In this work, high-performance liquid chromatography (HPLC) coupled to electrospray time-of-flight mass spectrometry (ESI-TOF-MS) and electrospray ion trap multiple-stage tandem mass spectrometry ...(ESI-IT-MS²) has been applied to screen phenolic compounds in olive leaf extracts. The use of a small particle size C18 column (1.8 μm) provided great resolution and made separation of a lot of isomers possible. The structural characterization was based on accurate mass data obtained by ESI-TOF-MS, and the nature of fragmentation ions were further confirmed by ESI-IT-MS² when possible. In addition, we employed tetrazolium salt (MTT)-based assays to assess the effects of olive leaf extracts on the growth of human tumor-derived cells. Upon this approach, we achieved an accurate profile of olive leaf phenolics along with the identification of several important isomers of secoiridoids and flavonoids. This will allow a better understanding of the complete composition of olive-leaf-bioactive compounds as well as their involvement in Olea europaea L. biochemical pathways. Importantly, olive leaf extracts exhibited dose-dependent inhibitory effects on the metabolic status (cell viability) of three breast cancer models in vitro. Since the tumoricidal activity of the extracts should be mainly attributed to the identified olive leaf phenolics, these findings warrant further investigation at the structure-function molecular level to definitely establish the anticancer value of these phytochemicals. graphic removed
Natural killer cells (NK) are important effectors of anti-tumor immunity, activated either by the downregulation of HLA-I molecules on tumor cells and/or the interaction of NK-activating receptors ...with ligands that are overexpressed on target cells upon tumor transformation (including NKG2D and NKP30). NK kill target cells by the vesicular delivery of cytolytic molecules such as Granzyme-B and Granulysin activating different cell death pathways, which can be Caspase-3 dependent or Caspase-3 independent. Multiple myeloma (MM) remains an incurable neoplastic plasma-cell disorder. However, we previously reported the encouraging observation that cord blood-derived NK (CB-NK), a new source of NK, showed anti-tumor activity in an in vivo murine model of MM and confirmed a correlation between high levels of NKG2D expression by MM cells and increased efficacy of CB-NK in reducing tumor burden. We aimed to characterize the mechanism of CB-NK-mediated cytotoxicity against MM cells. We show a Caspase-3- and Granzyme-B-independent cell death, and we reveal a mechanism of transmissible cell death between cells, which involves lipid-protein vesicle transfer from CB-NK to MM cells. These vesicles are secondarily transferred from recipient MM cells to neighboring MM cells amplifying the initial CB-NK cytotoxicity achieved. This indirect cytotoxicity involves the transfer of NKG2D and NKP30 and leads to lysosomal cell death and decreased levels of reactive oxygen species in MM cells. These findings suggest a novel and unique mechanism of CB-NK cytotoxicity against MM cells and highlight the importance of lipids and lipid transfer in this process. Further, these data provide a rationale for the development of CB-NK-based cellular therapies in the treatment of MM.
Intraoperative fluid administration is a ubiquitous intervention in surgical patients. But inadequate fluid administration may lead to poor postoperative outcomes. Fluid challenges (FCs), in or ...outside the so-called goal-directed fluid therapy, allows testing the cardiovascular system and the need for further fluid administration. Our primary aim was to evaluate how anesthesiologists conduct FCs in the operating room in terms of type, volume, variables used to trigger a FC and to compare the proportion of patients receiving further fluid administration based on the response to the FC.
This was a planned substudy of an observational study conducted in 131 centres in Spain in patients undergoing surgery.
A total of 396 patients were enrolled and analysed in the study. The median interquartile range amount of fluid given during a FC was 250ml (200–400). The main indication for FC was a decrease in systolic arterial pressure in 246 cases (62.2%). The second was a decrease in mean arterial pressure (54.4%). Cardiac output was used in 30 patients (7.58%), while stroke volume variation in 29 of 385 cases (7.32%). The response to the initial FC did not have an impact when prescribing further fluid administration.
The current indication and evaluation of FC in surgical patients is highly variable. Prediction of fluid responsiveness is not routinely used, and inappropriate variables are frequently evaluated for assessing the hemodynamic response to FC, which may result in deleterious effects.
