Search

There is an unmet need for novel non-invasive prognostic molecular tumour markers for breast cancer (BC). Accumulating evidence shows that miR-155 plays a pivotal role in tumorigenesis. Generally, miR-155 is considered an oncogenic miRNA promoting tumour growth, angiogenesis and aggressiveness of BC. Therefore, many researchers have focused on its use as a prognostic biomarker and therapeutic target. However, its prognostic value for BC patients remains controversial. To address this issue, the present systematic review aims to summarize the available evidence and give a picture of a prognostic significance of miR-155 in BC pathology. All eligible studies were searched on PubMed and EMBASE databases through various search strategies. Starting from 289 potential eligible records, data were examined from 28 studies, comparing tissue and circulating miR-155 expression levels with clinicopathological features and survival rates in BC patients. We discuss the pitfalls and challenges that need to be assessed to understand the power of miR-155 to respond to real clinical needs, highlighting the consistency, robustness or lack of results obtained to sate in translating this molecule to clinical practice. Our paper suggests that the prognostic role of miR-155 in the management of BC needs to be further verified.

We evaluated the outcome of 71 children with de novo acute myeloid leukemia enrolled in 2 consecutive protocols in the main pediatric hospital in Uruguay. In the LAM97 protocol (n=34), patients received, as consolidation, autologous or allogeneic hematopoietic stem cell transplantation (HSCT), depending on the availability or not of a matched sibling donor. In the LAM08 protocol (n=37), patients were stratified into risk groups, autologous HSCT was abandoned, and allogeneic HSCT was limited to intermediate-risk patients with matched sibling donor and to all patients who fulfilled the high-risk criteria. Complete remission was achieved in 91% and 92% of patients in LAM97 and LAM08, respectively. Deaths in complete remission were 9.6% and 17.6%, respectively. The incidence of relapse was significantly higher in LAM97, 35.4%, versus 12.5% in LAM08. The 5-year event-free survival and overall survival were 50.0% and 55.9% in LAM97 and 59.9% and 64.8% in LAM08. The 5-year overall survival rates in each of the risk groups were 85.7% and 100% for low risk, 50.0% and 61.2% for intermediate risk, and 42.9% and 50.0% for high risk in LAM97 and LAM08 protocols, respectively. Survival has improved over the last 2 decades, and results are comparable to those published in Europe and North America.

Leukemic cells originate from the malignant transformation of undifferentiated myeloid/lymphoid hematopoietic progenitors normally residing in bone marrow. As the precise molecular mechanisms underlying this heterogeneous disease are yet to be disclosed, the identification and the validation of novel actors in leukemia is of extreme importance. Here, we show that KCTD15, a member of the emerging class of KCTD ((K)potassium Channel Tetramerization Domain containing) proteins, is strongly upregulated in patients affected by B-cell type acute lymphoblastic leukemia (B-ALL) and in continuous cell lines (RS4;11, REH, TOM-1, SEM) derived from this form of childhood leukemia. Interestingly, KCTD15 downregulation induces apoptosis and cell death suggesting that it has a role in cellular homeostasis and proliferation. In addition, stimulation of normal lymphocytes with the pokeweed mitogen leads to increased KCTD15 levels in a fashion comparable to those observed in proliferating leukemic cells. In this way, the role of KCTD15 is likely not confined to the B-ALL pathological state and extends to activation and proliferation of normal lymphocytes. Collectively, data here presented indicate that KCTD15 is an important and hitherto unidentified player in childhood lymphoid leukemia, and its study could open a new scenario for the identification of altered and still unknown molecular pathways in leukemia.

BackgroundBreast cancer (BC) is the most common cancer in females and despite advances in treatment, it represents the leading cause of cancer mortality in women worldwide. Conventional therapeutic modalities have significantly improved the management of BC patients, but subtype heterogeneity, drug resistance, and tumor relapse remain the major factors to hamper the effectiveness of therapy for BC. In this scenario, miRNA(miR)-based therapeutics offer a very attractive area of study. However, the use of miR-based therapeutics for BC treatment still represents an underdeveloped topic. Therefore, this systematic review aims at summarizing current knowledge on promising miR-based therapeutics for BC exploring original articles focusing on in vivo experiments.MethodsThe current systematic review was performed according to PRISMA guidelines. PubMed and EMBASE databases were comprehensively explored to perform the article search.ResultsTwenty-one eligible studies were included and analyzed: twelve focused on antitumor miR-based therapeutics and nine on metastatic miR-based therapeutics. We found 18 different miRs tested as potential therapeutic molecules in animal model experiments. About 90% of the selected studies evaluate the efficiency and the safety of miRs as therapeutic agents in triple-negative (TN)-BC mouse models. Among all founded miR-based therapeutics, miR-21 emerged to be the most investigated and proposed as a potential antitumoral molecule for TNBC treatment. Besides, miR-34a and miR-205a appeared to be successful antitumoral and antimetastatic molecules.ConclusionsOur analysis provides a snapshot of the current scenario regarding the miRs as therapeutic molecules in BC. Nevertheless, despite many efforts, none of the selected studies goes beyond preclinical studies, and their translatability in the clinical practice seems quite premature.

Background Aberrant expression of microRNAs (miR) has been proposed as non-invasive biomarkers for breast cancers. The aim of this study was to analyse the miR-622 level in the plasma and in tissues of breast cancer patients and to explore the role of miR-622 and its target, the NUAK1 kinase, in this context. Methods miR-622 expression was analysed in plasma and in tissues samples of breast cancer patients by q-RT-PCR. Bioinformatics programs, luciferase assay, public dataset analysis and functional experiments were used to uncover the role of miR-622 and its target in breast cancer cells. Results miR-622 is downregulated in plasma and in tissues of breast cancer patients respect to healthy controls and its downregulation is significantly associated with advanced grade and high Ki67 level. Modulation of miR-622 affects the motility phenotype of breast cancer cells. NUAK1 kinase is a functional target of miR-622, it is associated with poor clinical outcomes of breast cancer patients and is inversely correlated with miR-622 level. Conclusions miR-622/NUAK1 axis is deregulated in breast cancer patients and affects the motility phenotype of breast cancer cells. Importantly, miR-622 and NUAK1 hold promises as biomarkers and as targets for breast cancers.

