High concordance between trained nurses and gastroenterologists in evaluating recordings of small bowel video capsule endoscopy (VCE)

Background & Aims: The video capsule endoscopy (VCE) is an accurate and validated tool to investigate the entire small bowel mucosa, but VCE recordings interpretation by the gastroenterologist is time-consuming. A pre-reading of VCE recordings by an expert nurse could be accurate and cost saving. We assessed the concordance between nurses and gastroenterologists in detecting lesions on VCE examinations. Methods: This was a prospective study enrolling consecutive patients who had undergone VCE in clinical practice. Two trained nurses and two expert gastroenterologists participated in the study. At VCE pre-reading the nurses selected any abnormalities, saved them as “thumbnails” and classified the detected lesions as a vascular abnormality, ulcerative lesion, polyp, tumor mass, and unclassified lesion. Then, the gastroenterologist evaluated and interpreted the selected lesions and, successively, reviewed the entire video for potential missed lesions. The time for VCE evaluation was recorded. Results: A total of 95 VCE procedures performed on consecutive patients (M/F: 47/48; mean age: 63 ± 12 years, range: 27−86 years) were evaluated. Overall, the nurses detected at least one lesion in 54 (56.8%) patients. There was total agreement between nurses and gastroenterologists, no missing lesions being discovered at a second look of the entire VCE recording by the physician. The pre-reading procedure by nurse allowed a time reduction of medical evaluation from 49 (33-69) to 10 (8-16) minutes (difference:-79.6%). Conclusions: Our data suggest that trained nurses can accurately identify and select relevant lesions in thumbnails that subsequently were faster reviewed by the gastroenterologist for a final diagnosis. This could significantly reduce the cost of VCE procedure

Involvement of the histaminergic system in the resuscitating effect of centrally acting leptin in haemorrhagic shock in rats

Leptin, acting centrally as a neuromodulator, induces the activation of the sympathetic nervous system, which may lead to a pressor action in normotensive animals. In haemorrhagic shock, leptin administered intracerebroventricularly (icv.) evokes the resuscitating effect, with long-lasting rises in mean arterial pressure (MAP) and heart rate (HR), subsequent increase in peripheral blood flows, and a 100% survival at 2 h. Since leptin is able to activate histaminergic neurons, and centrally acting histamine also induces the resuscitating effect with the activation of the sympathetic nervous system, in the present study, we investigated an involvement of the histaminergic system in leptin-evoked cardiovascular effects in haemorrhagic shock. The model of irreversible haemorrhagic shock, with MAP decreased to and stabilised at 20 - 25 mmHg, has been used. Leptin (20 μg) given icv. at 5 min of critical hypotension evoked 181.5% increase in extracellular hypothalamic histamine concentration during the first 10 min after injection. Rises in MAP, HR and renal, mesenteric and hindquarters blood flows induced by leptin were inhibited by icv. pre-treatment with histamine H1 receptor antagonist chlorpheniramine (50 nmol). In contrast, there was no effect of H2, H3 and H4 receptor antagonists ranitidine (25 nmol), VUF 5681 (25 nmol) and JNJ 10191584 (25 nmol), respectively. In conclusion, the histaminergic system is involved in centrally-acting leptin-induced resuscitating effect in haemorrhagic shock in rats

Reconstruction of seasonal temperature variability in the tropical Pacific Ocean from the shell of the scallop, <i>Comptopallium radula</i>

