CD16), was designed for use in the treatment of patients with leukaemias and lymphomas. The Fc‐portions of whole antibodies were deliberately eliminated in this construct to avoid undesired effector functions. A stabilised bsscFv, ds[CD19 × CD16], was generated, in which disulphide bonds bridging the respective variable light (VL) and variable heavy (VH) chains were introduced into both component single‐chain (sc)Fvs. After production in 293T cells and chromatographic purification, ds[CD19 × CD16] specifically and simultaneously bound both antigens. The serum stability of ds[CD19 × CD16] was increased more than threefold when compared with the unstabilised counterpart, while other biological properties were not affected by these mutations. In antibody‐dependent cellular cytotoxicity experiments, ds[CD19 × CD16] mediated specific lysis of both CD19‐positive malignant human B‐lymphoid cell lines and primary tumour cells from patients with B‐cell chronic lymphocytic leukaemia or B‐cell acute lymphoblastic leukaemia. Natural killer cells, mononuclear cells (MNCs) from healthy donors and, in some instances, MNCs isolated from patients after allogeneic stem cell transplantation, were used as effectors. Thus, ds[CD19 × CD16] holds promise for the treatment of CD19+ B‐lineage malignancies.
Participation of Tyrosine Phosphorylation in Cytoskeletal Reorganization, &agr;IIb&bgr;3 Integrin Receptor Activation, and Aspirin-Insensitive Mechanisms of Thrombin-Stimulated Human Platelets

BackgroundFibrinogen binding to the active conformation of the &agr;IIb&bgr;3 integrin receptor (glycoprotein IIb/IIIa) and cytoskeletal reorganization are important events in platelet function. Tyrosine phosphorylation of platelet proteins plays an essential role in platelet signal transduction pathways. We studied the participation of tyrosine kinases on these aspects of platelet reactivity and their importance in cyclooxygenase (COX)-1–independent mechanisms in thrombin-stimulated human platelets. Methods and ResultsUsing washed platelets from normal donors and tyrphostin-A47 and aspirin as tyrosine kinase and COX-1 inhibitors, respectively, we found that tyrphostin-A47 downregulated (1) the thrombin-activated conformational change of &agr;IIb&bgr;3, (2) actin polymerization and cytoskeletal reorganization, and (3) the quantity of tyrosine-phospho-rylated proteins associated with the reorganized cytoskeleton. The latter are important components of multimolecular signaling complexes. Concomitantly, platelet aggregation and secretion were significantly reduced. Aspirin did not affect receptor activation or tyrosine phosphorylation but did decrease the initial (30-second) burst of actin polymerization. Importantly, aspirin significantly amplified the inhibitory effect of tyrphostin-A47 on all aspects of platelet reactivity that we evaluated. ConclusionsTyrosine protein phosphorylation is a regulatory control system of the inside-out mechanism of &agr;IIb&bgr;3 activation and cytoskeletal assembly in thrombin-stimulated human platelets. Inhibition of these aspects of platelet function with tyrphostin-A47 is amplified when platelets are treated with aspirin. Therefore, tyrosine phosphorylation is a major component of early signaling events and of COX-1–independent mechanisms of thrombin-induced platelet reactivity. The study results may indicate a novel target for therapeutic intervention.
Functional and anatomical connection between the paraventricular nucleus of the thalamus and dopamine fibers of the nucleus accumbens