The aim of this study is to evaluate and discuss the impact that the restrictive measures adopted for coronavirus have had on the main air pollutants. CO and NOx trends showed a reduction in levels from January to April 2020. A reduction in NOx (54%) concentration and in CO (7.6%) was detected by comparing the average of their values measured from March 9th - April 15th in 2019 and in 2020. A reduction in NOx concentrations compared to the average of previous four years was detected in March (47%) and April 2020 (73%). PM2.5 and PM10 concentrations measured by the Lazio Regional Agency for Environmental Protection in various urban sites in Rome, were studied. PM2.5 and PM10 trends from January 1st to April 15th showed a concentration decrease, although during this period they exceeded the recommended daily level several times. PM10 has exceeded the limit value from March 28th-30th, and the analysis of the backward trajectories of the NOAA detected a desert dust transport from the Caspian Sea. PM2.5 showed high values from March 18th-22nd and from April 8th-13th. A long-range transport of air masses from regions with high SO2 emission sources was detected, while analyzing the daily trends of CO, SO2 and radon for these periods. The influence of domestic heating on PM levels was evaluated for the years 2018 and 2019. The results did not show a significant impact of domestic heating on PM levels.

This report presents the case of a 13-year-old female patient with history of acute myeloid leukemia, who, after a bone marrow transplant, began to vomit and experienced rapidly progressive deterioration of consciousness, in addition to disseminated erythematous-violaceous macules, and some blisters with hemorrhagic content inside. Skin biopsy evidenced intravascular filamentous structures. A blood culture confirmed the presence of Fusarium oxysporum. Intravenous treatment with voriconazole was initiated. The patient evolved unfavorably with multiple necrotic skin lesions, ischemic brain lesions, and death.

Breast cancer (BC) is a heterogeneous and complex disease as witnessed by the existence of different subtypes and clinical characteristics that poses significant challenges in disease management. The complexity of this tumor may rely on the highly interconnected nature of the various biological processes as stated by the new paradigm of Network Medicine. We explored The Cancer Genome Atlas (TCGA)-BRCA data set, by applying the network-based algorithm named SWItch Miner, and mapping the findings on the human interactome to capture the molecular interconnections associated with the disease modules. To characterize BC phenotypes, we constructed protein&ndash, protein interaction modules based on &ldquo, hub genes&rdquo, called switch genes, both common and specific to the four tumor subtypes. Transcriptomic profiles of patients were stratified according to both clinical (immunohistochemistry) and genetic (PAM50) classifications. 266 and 372 switch genes were identified from immunohistochemistry and PAM50 classifications, respectively. Moreover, the identified switch genes were functionally characterized to select an interconnected pathway of disease genes. By intersecting the common switch genes of the two classifications, we selected a unique signature of 28 disease genes that were BC subtype-independent and classification subtype-independent. Data were validated both in vitro (10 BC cell lines) and ex vivo (66 BC tissues) experiments. Results showed that four of these hub proteins (AURKA, CDC45, ESPL1, and RAD54L) were over-expressed in all tumor subtypes. Moreover, the inhibition of one of the identified switch genes (AURKA) similarly affected all BC subtypes. In conclusion, using a network-based approach, we identified a common BC disease module which might reflect its pathological signature, suggesting a new vision to face with the disease heterogeneity.

Introduction: Neuroblastoma is the most common extracranial solid tumor in children. Approximately 50% of patients are classified as high risk on the basis of clinical, biological, and histological characteristics. Objective: To describe the population of patients diagnosed with high-risk neuroblastoma at the Centro Hemato-Oncologico Pediatrico (CHOP, Center for Pediatric Hematology and Oncology) of the Centro Hospitalario Pereira Rossell (CHPR, Pereira Rossell Hospital), in terms of their treatment and survival. Method: Descriptive, retrospective study of all patients diagnosed with high-risk neuroblastoma at the CHOP between 2001 and 2015. The National Registry of Pediatric Cancer is located at the CHOP, as is the archive of Patient clinical Histories. The data are collected and analyzed by the statistics sector. Results: Among the 35 patients diagnosed, 20 (57%) were men, the median age was 36.6 months (range, 5-93 months), and the tumor had an adrenal location in 23 (66%). All of the tumors were classified as stage IV. Metastasis to the bone marrow or bone was seen in 27 (71%). Thirty-three patients (94%) received autologous hematopoietic stem-cell transplantation (HSCT). The status prior to HSCT was complete remission in 19 (58%) and partial remission in 14 (42%). The treatment-related mortality rate was 15%, and the relapse rate was 68%. The median time to relapse was 15 months (3-52 months). The probability of overall survival and 5-year event-free survival was 37.8% ± 8.4 and 23.8% ± 7.3 (median follow-up of 40 months), respectively. Conclusion: Despite intensive treatment and adequate support measures, the prognosis for high-risk neuroblastoma in children remains poor in Uruguay. There is a need to incorporate new therapeutic strategies not yet available in our country.

Exemestane (Exe) in combination with Everolimus (Eve) represents an important treatment option for patients diagnosed with hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2‑) metastatic breast cancer (MBC), which was previously treated with non‑steroidal aromatase inhibitors (NSAI). Data from unselected populations may be useful for defining the optimal therapeutic algorithm within a clinical setting. Data from 264 HR+, HER2‑ MBC patients who received Exe‑Eve treatment in combination, following the failure of NSAIs was retrospectively analyzed. Different lines of endocrine treatment (ET) were investigated to evaluate the efficacy and toxicity of the treatment within the ‘everyday clinical practice’ population. The disease control rate (DCR) was 73.1%, with no statistically significant difference among the different settings. At a median follow‑up of 42 months, the median progression free survival (PFS) was 11.6, 9.7 and 7.5 months for patients treated with Exe‑Eve as first, second or third line therapy, respectively. There was a statistically significant correlation with younger age, no previous adjuvant chemotherapy (CT), no previous adjuvant endocrine therapy (ET), HT duration ≥36 months, involvement of liver and/or lung, no prior CT for metastatic disease and PS=0 at the start of treatment. The median overall survival (OS) was 33.0 months; at a median follow‑up of 67 months, the median OS was 43.1, 31.7 and 27.9 months in patients treated with Exe‑Eve in first, second or third line therapy, respectively. On multivariate analysis, diabetes and previous CT for metastatic disease were revealed to correlate with a worse outcome. Conversely, the presence of mucositis was significantly associated with long‑term survival. Overall, Exe‑Eve was typically well tolerated and the majority toxicities were G1 or 2, while treatment discontinuation due to unacceptable toxicity was only required in 5.7% of patients. Despite the limitations due to the observational nature of this study, the findings suggest that treatment with Exe‑Eve is an active and safe therapeutic option for endocrine‑sensitive MBC patients in a real‑world clinical setting, regardless of treatment lines.