International audienceWe investigated the oxygen isotope composition (d18O) of shell striae from juvenile Comptopallium radula (Mollusca; Pectinidae) specimens collected live in New Caledonia. Bottom-water temperature and salinity were monitored in-situ throughout the study period. External shell striae form with a 2-day periodicity in this scallop, making it possible to estimate the date of precipitation for each calcite sample collected along a growth transect. The oxygen isotope composition of shell calcite (d18Oshell calcite) measured at almost weekly resolution on calcite accreted between August 2002 and July 2003 accurately tracks bottom-water temperatures. A new empirical paleotemperature equation for this scallop species relates temperature and d18Oshell calcite: t(°C)=20.00(+/-0.61)-3.66(+/-0.39)x(d18Oshell calcite VPDB -d18Owater VSMOW) The mean absolute accuracy of temperature estimated using this equation is 1.0 °C at temperatures between 20 and 30 °C. Uncertainties regarding the precise timing of CaCO3 deposition and the actual variations in d18Owater at our study sites probably contribute to this error. Comparison with a previously published empirical paleotemperature equation indicates that C. radula calcite is enriched in 18O by ~0.7‰ relative to equilibrium. Given the direction of this offset and the lack of correlation between shell growth rate and d18Oshell calcite, this disequilibrium is unlikely to be related to kinetic isotope effects. We suggest that this enrichment reflects (1) a relatively low pH in the scallop's marginal extrapallial fluid (EPF), (2) an isotopic signature of the EPF different from that of seawater, or (3) Rayleigh fractionation during the biocalcification process. Relative changes in d18Oshell calcite reflect seawater temperature variability at this location and we suggest that the shell of C. radula may be useful as an archive of past seawater temperatures

IL2 treatment for cancer: from biology to gene therapy.

In this review we shall discuss the biological rationale and the clinical findings obtained using Interleukin 2 (IL2)-based immunotherapy in the management of cancer patients. Objective and long-lived clinical responses have been documented in a proportion of cases, particularly renal cell carcinoma, melanoma and acute myeloid leukaemia. Though encouraging, the clinical use of IL2 has so far been limited by toxicity, as well as by the heterogeneous and unpredictable responses and by the lack of specific anti-tumour effect. These considerations have led to the belief that more sophisticated technologies aimed at introducing the IL2 gene into the neoplastic cells may potentially overcome some of the limitations coupled to the in vivo infusion of high doses of IL2. The data accumulated in animal models and, more recently, also with human tumour cells indicate that the IL2 gene may be successfully inserted into neoplastic cells. The constitutive secretion of IL2 by the tumour cells leads to a reduced or abrogated tumorigenicity in several different tumour models. The evidence that in some experimental tumours the transduction of the IL2 gene into the neoplastic cells may elicit a specific cytotoxic response and confer anti-tumour memory, suggests that vaccination protocols based on this innovative strategy may represent a potential new tool in the management of cancer patients

Similarity, precedent and argument from analogy

In this paper, it is shown (1) that there are two schemes for argument from analogy that seem to be competitors but are not, (2) how one of them is based on a distinctive type of similarity premise, (3) how to analyze the notion of similarity using story schemes illustrated by some cases, (4) how arguments from precedent are based on arguments from analogy, and in many instances arguments from classification, and (5) that when similarity is defined by means of episode schemes, we can get a clearer idea of how it integrates with the use of argument from classification and argument from precedent in case-based reasoning by using a dialogue structure

Interleukin-2 gene transfer into human transitional cell carcinoma of the urinary bladder

Transitional cell carcinoma of the bladder is one of the human cancers most responsive to immunotherapy, and local interleukin-2 (IL-2) production appears to be an important requirement for immunotherapy to be effective. In this study, we engineered two human bladder cancer cell lines (RT112 and EJ) to constitutively release human IL-2 by retroviral vector-mediated gene transfer. Following infection and selection, stable and consistent production of biologically active IL-2 was demonstrated at both the mRNA and the protein level. Morphology, in vitro growth rate and proliferation, as well as other cytokine gene mRNA or membrane adhesion receptor expression, were not altered in IL-2 transduced cells as compared to their parental or control vector-infected counterparts. Moreover, IL-2 engineered cells lost their tumorigenicity into nu/nu mice and the mechanism of rejection appeared to involve multiple host effector cell populations, among which a prominent role was played by neutrophils and radiosensitive cells. These findings may offer support to the development of an IL-2-based gene therapy approach to human bladder cancer. 1999 Cancer Research Campaig

u-PAR expression in cancer associated fibroblast: new acquisitions in multiple myeloma progression