The shell of the nucleus accumbens (NacSh) receives a dense innervation from dopamine (DA) neurons in the ventral tegmental area (VTA) and from glutamate neurons in the paraventricular nucleus of the thalamus (PVT). The present study examined in urethane‐anesthetized rats the effects of electrical stimulation of the PVT on DA levels in the NacSh as measured with amperometry and chronoamperometry. Stimulation of the PVT (40 Hz, 1.0 ms, 400 μA, 5 seconds) resulted in a brief increase in electrochemical currents detected in the NacSh. Inhibition of DA neurons in the VTA using lidocaine (4%, 500 nL) or intravenous apomorphine (0.15 mg/kg) decreased the resting voltammetric signal but had no effect on PVT‐evoked responses. Blocking of ionotropic glutamate receptors in the NacSh with local administration of kynurenic acid attenuated the PVT‐evoked responses. Anterograde tracing with biotinylated dextran amine demonstrated that PVT targets regions of very dense tyrosine hydroxylase fiber staining in the NacSh. Consistent with the projection pattern of the PVT to the NacSh, stimulation of the PVT evoked the largest oxidation current changes in the NacSh, whereas small or no changes were elicited in other areas of the striatum. This study suggests that glutamate release from PVT terminals can act on ionotropic glutamate receptors in the NacSh to induce DA efflux. Modulation of DA levels in the NacSh by the PVT may be linked to arousal‐induced increases in DA tone and could be involved in the facilitation of specific behavioral patterns associated with arousal or stressful situations. J. Comp. Neurol. 500:1050–1063, 2007. © 2006 Wiley‐Liss, Inc.
What do Students Gain from a Week at Science Camp? Youth perceptions and the design of an immersive, research‐oriented astronomy camp

This study explored American high school students’ perceptions of the benefits of a summer astronomy camp, emphasizing a full cycle of the research process and how the organization of the camp contributed to those perceptions. Semi‐structured interviews with students and staff were used to elicit the specific benefits that campers perceived from their experiences and examine them in relation to the stated goals and strategies of camp staff. Among the perceived benefits that students described were peer relationships, personal autonomy, positive relationships with staff, and deepened science knowledge. These perceived benefits appear to influence the kinds of identities students constructed for themselves in relation to science. Gee’s concept of ‘affinity space’ is used to consider how features of the camp’s design, especially those that promoted student autonomy, contributed to students’ positive perceptions, and to draw implications for the design of informal science learning experiences that can link youth with larger communities of scientists.
Discovering Implicit Customer Connections with a Cognitive Situation Model

Exploration of implicit information of customers is a vital task for industrial enterprises and organizations. Text and data mining are two indispensable means to accomplish above task. This paper presents a hybrid mining system, EIREx, which processes unstructured (text documents) and structured (data tables from databases) information as a whole source. The construction of EIREx is inspired by a cognitive situation model, Event-Indexing Model. EIREx monitors customer information in multidimensional vectors to simulate cognitive understanding processes of human beings. To ensure accuracy, EIREx implements syntactic parsing, lexical reference and semantic analysis in information extraction procedures from mining sources. In the procedures of information integration and cross referencing, EIREx delivers a structural description to reveal implicit connections among existing customers, which are valuable for further analysis of customer orders and purchase motivations or intentions, and dealing with customerspsila complaints and suggestions.
The Capsule-Encoding viaB Locus Reduces Intestinal Inflammation by a Salmonella Pathogenicity Island 1-Independent Mechanism

ABSTRACT Salmonella enterica serotype Typhimurium elicits acute neutrophil influx in the human intestinal mucosa within 1 or 2 days after infection, resulting in inflammatory diarrhea. In contrast, no overt symptoms are observed within the first 1 or 2 weeks after infection with S. enterica serotype Typhi. Here we show that introduction of the capsule-encoding viaB locus of serotype Typhi reduced the ability of serotype Typhimurium to elicit acute intestinal inflammation in a streptomycin-pretreated mouse model. Serotype Typhimurium requires a functional invasion-associated type III secretion system (type III secretion system 1 [T3SS-1]) to elicit cecal inflammation within 48 h after infection of streptomycin-pretreated mice, and the presence of the viaB locus reduced its invasiveness for human intestinal epithelial cells in vitro. However, a reduced activity of T3SS-1 could not account for the ability of the viaB locus to attenuate cecal inflammation, because introduction of the viaB locus into an invasion-deficient serotype Typhimurium strain (invA mutant) resulted in a significant reduction of pathology and inflammatory cytokine expression in the cecum 5 days after infection of mice. We conclude that a T3SS-1-independent mechanism contributes to the ability of the viaB locus to reduce intestinal inflammation.
Sex-Linkage of Sexually Antagonistic Genes is Predicted by Female, but Not Male, Effects in Birds