Background: Uncertainty exists about the optimal schedule of adjuvant treatment of breast cancer with aromatase inhibitors and, to our knowledge, no trial has directly compared the three aromatase inhibitors anastrozole, exemestane, and letrozole. We investigated the schedule and type of aromatase inhibitors to be used as adjuvant treatment for hormone receptor-positive early breast cancer. Methods: FATA-GIM3 is a multicentre, open-label, randomised, phase 3 trial of six different treatments in postmenopausal women with hormone receptor-positive early breast cancer. Eligible patients had histologically confirmed invasive hormone receptor-positive breast cancer that had been completely removed by surgery, any pathological tumour size, and axillary nodal status. Key exclusion criteria were hormone replacement therapy, recurrent or metastatic disease, previous treatment with tamoxifen, and another malignancy in the previous 10 years. Patients were randomly assigned in an equal ratio to one of six treatment groups: oral anastrozole (1 mg per day), exemestane (25 mg per day), or letrozole (2·5 mg per day) tablets upfront for 5 years (upfront strategy) or oral tamoxifen (20 mg per day) for 2 years followed by oral administration of one of the three aromatase inhibitors for 3 years (switch strategy). Randomisation was done by a computerised minimisation procedure stratified for oestrogen receptor, progesterone receptor, and HER2 status; previous chemotherapy; and pathological nodal status. Neither the patients nor the physicians were masked to treatment allocation. The primary endpoint was disease-free survival. The minimum cutoff to declare superiority of the upfront strategy over the switch strategy was assumed to be a 2% difference in disease-free survival at 5 years. Primary efficacy analyses were done by intention to treat; safety analyses included all patients for whom at least one safety case report form had been completed. Follow-up is ongoing. This trial is registered with the European Clinical Trials Database, number 2006-004018-42, and ClinicalTrials.gov, number NCT00541086. Findings: Between March 9, 2007, and July 31, 2012, 3697 patients were enrolled into the study. After a median follow-up of 60 months (IQR 46–72), 401 disease-free survival events were reported, including 211 (11%) of 1850 patients allocated to the switch strategy and 190 (10%) of 1847 patients allocated to upfront treatment. 5-year disease-free survival was 88·5% (95% CI 86·7–90·0) with the switch strategy and 89·8% (88·2–91·2) with upfront treatment (hazard ratio 0·89, 95% CI 0·73–1·08; p=0·23). 5-year disease-free survival was 90·0% (95% CI 87·9–91·7) with anastrozole (124 events), 88·0% (85·8–89·9) with exemestane (148 events), and 89·4% (87·3 to 91·1) with letrozole (129 events; p=0·24). No unexpected serious adverse reactions or treatment-related deaths occurred. Musculoskeletal side-effects were the most frequent grade 3–4 events, reported in 130 (7%) of 1761 patients who received the switch strategy and 128 (7%) of 1766 patients who received upfront treatment. Grade 1 musculoskeletal events were more frequent with the upfront schedule than with the switch schedule (924 [52%] of 1766 patients vs 745 [42%] of 1761 patients). All other grade 3–4 adverse events occurred in less than 2% of patients in either group. Interpretation: 5 years of treatment with aromatase inhibitors was not superior to 2 years of tamoxifen followed by 3 years of aromatase inhibitors. None of the three aromatase inhibitors was superior to the others in terms of efficacy. Therefore, patient preference, tolerability, and financial constraints should be considered when deciding the optimal treatment approach in this setting. Funding: Italian Drug Agency.

The aim of this study was to identify new disease-related circulating miRNAs with high diagnostic accuracy for breast cancer (BC) and to correlate their deregulation with the morpho-functional characteristics of the tumour, as assessed in vivo by positron emission tomography/magnetic resonance (PET/MR) imaging. A total of 77 untreated female BC patients underwent same-day PET/MR and blood collection, and 78 healthy donors were recruited as negative controls. The expression profile of 84 human miRNAs was screened by using miRNA PCR arrays and validated by real-time PCR. The validated miRNAs were correlated with the quantitative imaging parameters extracted from the primary BC samples. Circulating miR-125b-5p and miR-143-3p were upregulated in BC plasma and able to discriminate BC patients from healthy subjects (miR-125-5p area under the receiver operating characteristic ROC curve (AUC) = 0.85 and miR-143-3p AUC = 0.80). Circulating CA15-3, a soluble form of the transmembrane glycoprotein Mucin 1 (MUC-1) that is upregulated in epithelial cancer cells of different origins, was combined with miR-125b-5p and improved the diagnostic accuracy from 70% (CA15-3 alone) to 89% (CA15-3 plus miR-125b-5p). MiR-143-3p showed a strong and significant correlation with the stage of the disease, apparent diffusion coefficient (ADCmean), reverse efflux volume transfer constant (Kepmean) and maximum standardized uptake value (SUVmax), and it might represent a biomarker of tumour aggressiveness. Similarly, miR-125b-5p was correlated with stage and grade 2 but inversely correlated with the forward volume transfer constant (Ktransmean) and proliferation index (Ki67), suggesting a potential role as a biomarker of a relatively more favourable prognosis. In situ hybridization (ISH) experiments revealed that miR-143-3p was expressed in endothelial tumour cells, miR-125-5p in cancer-associated fibroblasts, and neither in epithelial tumour cells. Our results suggested that miR-125-5p and miR-143-3p are potential biomarkers for the risk stratification of BC, and Kaplan-Maier plots confirmed this hypothesis. In addition, the combined use of miR-125-b-5p and CA15-3 enhanced the diagnostic accuracy up to 89%. This is the first study that correlates circulating miRNAs with in vivo quantified tumour biology through PET/MR biomarkers. This integration elucidates the link between the plasmatic increase in these two potential circulating biomarkers and the biology of untreated BC. In conclusion, while miR-143-3b and miR-125b-5p provide valuable information for prognosis, a combination of miR-125b-5p with the tumour marker CA15-3 improves sensitivity for BC detection, which warrants consideration by further validation studies.

The effective management of patients with breast cancer (BC) depends on the early diagnosis of the disease. Currently, BC diagnosis is based on diagnostic imaging and biopsy, while the use of non-invasive circulating biomarkers for diagnosis remains an unmet need. Among the plethora of proposed non-invasive biomarkers, circulating microRNAs (miRNAs) have been considered promising diagnostic molecules because they are very stable in biological fluids and easily detectable. Although the discovery of miRNAs has opened a new avenue for their clinical application, the clinical translatability of these molecules remains unclear. This review analyses the role of circulating miRNAs as BC diagnostic biomarkers and focuses on two essential requirements to evaluate their clinical validity: i) Specificity and ii) consistent expression between the blood and tissue. These two issues were analyzed in depth using the Human miRNA Disease Database (HMDD v3.0) and the free search engine PubMed. One hundred and sixty three BC-associated miRNAs were selected and analyzed for their specificity among all human pathologies that shared deregulation (291) and consistent expression in the bloodstream and the tissue. In addition, we provide an overview of the current clinical trials examining miRNAs in BC. In conclusion, we highlight pitfalls in the translatability of circulating miRNAs into clinical practice due to the lack of specificity and a consistent expression pattern between the tissue and blood.