BACKGROUND: Multiple Myeloma (MM) is a B-cell malignancy in which clonal plasma cells progressively expand within the bone marrow (BM) as effect of complex interactions with extracellular matrix and a number of microenvironmental cells. Among these, cancer-associated fibroblasts (CAF) mediate crucial reciprocal signals with MM cells and are associated to aggressive disease and poor prognosis. A large body of evidence emphasizes the role of the urokinase plasminogen activator (u-PA) and its receptor u-PAR in potentiating the invasion capacity of tumor plasma cells, but little is known about their role in the biology of MM CAF. In this study, we investigated the u-PA/u-PAR axis in MM-associated fibroblasts and explore additional mechanisms of tumor/stroma interplay in MM progression. METHODS: CAF were purified from total BM stromal fraction of 64 patients including monoclonal gammopathy of undetermined significance, asymptomatic and symptomatic MM, as well as MM in post-treatment remission. Flow cytometry, Real Time PCR and immunofluorescence were performed to investigate the u-PA/u-PAR system in relation to the level of activation of CAF at different stages of the disease. Moreover, proliferation and invasion assays coupled with silencing experiments were used to prove, at functional level, the function of u-PAR in CAF. RESULTS: We found higher activation level, along with increased expression of pro-invasive molecules, including u-PA, u-PAR and metalloproteinases, in CAF from patients with symptomatic MM compared to the others stages of the disease. Consistently, CAF from active MM as well as U266 cell line under the influence of medium conditioned by active MM CAF, display higher proliferative rate and invasion potential, which were significantly restrained by u-PAR gene expression inhibition. CONCLUSIONS: Our data suggest that the stimulation of u-PA/u-PAR system contributes to the activated phenotype and function of CAF during MM progression, providing a biological rationale for future targeted therapies against MM

DARA-VD VERSUS DARA-RD AS SALVAGE THERAPY FOR PATIENTS WITH MYELOMA. INITIAL FOLLOW-UP OF AN ITALIAN MULTICENTER RETROSPECTIVE CLINICAL EXPERIENCE BY RETE EMATOLOGICA PUGLIESE

Background: Daratumumab is a CD38 monoclonal antibody approved in monotherapy or in combination with bortezomib and dexamethasone (Dara-Vd) or lenalidomide and dexamethasone (Dara-Rd) for the treatment of relapsed or refractory myeloma (rrMM). Aims: We report here an initial multicenter retrospective analysis of 126 consecutive patients with rrMM treated with daratumumab in combination with bortezomib or lenalidomide as salvage therapy at 9 haematological centers in Puglia, conducted to evaluate the outcomes, as well as the toxicity profile of these combination in a daily practice setting outside clinical trials. Methods: Of 126 patients, 122 were evaluable for response and toxicity. Forty-two patients (33%) (15 F and 27 M) received Dara-Vd and 84 patients (67%) (41 F and 43 M) with Dara-Rd; 74% of them had relapsed MM and 26% MM refractory to one or more previous treatment lines. The median age at diagnosis was 62 years (range 36-77) in the Vd-group, 66 years (range 32-83) in the Rd-group. The median time to initiation of daratumumab from diagnosis was 5 years (range 3-9) in the Vd-group, 3 years (range 1-10) in the Rd-group. Patients had received a median 2 prior lines of therapy (range 1-6) in the Vd-group, a median 1 prior course of therapy (range 1-4) in the Rd-group. Twenty patients (48%) in the Vd-group and 30 patients (37%) in the Rd-group had previously undergone single or tandem ASCT. In the Vd-group all patients were previously exposed to at least one proteasome inhibitor (91% of patients to bortezomib, 37% of patients to carfilzomib), in the Rd-group only 18% of patients was exposed to lenalidomide. Results: The median number of administered cycles was 9 (range 1-23) in the VD-group and 8.5 (range 1-23) in the Rd-group. The ORR was 68.2% in the Vd-group (CR 4.8%, VGPR 12.2%, PR 51.2%) and 81.5% in the Rd-group (CR 21%, VGPR 35.8%, pr 24.7%). Median TTR was 2 months (range 1-6) in the Vd-group and 1.5 months (range 1-5) in the Rd-group. Median PFS was 10 months (range 8-16; 95% &gt; CI) in the Vd-group; median PFS was not reached in the Rd-group (fig.1). Grade 3/4 neutropenia (37%) was the most common adverse event in the Rd-group, grade 3/4 thrombocytopenia (24%) was the most common adverse event in the Vd-group. Seventeen (41%) patients in the Vd-group discontinued treatment due to relapse, 16 patients (19%) in the Rd-group because of haematological toxicity (4.5%), relapse (7.5%), death (6%) and the development of urological cancer (1%). Summary/Conclusion: A higher rate of ORR (81.5% vs 68.2%) and very good partial response or better (responses &gt; VGPR 56.8% vs 17%) was observed in the Dara-Rd group compared to Dara-Vd group. This difference could be due to the fact that: 1) in the Dara- Rd group the patients had received a lower number of prior antimyeloma therapies compared to Dara-Vd group; 2) the patients in the Dara-Rd group had a more indolent myeloma (median ISS 1) compared to the patients in the Dara-Vd group, who had a more advanced disease (median ISS 3); 3) in the Rd-group only 18% of patients was exposed to lenalidomide, in the Vd-group all patients were previously exposed to at least one proteasome inhibitor. Unfortunately, the interference of daratumumab with immunofixation and serum protein electrophoresis assays may lead to underestimation of CR

