S-100 protein and neuron-specific enolase (NSE) have recently been proposed as serum markers for melanoma. In this study NSE and S-100 serum levels were assayed by commercial IRMA methods in 53 ...patients with melanoma. The overall prevalence of abnormal marker levels was similar for NSE (26%) and S-100 (30%). The 24 patients in stages I and II had uniformly normal S-100 levels, but abnormal NSE levels were observed in 3 out of the 12 patients in stage II (33%) and in 1 out of 12 in stage I. NSE appears thus to be the marker of choice in the early stages, where its increase points to disease progression. In patients in stages III and IV the prevalence of abnormal values was 34% for NSE and 55% for S-100 (p = < 0.05). In the latter group diagnostic sensitivity increased to 62% if isolated elevation of each marker was considered. In patients with advanced stage disease, both NSE and S-100 should be assayed.
Although multiple populations of macrophages have been described in the human liver, their function and turnover in patients with obesity at high risk of developing non-alcoholic fatty liver disease ...(NAFLD) and cirrhosis are currently unknown. Herein, we identify a specific human population of resident liver myeloid cells that protects against the metabolic impairment associated with obesity. By studying the turnover of liver myeloid cells in individuals undergoing liver transplantation, we find that liver myeloid cell turnover differs between humans and mice. Using single-cell techniques and flow cytometry, we determine that the proportion of the protective resident liver myeloid cells, denoted liver myeloid cells 2 (LM2), decreases during obesity. Functional validation approaches using human 2D and 3D cultures reveal that the presence of LM2 ameliorates the oxidative stress associated with obese conditions. Our study indicates that resident myeloid cells could be a therapeutic target to decrease the oxidative stress associated with NAFLD.
This study evaluates the short- and long-term therapeutic efficacy of 186Re-1,1-hydroxyethylidene diphosphonate (HEDP) in the palliation of painful bone metastases and the influence of variables ...before therapy in determining the characteristics of pain palliation.
Sixty patients with painful bone metastases from different tumor types were treated with 1406 MBq 186Re-HEDP. After treatment, the patients were followed up clinically at weekly intervals for the first month and monthly thereafter up to 1 y, until death or pain relapse. Pain response was graded as complete, partial, minimal, or absent using the Wisconsin test scoring system. Duration of pain relief, performance status, tumor markers, serum alkaline phosphatase levels, hematologic toxicity, and metastatic bone progression were also evaluated.
Overall, 80% of individuals experienced prompt relief of pain, with 31% complete, 34% partial, and 15% minimal responses. Transient World Health Organization grade 1-2 hematologic toxicity was apparent, with a decrease in the mean platelet (32%) and mean leukocyte (18%) counts at 3 and 4 wk, respectively. The degree of pain response did not correlate with any pretreatment variable. The duration of pain relief ranged from 3 wk to 12 mo and correlated positively with the degree of response (P = 0.02) and negatively with pretreatment scintigraphic scores and alkaline phosphatase levels (P = 0.02).
186Re-HEDP is effective for fast palliation of painful bone metastases from various tumors. The effect tends to last longer if patients are treated early in the course of their disease.