Evolutionary theory predicts that sexually antagonistic loci will be preferentially sex-linked, and this association can be empirically testes with data on sex-blased gene expression with the assumption that sex-blased gene expression represents the resolution of past sexual antagonism. However, incomplete dosage compensating mechanisms and meiotic sex chromosome inactivation have hampered efforts to connect expression data to theoretical predictions regarding the genomic distribution of sexually antagonistic loci in a variety of animals. Here we use data on the underlying regulatory mechanism that produce expression sex-blas to test the genomic distribution of sexually antagonistic genes in chicken. Using this approach, which is free from problems associated with the lack of dosage compensation in birds, we show that female-detriment genes are significantly overrepresented on the Z chromosome, and female-benefit genes underrepresented. By contrast, male-effect genes show no over- or underrepresentation on the Z chromosome. These data are consistent with a dominant mode of inheritance for sexually antagonistic genes, in which male-benefit coding mutations are more likely to be fixed on the Z due to stronger male-specific selective pressures. After fixation of male-benefit alleles, regulatory changes in females evolve to minimize antagonism by reducing female expression.
Survival and prognostic variables of cutaneous melanoma observed between 1995 and 2000 at Istituto Dermopatico Dell'Immacolata (IDI-IRCCS), Rome, Italy

Introduction Melanoma is an increasingly common malignancy of melanocytes, with incidence rates steadily rising over the past several decades. The objective of this study was to evaluate 5-year survival and to investigate the association between melanoma mortality and clinical and histological features. Methods We conducted a 5-year cohort study among 1020 patients from the same geographic area (Rome) with a single primary cutaneous melanoma diagnosed between January 1995 and December 2000. Survival probability was determined by Kaplan–Meier estimates, and prognostic factors were evaluated by multivariate analysis (Cox proportional hazards model). Results Survival decreased with increasing age (P for trend <0.049) and Breslow thickness (P for trend <0.0001). In the multivariate Cox model, Breslow thickness was the only independent prognostic factor for mortality in primary melanoma patients. The risk of death among patients with melanoma increased with increasing tumour thickness 0.76–1.49 mm (relative risk (RR) 2.67, 95% confidence interval (95% CI) 0.63–11.4); 1.50–4.0 mm (RR 6.38, 95% CI 1.75–23.2), >4.0 mm (RR 34.6, 95% CI 8.23–145.7) (P for trend <0.0001). The Years of Life Lost (YLLs) for the Breslow categories ≤0.75 mm, 0.76–1.49 mm, 1.50–4.0 mm and >4.0 mm were 65.4, 153.6, 274.3 and 317.6 years, respectively. Conclusion This study shows the great importance of secondary melanoma prevention and illustrates how many years of life could be saved by early diagnosis.
The severity and pattern of emesis following different cytotoxic agents.

Different cytotoxic drugs induce different patterns of emesis. This is relevant to clinical practice since we often see in the medical literature oversimplifications in the recommendation for management of chemotherapy-induced emesis, so that the same guidelines are given for cisplatin and non-cisplatin-containing chemotherapy. In particular, cisplatin induces a biphasic pattern of emesis which is characterized by an acute immediate phase and a delayed phase. These two phases are clearly different, especially when cisplatin is given in short i.v. administration (e.g. over 20 min to 1 h) and in high doses (1000-120 mg/m2). On the other hand, cyclophosphamide and carboplatin induce a quite different pattern of emesis, characterized by a monophasic curve which although more intense in the first 24 h, may continue for a number of days. The antiemetic response to 5-HT3 receptor antagonists on days 2-5 is good in the case of carboplatin and cyclophosphamide and poor in the case of cisplatin (delayed emesis after cisplatin). This firmly suggests that the pathogenesis of cisplatin-induced emesis may differ from that induced by other cytotoxic drugs, especially in the delayed phase of emesis. We think that we should reserve the term 'delayed emesis' for the late emesis induced by cisplatin, while 'prolonged emesis' could be a better denomination for the late emesis induced by cyclophosphamide and carboplatin. The main clinical implication of these observations is that 5-HT3 receptor antagonists should be administered over 3-5 days in the case of carboplatin and cyclophosphamide, while a short treatment during the first day could be sufficient to control the acute phase of cisplatin-induced emesis.
Alcohol Teratogenesis: Mechanisms of Damage and Strategies for Intervention