Reversal of <i>MYB </i>-dependent suppression of <i>MAFB </i>expression overrides leukaemia phenotype in MLL-rearranged AML

Abstract The transcription factor MYB plays a pivotal role in haematopoietic homoeostasis and its aberrant expression is involved in the genesis and maintenance of acute myeloid leukaemia (AML). We have previously demonstrated that not all AML subtypes display the same dependency on MYB expression and that such variability is dictated by the nature of the driver mutation. However, whether this difference in MYB dependency is a general trend in AML remains to be further elucidated. Here, we investigate the role of MYB in human leukaemia by performing siRNA-mediated knock-down in cell line models of AML with different driver lesions. We show that the characteristic reduction in proliferation and the concomitant induction of myeloid differentiation that is observed in MLL-rearranged and t(8;21) leukaemias upon MYB suppression is not seen in AML cells with a complex karyotype. Transcriptome analyses revealed that MYB ablation produces consensual increase of MAFB expression in MYB-dependent cells and, interestingly, the ectopic expression of MAFB could phenocopy the effect of MYB suppression. Accordingly, in silico stratification analyses of molecular data from AML patients revealed a reciprocal relationship between MYB and MAFB expression, highlighting a novel biological interconnection between these two factors in AML and supporting new rationales of MAFB targeting in MLL-rearranged leukaemias

Large-eddy simulation of low-frequency unsteadiness in a turbulent shock-induced separation bubble

The need for better understanding of the low-frequency unsteadiness observed in shock wave/turbulent boundary layer interactions has been driving research in this area for several decades. We present here a large-eddy simulation investigation of the interaction between an impinging oblique shock and a Mach 2.3 turbulent boundary layer. Contrary to past large-eddy simulation investigations on shock/turbulent boundary layer interactions, we have used an inflow technique which does not introduce any energetically significant low frequencies into the domain, hence avoiding possible interference with the shock/boundary layer interaction system. The large-eddy simulation has been run for much longer times than previous computational studies making a Fourier analysis of the low frequency possible. The broadband and energetic low-frequency component found in the interaction is in excellent agreement with the experimental findings. Furthermore, a linear stability analysis of the mean flow was performed and a stationary unstable global mode was found. The long-run large-eddy simulation data were analyzed and a phase change in the wall pressure fluctuations was related to the global-mode structure, leading to a possible driving mechanism for the observed low-frequency motions