Background: Intra-arterial injection of super(90)Y resin microspheres radiotherapy (SIRT) enables delivery of tumorcidal doses of radiation to malignant tumor, with minimal damage to adjacent tissue. ...This multicentre phase II study is the first prospective evaluation of SIRT as salvage therapy for patients with colorectal liver metastases who had failed prior oxaliplatin- and irinotecan-based regimens. Methods: Eligible patients had a life expectancy of >6 months, adequate hepatic and renal function and an absence of major vascular anomalies and pulmonary shunt >10%. The gastroduodenal and right gastric arteries were embolized before injection of microspheres (median dose 1.7 GBq; range 0.9-2.2) into the hepatic artery by arteriography. Results: Patients were enrolled and followed up for a median of 11 months (mos) (range 2-27). Of 50 eligible patients, 38 (76%) had received at least 4 lines of chemotherapy. Most patients had synchronous disease (72%), >4 hepatic metastases (58%) (median size 50 mm; range 8-120), involving 25-50% of the liver tissue (60%) and bilateral spread (70%). Early and late (after 48 h) WHO G1-2 toxic events (mostly fever and pain) were observed in 16% and 22% of patients, respectively. One responding patient died after 60 days due to liver failure. Of 46 patients who were evaluable for response using RECIST criteria, 1 patient (2%) had a complete response (CR), 11 (22%) a partial response (PR), 12 (24%) stable disease (SD) and 22 (44%) progressive disease (PD). In responders (CR + PR + SD), the maximum diameter of nodules diminished to 35 mm. The Kaplan-Meyer overall median survival was 13 (CI 7-18) mos, with a significant difference (p=0.0006) between responders 16 (CI 13-19) mos and PD 8 (CI 4-12) mos. At 2 years, survival was 40.3% and 0% in responders and PD, respectively. The median time to progression (mostly extrahepatic) was 4 (CI 3-5) mos. Conclusion: In heavily pretreated patients, super(90)Y resin microspheres produced an encouraging median survival, with acceptable toxicity, that compares favorably with previous phase II/III studies of chemotherapy regimens used as third- or subsequent lines of therapy.
Objective
To identify disease characteristics leading to progression of joint damage in patients with early rheumatoid arthritis (RA) treated with methotrexate (MTX) versus those treated with ...infliximab plus MTX.
Methods
Patients who had not previously been treated with MTX with active RA were randomly assigned to receive escalating doses of MTX up to 20 mg/week plus placebo or infliximab at weeks 0, 2, and 6, and every 8 weeks thereafter through week 46. Radiographic joint damage was assessed using the modified Sharp/van der Heijde score (SHS). The relationship between disease activity measures at baseline and week 14, as well as those averaged over time, were examined in relation to the change in SHS from baseline through week 54.
Results
C‐reactive protein (CRP) levels, erythrocyte sedimentation rate (ESR), and swollen joint count were associated with greater joint damage progression in the MTX‐only group, while none of these parameters was associated with progression in the infliximab plus MTX group. Mean changes in SHS among patients in the highest CRP (≥3 mg/dl) and ESR (≥52 mm/hour) tertiles in the MTX‐only group were 5.62 and 5.89, respectively, compared with 0.73 and 1.12 in the infliximab plus MTX group (P < 0.001). Patients with greater joint damage at baseline (SHS ≥10.5) showed less progression with infliximab plus MTX compared with MTX alone (−0.39 versus 4.11; P < 0.001). Patients receiving MTX alone who had persistently active disease at week 14 showed greater radiographic progression of joint damage than those taking MTX plus infliximab.
Conclusion
High CRP level, high ESR, or persistent disease activity was associated with greater radiographic progression in the group taking MTX alone, while little radiographic progression was seen in patients receiving both MTX and infliximab, regardless of the abnormal levels of these traditional predictors.
Since 2010, array-CGH (aCGH) has been the first-tier test in the diagnostic approach of children with neurodevelopmental disorders (NDD) or multiple congenital anomalies (MCA) of unknown origin. Its ...broad application led to the detection of numerous variants of uncertain clinical significance (VOUS). How to appropriately interpret aCGH results represents a challenge for the clinician.
We present a retrospective study on 293 patients with age range 1 month - 29 years (median 7 years) with NDD and/or MCA and/or dysmorphisms, investigated through aCGH between 2005 and 2016. The aim of the study was to analyze clinical and molecular cytogenetic data in order to identify what elements could be useful to interpret unknown or poorly described aberrations. Comparison of phenotype and cytogenetic characteristics through univariate analysis and multivariate logistic regression was performed.
Copy number variations (CNVs) with a frequency < 1% were detected in 225 patients of the total sample, while 68 patients presented only variants with higher frequency (heterozygous deletions or amplification) and were considered to have negative aCGH. Proved pathogenic CNVs were detected in 70 patients (20.6%). Delayed psychomotor development, intellectual disability, intrauterine growth retardation (IUGR), prematurity, congenital heart disease, cerebral malformations and dysmorphisms correlated to reported pathogenic CNVs. Prematurity, ventricular septal defect and dysmorphisms remained significant predictors of pathogenic CNVs in the multivariate logistic model whereas abnormal EEG and limb dysmorphisms were mainly detected in the group with likely pathogenic VOUS. A flow-chart regarding the care for patients with NDD and/or MCA and/or dysmorphisms and the interpretation of aCGH has been made on the basis of the data inferred from this study and literature.