There are multiple mechanisms by which alcohol can damage the developing brain, but the type of damage induced will depend on the amount and developmental timing of exposure, along with other maternal and genetic factors. This article reviews current perspectives on how ethanol can produce neuroteratogenic effects by its interactions with molecular regulators of brain development. The current evidence suggests that alcohol produces many of its damaging effects by exerting specific actions on molecules that regulate key developmental processes (e.g., L1 cell adhesion molecule, alcohol dehydrogenase, catalase), interfering with the early development of midline serotonergic neurons and disrupting their regulatory-signaling function for other target brain structures, interfering with trophic factors that regulate neurogenesis and cell survival, or inducing excessive cell death via oxidative stress or activation of caspase-3 proteases. The current understanding of pathogenesis mechanisms suggests several strategic approaches to develop rational molecular prevention. However, the development of behavioral and biologic treatments for alcohol-affected children is crucial because it is unlikely that effective delivery of preventative interventions can realistically be achieved in ways to prevent prenatal damage in at-risk pregnancies. Toward that end, behavioral training that promotes experience-dependent neuroplasticity has been effective in a rat model of cerebellar damage induced by alcohol exposure during the period of brain development that is comparable to that of the human third trimester.
A split-face comparison of facial hair removal with the long-pulsed alexandrite laser and intense pulsed light system

Abstract Background: Undesirable hair growth presents a significant problem for many patients. Photoepilation has become a very popular procedure in esthetic and cosmetic practice. Among the systems used are the long-pulsed alexandrite laser (755 nm) (ALX) and intense pulsed light (IPL). Objective: To compare the safety and efficacy of long-pulsed ALX and IPL for hair removal. Patients and methods: This comparative study was carried out in the outpatient Department of Dermatology and Venereology, Al-Sadir Teaching Hospital, Al Najaf City during the period from June 2009 to July 2010. Thirty-five patients were included; thirty of them completed the study. They received six treatment sessions with the ALX on the left side of the face and IPL on the right side of face with 4-week intervals between sessions. Response to treatment on both sides of the face was assessed at 1, 3, and 6 treatment sessions. Hair-free intervals and patient's satisfaction were recorded in each visit. Results: After six treatment sessions, IPL-treated sides showed longer median hair-free intervals compared with ALX-treated sides. Reduction in hair counts was significantly larger on the IPL compared with that on the ALX-treated sides at 1, 3, and 6 sessions. Three patients (10%) developed postinflammatory hyperpigmentation, one of them on the left side and the others on the right side. It was more severe on the right side and both the patients were of skin type IV. Slight stinging and burning sensation at time of the treatment were recorded in all patients. All reported side effects were transient and tolerated by the patients except postinflammatory hyperpigmentation which persisted and was decreasing gradually toward the end of the study. Conclusions: The results of this study suggested that IPL is more effective in reducing excessive facial hair growth, with longer hair-free intervals and greater patient satisfaction than the ALX.
Preoperative serum CA-125 levels in treating endometrial cancer.

OBJECTIVE To evaluate preoperative levels of CA-125 for the prediction of advanced stages of uterine cancer. STUDY DESIGN Retrospective chart review of 141 women with endometrial cancer who were treated by a single gynecologic oncologist at a community teaching hospital in North Carolina between November 1994 and September 2002. RESULTS Ninety-three of 106 patients (87.7%) with surgical stage I or II endometrial cancer had normal preoperative CA-125 levels. Ten of 11 (91%) women with stage IV endometrial cancer had elevated preoperative CA-125 levels. High CA-125 levels and positive lymph vascular space invasion correlated most strongly with advanced stage (p < 0.01). Similar trends in correlation of CA-125 levels were seen with the highest grade and the deepest myometrial invasion. The sensitivity and specificity of a CA-125 cutoff level of 35 U/mL were 63% and 88%, respectively, with a positive predictive value of 61% and negative predictive value of 89%. CONCLUSION Measurement of preoperative CA-125 is a clinically useful test in endometrial cancer patients. CA-125 appears to be a significant independent predictor of the extrauterine spread of disease and is a better predictor of disease than depth of invasion or grade. This evidence complements a growing body of literature that supports the strong relationship between CA-125 level and stage of disease. A CA-125 level should be included as part of the preoperative workup for all patients with endometrial cancer.
Characterization of creatine guanidinium proton exchange by water‐exchange (WEX) spectroscopy for absolute‐pH CEST imaging in vitro