The presence of significant fibrosis is an indicator for liver disease staging and prognosis. The aim of the study was to determine reproducibility of real-time shear wave elastography using a hepatic biopsy as the reference standard to identify patients with chronic liver disease. Forty patients with chronic liver disease and 12 normal subjects received shear wave elastography performed by skilled operators. Interoperator reproducibility was studied in 29 patients. Fibrosis was evaluated using the Metavir score. The median and range shear wave elastography values in chronic liver disease subjects were 6.15 kPa and 3.14-16.7 kPa and were 4.49 kPa and 2.92-7.32 kPa in normal subjects, respectively. With respect to fibrosis detected by liver biopsy, shear wave elastography did not change significantly between F0 and F1 (p = 0.334), F1 and F2 (p = 0.611), or F3 and F4 (0.327); a significant difference was observed between the F0-F2 and F3-F4 groups (p = 0.002). SWE also correlated with inflammatory activity (Rs = 0.443, p = 0.0023) and ALT levels (Rs = 0.287, p = 0.0804). Age, sex and body mass index did not affect shear wave elastography measurements. Using receiver operator characteristic curves, two threshold values for shear wave elastography were identified: 5.62 kPa for patients with fibrosis (≥F2; sensitivity 80%, specificity 69.4%, and accuracy 77%) and 7.04 kPa for patients with severe fibrosis (≥F3; sensitivity 88.9%, specificity 81%, and accuracy 89%). Overall interobserver agreement was excellent and was analysed using an interclass correlation coefficient (0.94; CI 0.87-0.97).This study shows that shear wave elastography executed by skilled operators can be performed on almost all chronic liver disease patients with high reproducibility. It is not influenced by age, sex or body mass index, identifies severely fibrotic patients and is also related to inflammatory activity.

Leukocytes are major cellular components of the inflammatory and immune response systems. After their generation in the bone marrow from hematopoietic stem cells, they maturate as granulocytes (neutrophils, eosinophils, and basophils), monocytes, and lymphocytes. The abnormal accumulation and proliferation of immature blood cells (blasts) lead to severe and widespread diseases such as leukemia. We have recently shown that KCTD15, a member of the potassium channel tetramerization domain containing protein family (KCTD), is remarkably upregulated in leukemic B-cells. Here, we extend our investigation by monitoring the KCTD15 expression levels in circulating lymphocytes, monocytes, and granulocytes, as well as in leukemia cells. Significant differences in the expression level of KCTD15 were detected in normal lymphocytes, monocytes, and granulocytes. Interestingly, we also found overexpression of the protein following leukemic transformation in the case of myeloid cell lineage. Indeed, KCTD15 was found to be upregulated in K562 and NB4 cells, as well as in HL-60 cell lines. This in vitro finding was corroborated by the analysis of KCTD15 mRNA of acute myeloid leukemia (AML) patients reported in the Microarray Innovations in Leukemia (MILE) dataset. Collectively, the present data open interesting perspectives for understanding the maturation process of leukocytes and for the diagnosis/therapy of acute leukemias.

The goal of this review is to provide an overview of the studies aimed at integrating imaging parameters with molecular biomarkers for improving breast cancer patient’s diagnosis and prognosis. The use of diagnostic imaging to extract quantitative parameters related to the morphology, metabolism, and functionality of tumors, as well as their correlation with cancer tissue biomarkers is an emerging research topic. Thanks to the development of imaging biobanks and the technological tools required for extraction of imaging parameters including radiomic features, it is possible to integrate imaging markers with genetic data. This new field of study represents the evolution of radiology–pathology correlation from an anatomic–histologic level to a genetic level, which paves new interesting perspectives for breast cancer management.

46 patients with histologically confirmed breast cancer were enrolled and imaged with a 3T hybrid PET/MRI system, at staging. Diffusion, functional and perfusion parameters (measured by Tofts and shutter speed models) were compared. Results showed a good correlation between pharmacokinetic parameters and the SUV.

With the expansion of the production and applications of multiwalled carbon nanotubes (MWCNTs) in several industrial and science branches, the potential adverse effects on human health have attracted attention. Numerous studies have been conducted to evaluate how chemical functionalization may affect MWCNT effects; however, controversial data have been reported, showing either increased or reduced toxicity. In particular, the impact of carboxylation on MWCNT cytotoxicity is far from being completely understood. The aim of this work was the evaluation of the modifications induced by carboxylated-MWCNTs (MWCNTs-COOH) on cell surface and the study of cell-MWCNT-COOH interactions by means of field emission scanning electron microscope (FESEM). Human pulmonary epithelial cells (A549) were incubated with MWCNTs-COOH for different exposure times and concentrations (10 μg/mL for 1, 2, 4 h; 5, 10, 20 μg/mL for 24 h). At short incubation time, MWCNTs-COOH were easily observed associated with plasma membrane and in contact with microvilli. After 24 h exposure, FESEM analysis revealed that MWCNTs-COOH induced evident changes in the cellular surface in comparison to control cells: treated cells showed blebs, holes and a depletion of the microvilli density in association with structure modifications, such as widening and/or lengthening. In particular, an increase of cells showing holes and microvilli structure alterations was observed at 20 μg/mL concentration. FESEM analysis showed nanotube agglomerates, of different sizes, entering into the cell with two different mechanisms: inward bending of the membrane followed by nanotube sinking, and nanotube internalization directly through holes. The observed morphological microvilli modifications, induced by MWCNTs-COOH, could affect epithelial functions, such as the control of surfactant production and secretion, leading to pathological conditions, such as alveolar proteinosis. More detailed studies will be, however, necessary to examine in depth the effects induced by MWCNTs-COOH and, in particular, the timing of the MWCNT-COOH-cell interaction.