La administración intraoperatoria de fluidos es una intervención ubicua en los pacientes quirúrgicos. Pero la administración inadecuada de fluidos puede llevar a malos resultados postoperatorios. La prueba de volumen (PV), dentro o fuera de la denominada fluidoterapia guiada por objetivos, permite probar el sistema cardiovascular y la necesidad de administración adicional de fluidos. Nuestro objetivo primario fue evaluar el modo en el que el anestesiólogo realiza la PV en el quirófano en términos de tipo, volumen, variables utilizadas para impulsar la PV, y comparar la proporción de pacientes que recibieron administración adicional de fluidos basada en la respuesta a la PV.
Se trata de un subestudio planificado de un estudio observacional realizado en 131 centros en España, en pacientes sometidos a cirugía.
En el estudio se incluyó y analizó a 396 pacientes. La cantidad media rango intercuartílico de fluidos administrados durante la PV fue de 250ml (200–400). La principal indicación de la PV fue el descenso de la presión arterial sistólica en 246 casos (62,2%). La segunda indicación fue el descenso de la presión arterial media (54,4%). Se utilizó el gasto cardiaco en 30 pacientes (7,58%), y la variación del volumen sistólico en 29 de entre 385 casos (7,32%). La respuesta a la PV inicial no tuvo impacto a la hora de prescribir administración adicional de fluidos.
La indicación y evaluación actual de la PV en los pacientes quirúrgicos es altamente variable. La predicción de la receptividad a los fluidos no se utiliza rutinariamente, evaluándose a menudo las variables no adecuadas para valorar la respuesta hemodinámica a la PV, pudiendo causar efectos perjudiciales.
As part of phase I/II melanoma BNCT clinical trial conducted in Argentina in a cooperative effort of the Argentine Atomic Energy Commission (CNEA) and the Oncology Institute Angel H. Roffo (IOAHR), 7 ...patients (6 female–1 male) received eight treatment sessions covering ten anatomical areas located in extremities. Mean age of the patients was 64 years (51–74). The treatments were performed between October 2003 and June 2007. All patients presented multiple subcutaneous skin metastases of melanoma and received an infusion containing ∼14
gr/m
2 of
10borophenyl-alanine (BPA) followed by the exposition of the area to a mixed thermal-epithermal neutron beam at the RA-6 reactor. The maximum prescribed dose to normal skin ranged from 16.5 to 24
Gy-Eq and normal tissue administered dose varied from 15.8 to 27.5
Gy-Eq. Considering evaluable nodules, 69.3% of overall response and 30.7% of no changes were seen. The toxicity was acceptable, with 3 out of 10 evaluable areas showing ulceration (30% toxicity grade 3).
In December 2019, a new coronavirus known as 2019-nCoV emerged in Wuhan, China. The virus has spread globally and the infection was declared pandemic in March 2020. Although most cases of coronavirus ...disease 2019 (COVID-19) are mild, some of them rapidly develop acute respiratory distress syndrome. In the clinical management, chest X-rays (CXR) are essential, but the evaluation of COVID-19 CXR could be a challenge. In this context, we developed
COVID-19 TRAINING
, a free Web application for training on the evaluation of COVID-19 CXR. The application included 196 CXR belonging to three categories:
non-pathological
,
pathological compatible with COVID-19
, and
pathological non-compatible with COVID-19
. On the training screen, images were shown to the users and they chose a diagnosis among those three possibilities. At any time, users could finish the training session and be evaluated through the estimation of their diagnostic accuracy values: sensitivity, specificity, predictive values, and global accuracy. Images were hand-labeled by four thoracic radiologists. Average values for sensitivity, specificity, and global accuracy were .72, .64, and .68. Users who achieved better sensitivity registered less specificity (
p
< .0001) and those with higher specificity decreased their sensitivity (
p
< .0001). Users who sent more answers achieved better accuracy (
p
= .0002). The application
COVID-19 TRAINING
provides a revolutionary tool to learn the necessary skills to evaluate COVID-19 on CXR. Diagnosis training applications could provide a new original manner of evaluation for medical professionals based on their diagnostic accuracy values, and an efficient method to collect valuable data for research purposes.