Chemical exchange saturation transfer (CEST) enables indirect detection of small metabolites in tissue by MR imaging. To optimize and interpret creatine‐CEST imaging we characterized the dependence of the exchange‐rate constant ksw of creatine guanidinium protons in aqueous creatine solutions as a function of pH and temperature T in vitro. Model solutions in the low pH range (pH = 5–6.4) were measured by means of water‐exchange (WEX)‐filtered 1H NMR spectroscopy on a 3 T whole‐body MR tomograph. An extension of the Arrhenius equation with effective base‐catalyzed Arrhenius parameters yielded a general expression for ksw(pH, T). The defining parameters were identified as the effective base‐catalyzed rate constant kb,eff(298.15 K) = (3.009 ± 0.16) × 109 Hz l/mol and the effective activation energy EA,b,eff = (32.27 ± 7.43) kJ/mol at a buffer concentration of cbuffer = (1/15) M. As expected, a strong dependence of ksw on temperature was observed. The extrapolation of the exchange‐rate constant to in vivo conditions (pH = 7.1, T = 37 °C) led to the value of the exchange‐rate constant ksw = 1499 Hz. With the explicit function ksw(pH, T) available, absolute‐pH CEST imaging could be realized and experimentally verified in vitro. By means of our calibration method it is possible to adjust the guanidinium proton exchange‐rate constant ksw to any desired value by preparing creatine model solutions with a specific pH and temperature. Copyright © 2014 John Wiley & Sons, Ltd.
Phase-locked multi-terahertz electric fields exceeding 13  MV/cm at a 190  kHz repetition rate.

We demonstrate a compact source of energetic and phase-locked multi-terahertz pulses at a repetition rate of 190 kHz. Difference frequency mixing of the fundamental output of an Yb:KGW amplifier with the idler of an optical parametric amplifier in GaSe and LiGaS2 crystals yields a passively phase-locked train of waveforms tunable between 12 and 42 THz. The shortest multi-terahertz pulses contain 1.8 oscillation cycles within the intensity full width at half-maximum. Pulse energies of up to 0.16 μJ and peak electric fields of 13 MV/cm are achieved. Electro-optic sampling reveals a phase stability better than 0.1 π over multiple hours, combined with free carrier-envelope phase tunability. The scalable scheme opens the door to strong-field terahertz optics at unprecedented repetition rates.
Initial Management of Children with Hypothalamic and Thalamic Tumors and the Modifying Role of Neurofibromatosis-1

Diencephalic gliomas may be grouped into 2 clinical categories. Optic pathway/hypothalamus gliomas (OPG) arise primarily from a slower-growing juvenile pilocytic astrocytoma, and thalamic gliomas arise primarily from a fibrillary astrocytoma which can become clinically and histologically more aggressive. Children with OPG have an excellent long-term prognosis with a 10-year survival of over 85%. The major therapeutic challenge for these patients is to maximize their quality of life by preserving visual and endocrine function while minimizing treatment-related morbidity. Treatment is often initiated at diagnosis in infants and toddlers who have a major visual impairment or the diencephalic syndrome. The judicious application of chemotherapy may serve to forestall the need for radiotherapy or surgery. Children with neurofibromatosis-1 (NF-1) usually have a more indolent course. Tumors may grow more slowly or occasionally regress spontaneously. However, over 90% of children with OPG without NF-1 will require some form of therapy. Patients with thalamic gliomas present with a shorter history, often with hydrocephalus. Surgical intervention is often required to relieve intracranial pressure and establish the histologic identity of the tumor. Over 75% of these tumors will become locally aggressive. Current multimodality therapy is relatively ineffective. The bithalamic variant behaves similarly to a pontine glioma.