The aim of this study was to determine if functional parameters extracted from the hybrid positron emission tomography/magnetic resonance imaging (PET/MRI) correlate with the immunohistochemical markers of breast cancer (BC) lesions, to assess their ability to predict BC subtype. This prospective study was approved by the institution’s Ethics Committee, and all patients provided written informed consent. A total of 50 BC patients at diagnosis underwent PET/MRI before pharmacological and surgical treatment. For each primary lesion, the following data were extracted: morphological data including tumour-node-metastasis stage and lesion size; apparent diffusion coefficient (ADC); perfusion data including forward volume transfer constant (Ktrans), reverse efflux volume transfer constant (Kep) and extravascular extracellular space volume (Ve); and metabolic data including standardized uptake value (SUV), lean body mass (SUL), metabolic tumour volume and total lesion glycolysis. Immunohistochemical reports were used to determine receptor status (oestrogen, progesterone, and human epidermal growth factor receptor 2), cellular differentiation status (grade), and proliferation index (Ki67) of the tumour lesions. Correlation studies (Mann–Whitney U test and Spearman’s test), receiver operating characteristic (ROC) curve analysis, and multivariate analysis were performed. Association studies were performed to assess the correlations between imaging and histological prognostic markers of BC. Imaging biomarkers, which significantly correlated with biological markers, were selected to perform ROC curve analysis to determine their ability to discriminate among BC subtypes. SUVmax, SUVmean and SUL were able to discriminate between luminal A and luminal B subtypes (AUCSUVmean = 0.799; AUCSUVmax = 0.833; AUCSUL = 0.813) and between luminal A and nonluminal subtypes (AUCSUVmean = 0.926; AUCSUVmax = 0.917; AUCSUL = 0.945), and the lowest SUV and SUL values were associated with the luminal A subtype. Kepmax was able to discriminate between luminal A and luminal B subtypes (AUC = 0.779), and its highest values were associated with the luminal B subtype. Ktransmax (AUC = 0.881) was able to discriminate between luminal A and nonluminal subtypes, and the highest perfusion values were associated with the nonluminal subtype. In addition, ADC (AUC = 0.877) was able to discriminate between luminal B and nonluminal subtypes, and the lowest ADCmean values were associated with the luminal B subtype. Multivariate analysis was performed to develop a prognostic model, and the best predictive model included Ktransmax and SUVmax parameters. Using multivariate analysis of both PET and MRI parameters, a prognostic model including Ktransmax and SUVmax was able to predict the tumour subtype in 38 of 49 patients (77.6%, p

Breast cancer is a disease affecting an increasing number of women worldwide. Several efforts have been made in the last years to identify imaging biomarker and to develop noninvasive diagnostic tools for breast tumor characterization and monitoring, which could help in patients’ stratification, outcome prediction, and treatment personalization. In particular, radiomic approaches have paved the way to the study of the cancer imaging phenotypes. In this work, a group of 49 patients with diagnosis of invasive ductal carcinoma was studied. The purpose of this study was to select radiomic features extracted from a DCE-MRI pharmacokinetic protocol, including quantitative maps of ktrans, kep, ve, iAUC, and R1 and to construct predictive models for the discrimination of molecular receptor status (ER+/ER-, PR+/PR-, and HER2+/HER2-), triple negative (TN)/non-triple negative (NTN), ki67 levels, and tumor grade. A total of 163 features were obtained and, after feature set reduction step, followed by feature selection and prediction performance estimations, the predictive model coefficients were computed for each classification task. The AUC values obtained were 0.826±0.006 for ER+/ER-, 0.875±0.009 for PR+/PR-, 0.838±0.006 for HER2+/HER2-, 0.876±0.007 for TN/NTN, 0.811±0.005 for ki67+/ki67-, and 0.895±0.006 for lowGrade/highGrade. In conclusion, DCE-MRI pharmacokinetic-based phenotyping shows promising for discrimination of the histological outcomes.

The aim of the study was to enhance the antioxidant properties of fish burgers with microencapsulated propolis. Spray-drying process was used to microencapsulate propolis (30 g in 100 mL of ethanol 70% v/v) by means of gum Arabic and Capsul in different ratios (1:6 for gum Arabic and Capsul and then 1:20 just for Capsul). Once defined the optimal microencapsulation conditions, an alcohol-free powder able to mask the strong odor of propolis was obtained, thus promoting a potential food application as source of phenolics and antioxidants. Specifically, 5% w/w of spray-dried propolis was incorporated in fish burgers. To improve their sensory properties, new ingredients such as potato flakes (3%, 5%, 7% and 10% w/w) and extra virgin olive oil (9% w/w) were tested and optimized to give a final fish product with good acceptability. Proper tests on burgers also demonstrated an effective increase of both phenolic content and antioxidant activity.

Although recent successes in clinical trials are strengthening research focused on cancer immunology, the poor immunogenicity and off-target side effects of immunotherapeutics remain major challenges in translating these promising approaches to clinically feasible therapies in the treatment of a large range of tumors. Nanotechnology offers target-based approaches, which have shown significant improvements in the rapidly advancing field of cancer immunotherapy. Here, we first discuss the chemical and physical features of nanoparticulate systems that can be tuned to address the anticancer immune response, and then review recent, key examples of the exploited strategies, ranging from nanovaccines to NPs revising the tumor immunosuppressive microenvironment, up to immunotherapeutic multimodal NPs. Finally, the paper concludes by identifying the promising and outstanding challenges the field of emerging nanotechnologies is facing for cancer immunotherapy.

PED (phosphoprotein enriched in diabetes) is a death-effector domain (DED) family member with a broad anti-apoptotic action. PED inhibits the assembly of the death-inducing signalling complex (DISC) of death receptors following stimulation. Recently, we reported that the expression of PED is increased in breast cancer cells and determines the refractoriness of these cells to anticancer therapy. In the present study, we focused on the role of PED in non-small cell lung cancer (NSCLC), a tumour frequently characterized by evasion of apoptosis and drug resistance. Immunohistochemical analysis of a tissue microarray, containing 160 lung cancer samples, indicated that PED was strongly expressed in different lung tumour types. Western blotting performed with specimens from NSCLC-affected patients showed that PED was strongly up-regulated (>6 fold) in the areas of tumour compared to adjacent normal tissue. Furthermore, PED expression levels in NSCLC cell lines correlated with their resistance to tumour necrosis factor related apoptosis-inducing ligand (TRAIL)-induced cell death. The involvement of PED in the refractoriness to TRAIL-induced cell death was investigated by silencing PED expression in TRAIL-resistant NSCLC cells with small interfering (si) RNAs: transfection with PED siRNA, but not with cFLIP siRNA, sensitized cells to TRAIL-induced cell death. In conclusion, PED is specifically overexpressed in lung tumour tissue and contributes to TRAIL resistance.