Our work contributes to make the investigative process of CNVs more informative and suggests possible directions in aCGH interpretation and phenotype correlation.
Experimental evidence suggests that antiangiogenic therapy gives rise to a transient window of vessel normalization, within which the efficacy of radiotherapy and chemotherapy may be enhanced. ...Preclinical experiments that measure components of vessel normalization are invasive and expensive. We have developed a mathematical model of vascular tumor growth from preclinical time‐course data in a breast cancer xenograft model. We used a mixed‐effects approach for model parameterization, leveraging tumor size data to identify a period of enhanced tumor growth that could potentially correspond to the transient window of vessel normalization. We estimated the characteristics of the window for mice treated with an anti‐VEGF antibody (bevacizumab) or with a bispecific anti‐VEGF/anti‐angiopoietin‐2 antibody (vanucizumab). We show how the mathematical model could theoretically be used to predict how to coordinate antiangiogenic therapy with radiotherapy or chemotherapy to maximize therapeutic effect, reducing the need for preclinical experiments that directly measure vessel normalization parameters.
We present a web-repository (SYNTHESIS 0.2, SYNTHEtic SeISmograms database) designed to archive and distribute synthetic waveforms computed by physic-based models. The structure of the database ...derives from the ITalian ACcelerometric Archive (ITACA Working Group in ITalian ACcelerometric Archive, version 2.1,
2016
. doi:
10.13127/ITACA/2.1
), devoted to archive and distribute recorded strong motion data. To date, SYNTHESIS includes more than 4500 simulated accelerograms associated to earthquake scenarios of either occurred events or possible future events. The database also includes information about kinematic rupture models and propagation medium related to the synthetic waveforms. The main features of the SYNTHESIS web-portal for dissemination of synthetics are here illustrated. A wide range of key fields enables the user to interactively retrieve simulated waveforms, modeling parameters and information on simulation sites. A range of display options allows users to view data in different frameworks, to extract and download synthetic waveforms and to display maps of selected peak ground motion parameters. SYNTHESIS is a prototype designed to fulfill specific needs of two Italian projects, and developed with the aim of promoting the use of simulated waveforms for hazard analysis. Ground motion simulations can be employed in a variety of applications, such as: (1) to evaluate shaking scenarios for seismic risk mitigation; (2) to define seismic inputs for site response or structural response analyses; (3) to integrate observed data for the calibration of ground motion prediction equations and (4) to evaluate the different components of the ground motion variability.
STATEMENT OF FINDINGS: Mesenchymal precursor cells found in the blood (BMPCs) of normal persons adhere to plastic and glass and proliferate logarithmically in DMEM-20% fetal calf serum (FCS) without ...growth factors. They form cells with fibroblast-like and stromal morphology, which is not affected by eliminating CD34, CD3, or CD14 cells. Osteogenic supplements (dexamethasone, ascorbic acid, and beta-glycerophosphate) added to the culture inhibited fibroblast formation, and BMPCs assumed the cuboidal shape of osteoblasts. After 5 days in supplemented medium, the elutriated cells displayed alkaline phosphatase (AP), and the addition of bone morphogenetic protein (BMP)2 (1 ng) doubled AP production (P < 0.04). Two weeks later, 30% of the cells were very large and reacted with anti-osteocalcin antibody. The same cultures also contained sudanophlic adipocytes and multinucleated giant cells that stained for tartrate-resistant acid phosphatase (TRAP) and vitronectin receptors. Cultured BMPCs immunostain with antibodies to vimentin, type I collagen, and BMP receptors, heterodimeric structures expressed on mesenchymal lineage cells. In addition, BMPCs stain with anti-CD105 (endoglin), a putative marker for bone-marrow mesenchymal stem cells (MSCs).
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