Dysregulation of the c-Myc oncogene occurs in a wide variety of hematologic malignancies, and its overexpression has been linked with aggressive tumor progression. Here, we show that poly ...(ADP-ribose) polymerase 1 (PARP-1) and PARP-2 exert opposing influences on progression of c-Myc-driven B-cell lymphoma. PARP-1 and PARP-2 catalyze the synthesis and transfer of ADP-ribose units onto amino acid residues of acceptor proteins in response to DNA strand breaks, playing a central role in the response to DNA damage. Accordingly, PARP inhibitors have emerged as promising new cancer therapeutics. However, the inhibitors currently available for clinical use are not able to discriminate between individual PARP proteins. We found that genetic deletion of PARP-2 prevents c-Myc-driven B-cell lymphoma, whereas PARP-1 deficiency accelerates lymphomagenesis in the Eμ-Myc mouse model of aggressive B-cell lymphoma. Loss of PARP-2 aggravates replication stress in preleukemic Eμ-Myc B cells, resulting in accumulation of DNA damage and concomitant cell death that restricts the c-Myc-driven expansion of B cells, thereby providing protection against B-cell lymphoma. In contrast, PARP-1 deficiency induces a proinflammatory response and an increase in regulatory T cells, likely contributing to immune escape of B-cell lymphoma, resulting in an acceleration of lymphomagenesis. These findings pinpoint specific functions for PARP-1 and PARP-2 in c-Myc-driven lymphomagenesis with antagonistic consequences that may help inform the design of new PARP-centered therapeutic strategies, with selective PARP-2 inhibition potentially representing a new therapeutic approach for the treatment of c-Myc-driven tumors.
Abstract
Background
Regadenoson is a selective A2A adenosine receptor agonist approved for the detection of myocardial with SPECT-MIBI. To date, few studies have appraised the utility of this drug ...using transthoracic echocardiography with the same purpose. We designed this prospective study to evaluate the diagnostic agreement between these two techniques used simultaneously to detect myocardial ischemia. We report our first results evaluating the concordance between both techniques.
Methods
Patients enrolled were referred to our clinic for the evaluation of chest pain. Myocardial perfusion imaging was performed with regadenoson (400 µg ) which was injected before 99mTc-MIBI. Stress and rest sets of images were evaluated for relative uptake of the radiotracer in order to detect and characterize perfusion defects. The echocardiogram was acquired 60-90 seconds after the administration of the drug using a standardized technique. Two independent observers (one cardiologist and one specialist in nuclear medicine) interpreted the images, both unaware of the result of the complementary technique.
Results
One hundred twenty five patients were included, 69 (55%) of them males. Median age was 73 years (IQR 65-79). One hundred seventeen patients had both studies interpretable. Thirty-nine (32.5%) patients had had a diagnosis of ischemic heart disease before the study (either a myocardial infarction or a coronary revascularization). The median pre-test probability of coronary artery disease in those without a true previous diagnosis was 30.5% (16.0-50.8), being 50% in the intermediate risk (15-85%) and 49% in the low risk stratum (less than 15%). Significant reductions is systolic and diastolic blood pressure were detected with regadenoson systolic 134 (21) mmHg Vs 131 (23) mmHg, p < 0.001; diastolic: 78 (12) mmHg Vs 73 (13) mmHg, p < 0.001, with a striking increase in heart rate: 67 (13) bpm Vs 91 (17) bpm, p < 0.001. More patients had a SPECT test showing myocardial ischemia (28% Vs 16%; p < 0.001). Agreement between both tests were 84%. The kappa index obtained from this sample was 0.34 (CI95% 0.15-0.53). Segregating those patients without a history of coronary artery disease (n = 81), the positive test rate were 14% for echo and 20% for SPECT-MIBI (p = 0.019). Kappa index was even lower: 0.29 (CI95% 0.02-0.56). Conclusions. SPECT-MIBI provides more positive tests than stress echocardiography when regadenoson is used as the stressor agent. The concordance between tests is low.
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