Ultraconserved regions (UCRs) have been shown to originate non-coding RNA transcripts (T-UCRs) that have different expression profiles and play functional roles in the pathophysiology of multiple cancers. The relevance of these functions to the pathogenesis of bladder cancer (BlCa) is speculative. To elucidate this relevance, we first used genome-wide profiling to evaluate the expression of T-UCRs in BlCa tissues. Analysis of two datasets comprising normal bladder tissues and BlCa specimens with a custom T-UCR microarray identified ultraconserved RNA (uc.) 8+ as the most upregulated T-UCR in BlCa tissues, although its expression was lower than in pericancerous bladder tissues. These results were confirmed on BlCa tissues by real-time PCR and by in situ hybridization. Although uc.8+ is located within intron 1 of CASZ1, a zinc-finger transcription factor, the transcribed non-coding RNA encoding uc.8+ is expressed independently of CASZ1. In vitro experiments evaluating the effects of uc.8+ silencing, showed significantly decreased capacities for cancer cell invasion, migration, and proliferation. From this, we proposed and validated a model of interaction in which uc.8+ shuttles from the nucleus to the cytoplasm of BlCa cells, interacts with microRNA (miR)-596, and cooperates in the promotion and development of BlCa. Using computational analysis, we investigated the miR-binding domain accessibility, as determined by base-pairing interactions within the uc.8+ predicted secondary structure, RNA binding affinity, and RNA species abundance in bladder tissues and showed that uc.8+ is a natural decoy for miR-596. Thus uc.8+ upregulation results in increased expression of MMP9, increasing the invasive potential of BlCa cells. These interactions between evolutionarily conserved regions of DNA suggest that natural selection has preserved this potentially regulatory layer that uses RNA to modulate miR levels, opening up the possibility for development of useful markers for early diagnosis and prognosis as well as for development of new RNA-based cancer therapies.

Entry of enveloped viruses requires fusion of viral and cellular membranes, driven by conformational changes of viral glycoproteins. The crystallized trimeric glycoprotein gB of herpes simplex virus has been described as a postfusion conformation, and several studies prove that like other class III fusion proteins, gB undergoes a pH-dependent switch between the pre- and postfusion conformations. Using several biophysical techniques, we show that peptides corresponding to the long helix of the gB postfiision structure interfere with the membrane fusion event, likely hampering the conformational rearrangements from the pre- to the postfusion structures. Those peptides represent good candidates for further design of peptidomimetic antagonists capable of blocking the fusion process.

MicroRNAs (miRNAs) control cell cycle progression by targeting the transcripts encoding for cyclins, CDKs and CDK inhibitors, such as p27(KIP1) (p27). p27 expression is controlled by multiple transcriptional and posttranscriptional mechanisms, including translational inhibition by miR-221/222 and posttranslational regulation by the SCF(SKP2) complex. The oncosuppressor activity of miR-340 has been recently characterized in breast, colorectal and osteosarcoma tumor cells. However, the mechanisms underlying miR-340-induced cell growth arrest have not been elucidated. Here, we describe miR-340 as a novel tumor suppressor in non-small cell lung cancer (NSCLC). Starting from the observation that the growth-inhibitory and proapoptotic effects of miR-340 correlate with the accumulation of p27 in lung adenocarcinoma and glioblastoma cells, we have analyzed the functional relationship between miR-340 and p27 expression. miR-340 targets three key negative regulators of p27. The miR-340-mediated inhibition of both Pumilio family RNA-binding proteins (PUM1 and PUM2), required for the miR-221/222 interaction with the p27 3'-UTR, antagonizes the miRNA-dependent downregulation of p27. At the same time, miR-340 induces the stabilization of p27 by targeting SKP2, the key posttranslational regulator of p27. Therefore, miR-340 controls p27 at both translational and posttranslational levels. Accordingly, the inhibition of either PUM1 or SKP2 partially recapitulates the miR-340 effect on cell proliferation and apoptosis. In addition to the effect on tumor cell proliferation, miR-340 also inhibits intercellular adhesion and motility in lung cancer cells. These changes correlate with the miR-340-mediated inhibition of previously validated (MET and ROCK1) and potentially novel (RHOA and CDH1) miR-340 target transcripts. Finally, we show that in a small cohort of NSCLC patients (n=23), representative of all four stages of lung cancer, miR-340 expression inversely correlates with clinical staging, thus suggesting that miR-340 downregulation contributes to the disease progression.

Background ABT-737 is a BH3 mimetic small-molecule inhibitor that binds with high affinity to Bcl-2 to induce apoptosis in malignant cells and has shown promise as an effective anti-leukemic agent in pediatric preclinical tests. This study focuses on the effects of ABT-737 on leukemia cells with MLL rearrangement and identifies some of the biological correlates of its activity. Procedure Cells were cultured in the presence of increasing concentrations of ABT-737 alone or in combination with other agents. After 4 days in culture, cell growth inhibition was measured by Alamar blue assay. The expression and activation of potential intracellular targets of ABT-737 activity were determined by Western blot analysis. Results Significant Bcl-2 expression was detected in all infant leukemia cells investigated. ABT-737 induced cell death in all cell lines studied although the IC50 values differed somewhat between cell lines. Western blot analysis identified the effects of ABT-737 on survival and apoptosis-regulatory proteins PARP, caspase-8, and cytochrome-c. Drug combination studies indicated synergy with distinct anti-neoplastic agents, including the multi-tyrosine kinase inhibitor sunitinib. This effective drug synergy appears to be mediated by the combined inhibition of Bcl-2 and intracellular signaling pathways. Conclusions We describe the in vitro studies to demonstrate the activity and drug combinability of ABT-737 against MLL rearranged leukemia cells. In addition, identification of the molecular changes that occur in the presence of ABT-737 provides information regarding effective target validation and target modulation analyses in future clinical trials. Pediatr Blood Cancer 2011;56:353–360. © 2010 Wiley-Liss, Inc.

Swapnil Gaikwad,1 Avinash Ingle,1 Aniket Gade,1 Mahendra Rai,1 Annarita Falanga,3 Novella Incoronato,2 Luigi Russo,2 Stefania Galdiero,3 Massimilano Galdiero2 1Department of Biotechnology, Sant Gadge Baba Amravati University, Amravati, Maharashtra, India; 2Department of Experimental Medicine, Division of Microbiology, II University of Naples, 3Department of Pharmacy, University of Naples “Federico II”, DFM and Institute of Biostructures and Bioimages, Naples, Italy Abstract: The interaction between silver nanoparticles and viruses is attracting great interest due to the potential antiviral activity of these particles, and is the subject of much research effort in the treatment of infectious diseases. In this work, we demonstrate that silver nanoparticles undergo a size-dependent interaction with herpes simplex virus types 1 and 2 and with human parainfluenza virus type 3. We show that production of silver nanoparticles from different fungi is feasible, and their antiviral activity is dependent on the production system used. Silver nanoparticles are capable of reducing viral infectivity, probably by blocking interaction of the virus with the cell, which might depend on the size and zeta potential of the silver nanoparticles. Smaller-sized nanoparticles were able to inhibit the infectivity of the viruses analyzed. Keywords: silver nanoparticles, antiviral, herpes simplex virus, parainfluenza virus

Background On the basis of the results of two pivotal phase III clinical trials, eribulin mesylate is currently approved in EU for the treatment of advanced breast cancer (aBC) in patients who have previously received an anthracycline and a taxane in either the adjuvant or the metastatic setting, and at least one chemotherapeutic regimen for metastatic disease. Methods In our study, we investigated the efficacy and tolerability of eribulin as second or further line chemotherapy in 137 women affected by aBC. Results Eribulin as monotherapy provided benefit in terms of progression-free survival (PFS), response rate (RR) and disease control rate (DCR) independently of its use as second or late-line therapy. The overall RR and DCR were 17.5% and 64%, respectively. In particular, DCR and overall RR were 50% and 13.6%, 65.4% and 21.1%, 70.4% and 14.8% and 66.7% and 16.7% in second, third, fourth and further lines of treatment, respectively. Median PFS (mPFS) according to the line of therapy was 5.7, 6.3, 4.5 and 4.0 months in patients treated with eribulin in second, third, fourth and over the fourth line, respectively. No significant difference in terms of mPFS was found between the various BC subtypes. Overall, eribulin resulted safe and most adverse events were of grade 1 or 2 and easily manageable. Grades 3–4 toxicities were neutropaenia and neurotoxicity. Conclusions With the limitations due to the observational nature of our findings, eribulin was shown to be an effective and safe therapeutic option in heavily pretreated patients with aBC.

Glioblastoma is the most frequent brain tumor in adults and is the most lethal form of human cancer. Despite the improvements in treatments, survival of patients remains poor. In order to identify microRNAs (miRs) involved in glioma tumorigenesis, we evaluated, by a miRarray, differential expression of miRs in the tumorigenic glioma LN-18, LN-229 and U87MG cells compared with the non-tumorigenic T98G cells. Among different miRs we focused our attention on miR-221 and -222. We demonstrated the presence of a binding site for these two miRs in the 3′ untranslated region of the protein tyrosine phosphatase μ (PTPμ). Previous studies indicated that PTPμ suppresses cell migration and is downregulated in glioblastoma. Significantly, we found that miR-221 and -222 over-expression induced a downregulation of PTPμ as analyzed by both western blot and real-time PCR. Furthermore, miR-222 and -221 induced an increase in cell migration and growth in soft agar in glioma cells. Interestingly, the re-expression of PTPμ gene was able to revert the miR-222 and -221 effects on cell migration. Furthermore, we found an inverse correlation between miR-221 and -222 and PTPμ in human glioma cancer samples. In conclusion, our results suggest that miR-221 and -222 regulate glioma tumorigenesis at least in part through the control of PTPμ protein expression.

PED/PEA-15 (PED) is a death effector domain family member of 15 kDa with a broad antiapoptotic function found overexpressed in a number of different human tumors, including lung cancer. To date, the mechanisms that regulate PED expression are unknown. Therefore, we address this point by the identification of microRNAs that in non–small cell lung cancer (NSCLC) modulate PED levels. In this work, we identify miR-212 as a negative regulator of PED expression. We also show that ectopic expression of this miR increases tumor necrosis factor–related apoptosis-inducing ligand (TRAIL)–induced cell death in NSCLC cells. In contrast, inhibition of endogenous miR-212 by use of antago-miR results in increase of PED protein expression and resistance to TRAIL treatment. Besides, in NSCLC, we show both in vitro and in vivo that PED and miR-212 expressions are inversely correlated, that is, PED is upregulated and miR-212 is rarely expressed. In conclusion, these findings suggest that miR-212 should be considered as a tumor suppressor because it negatively regulates the antiapoptotic protein PED and regulates TRAIL sensitivity. Cancer Res; 70(9); 3638–46. ©2010 AACR.

Mendelian primary immunodeficiency diseases (MPIDs) are rare disorders affecting distinct constituents of the innate and adaptive immune system. Although they are genetically heterogeneous, a substantial group of MPIDs is due to mutations in genes affecting the nuclear factor-?B (NF-?B) transcription pathway, essential for cell proliferation and cell survival and involved in innate immunity and inflammation. Many of these genes encode for crucial regulatory components of the NF-?B pathway and their mutations are associated with immunological and developmental signs somehow overlapping in patients with MPIDs. At present, nine different MPIDs listed in the online mendelian inheritance in man (OMIM) are caused by mutations in at least nine different genes strictly involved in the NF-?B pathway that result in defects in immune responses. Here we report on the distinct function of each causative gene, on the impaired NF-?B step and more in general on the molecular mechanisms underlining the pathogenesis of the disease. Overall, the MPIDs affecting the NF-?B signalosome require a careful integrated diagnosis and appropriate genetic tests to be molecularly identified. Their discovery at an ever-increasing rate will help establish a common therapeutic strategy for a subclass of immunodeficient patients.Genes and Immunity advance online publication, 12 March 2015; doi:10.1038/gene.2015.3.

In the last few years, biomedical research has been boosted by the technological development of analytical instrumentation generating a large volume of data. Such information has increased in complexity from basic (i.e., blood samples) to extensive sets encompassing many aspects of a subject phenotype, and now rapidly extending into genetic and, more recently, radiomic information. Radiogenomics integrates both aspects, investigating the relationship between imaging features and gene expression. From a methodological point of view, radiogenomics takes advantage of non-conventional data analysis techniques that reveal meaningful information for decision-support in cancer diagnosis and treatment. This survey is aimed to review the state-of-the-art techniques employed in radiomics and genomics with special focus on analysis methods based on molecular and multimodal probes. The impact of single and combined techniques will be discussed in light of their suitability in correlation and predictive studies of specific oncologic diseases.

Background: The aim of this study was to evaluate the value of CA15-3 for the diagnostic integration of molecular imaging findings performed with hybrid positron emission tomography and computed tomography (PETCT) technology. Methods: We retrospectively selected 45 patients with a median age of 60 years (range 39–85 years) and a previous history of breast cancer (BC) who had already been treated with surgery and other treatments. Three measurements of CA15-3 were collected within 1 year before PETCT examination, at 6–9 months 3–6 months and 0–3 months before PETCT. The prolonged clinical outcome or imaging follow-up was used to define disease relapse. An increase in tumor marker value was compared with PETCT findings and disease relapse. Sensitivity and specificity for both tests were calculated with respect to clinical outcome. Results: Disease relapse was detected in 16 out of 45 BC patients. CA15-3 and PETCT showed 75% sensitivity with a specificity percentage of 76% for CA15-3 and 79% for PETCT. Serum CA15-3 expression levels were significantly higher in BC patients with multiple metastatic sites with hepatic involvement. Analysis of serial CA15-3 serum levels showed an increase in CA15-3 3–6 months before PETCT could identify BC patients at risk for relapse (AUC = 0.81). Moreover, patients receiving anti-hormonal or chemotherapy medications with negative PETCT and positive CA15-3 relapsed after a median time of 158 days compared to patients who were negative for both tests and who were free from disease for at least 1 year. Conclusions: Our results showed that serial increases in CA15-3 can be used to predict positive PETCT results in BC patients during follow-up. Increased levels of CA15-3 may be considered an early warning sign in patients needing accurate molecular imaging investigations, as they are at higher risk of recurrence. In cases of elevated levels, multiple lesions or liver involvement may exist. Also, patients receiving chemotherapeutic or anti-hormonal treatment who have negative PETCT scans and increased CA15-3 serum levels should be considered at risk for relapse, because the CA15-3-linked biochemical signal of the presence of a tumor can predict positive metabolic imaging.

The Shp-2 and Shp-1 non-transmembrane tyrosine phosphatases display different and even opposing effects on downstream signaling events initiated by Ret activation. By using rat pheochromocytoma-derived PC 12 cells, here we studied the interactions of Shp-2 and Shp-1 with two activated mutants of Ret receptor, Ret(C634Y) and Ret(M918T). Each of these mutated receptors causes inheritance of distinct cancer syndromes, multiple endocrine neoplasia (MEN) type 2A and type 2B, respectively. We show that: (i) both Shp-1 and Shp-2 are associated to a multiprotein complex that includes Ret mutants; (ii) the Shp-1-Ret complexes are distinct from Shp-2-Ret complexes, and these complexes are differently distributed inside and outside lipid rafts; (iii) constitutively activated Ret proteins neither directly bind to nor are substrates of these phosphatases. Our results well support the evidence that Ret complexes within and outside rafts mediate distinct biological functions, and indicate that the presence of either Slips participates to determine such functions.

Postmenopausal hormone replacement therapy (HRT) relieves menopausal symptoms and may decrease mortality in recently postmenopausal women, but increases breast cancer risk. Low-dose tamoxifen has shown retained activity in phase-II studies.We conducted a phase-III trial in 1884 recently postmenopausal women on HRT who were randomly assigned to either tamoxifen, 5 mg/day, or placebo for 5 years. The primary end point was breast cancer incidence.After 6.2 ± 1.9 years mean follow-up, there were 24 breast cancers on placebo and 19 on tamoxifen (risk ratio, RR, 0.80; 95% CI 0.44-1.46). Tamoxifen showed favorable trends in luminal-A tumors (RR, 0.32; 95% CI 0.12-0.86), in HRT users5 years (RR, 0.35; 95% CI 0.15-0.82) and in women completing at least 12 months of treatment (RR, 0.49; 95% CI 0.23-1.02). Serious adverse events did not differ between placebo and tamoxifen, including, respectively, coronary heart syndrome (6 versus 4), cerebrovascular events (2 versus 5), VTE (2 versus 5) and uterine cancers (3 versus 1). Vasomotor symptoms were 50% more frequent on tamoxifen.The addition of low-dose tamoxifen to HRT did not significantly reduce breast cancer risk and increased climacteric symptoms in recently postmenopausal women. However, we noted beneficial trends in some subgroups which may deserve a larger study.

The present phase I study was designed to determine the maximum tolerated dose (MTD) of epirubicin, administered every 3 weeks to patients with advanced non-small cell lung cancer (NSCLC), and combined with a conventional dose of vinorelbine [25 mg/m2 intravenously (i.v.) days 1 and 8] with or without the support of granulocyte-colony stimulating factor (G-CSF). 18 patients entered the study. The patients received the following four dose levels of epirubicin (i.v., day 1): 50 mg/m2 (3 patients) and 60 mg/m2 (6 patients) without G-CSF, 75 mg/m2 (3 patients) and 90 mg/m2 (6 patients) with G-CSF (5 micrograms/kg days 4-6 and 9-15). In the patients treated without G-CSF the MTD of epirubicin was 60 mg/m2 and leukopenia was the dose-limiting toxicity. In the patients treated with G-CSF the MTD was 90 mg/m2, myelotoxicity being the dose-limiting toxicity. We observed 1/3 partial response (PR) with epirubicin at the dose of 75 mg/m2 and 2/6 PR at 90 mg/m2. These results would indicate the usefulness of a phase II study with epirubicin at the dose of 90 mg/m2 in association with conventional dose of vinorelbine with the support of G-CSF in advanced NSCLC.

In total, 17 pediatric patients with hematologic malignancies (n=14) and Fanconi anemia (FA) (n=3) underwent haploidentical SCT with T-cell depletion. The patients were conditioned with reduced-intensity regimens, and CYA was used for GVHD prophylaxis. Successful engraftment occurred in 16 patients (94%). One patient failed to achieve a primary engraftment. Another patient rejected the first SCT after 10 weeks and had a successful second transplant. Of all engrafted patients, only one developed severe acute GVHD. Ten patients were alive at a median follow-up of 18 months (range, 5–62 months). The 5-years’ OS was 53.8%. The three patients with FA are currently well with full-donor chimerism at 16, 6 and 5 months post transplant, respectively. The OS of 14 patients with high-risk hematologic malignancies was 47.6%. Three patients died as a result of post transplant leukemia relapse. CMV infection, GVHD and organ injury were other causes of mortality. Haploidentical SCT was found to be an alternative feasible treatment in Uruguay for patients who need allogenic transplantation but lack an HLA-identical family donor. It should be considered as an early option in FA patients before transformation or significant exposure to blood products.

The combined use of antimicrobial compounds and modified atmosphere packaging (MAP) on shelf life of reduced pork back-fat content sausages was investigated in this study. First, a pre-screening of different antimicrobial compounds and MAP was addressed. In particular, the consumer test was used as a tool to select the most pleasant antimicrobial compounds, whereas both sausage color and cell load of main spoilage microorganisms were used to choose optimal MAP. Afterwards, antimicrobial compounds (lemon alkott and thymol) and MAP (MAP1: 20% CO2, 5% O2, 75% N2) that had shown the best performance were used to run the shelf life tests. In order to assess the influence of the variables described beforehand on the shelf life of investigated sausages, the sensorial and microbiological (mesophilic and psychrotrophic bacteria, Enterobacteriaceae, Pseudomonas spp., lactic acid bacteria and coccus-shaped lactic acid bacteria) quality was monitored during storage. Results recorded in this study suggested that Pseudomonas spp. were responsible for sausage unacceptability in all samples, except for thymol and thymol-MAP samples. For these samples, the sensorial quality was the limiting factor while the microbial growth did not limit the shelf life. In particular, for thymol and thymol-MAP samples a shelf life value of more than 5 days with respect to the other samples (2 days) was obtained.

Interference with the molecular mechanisms that generate tumor supportive niches in the bone microenvironment is a rational approach to inhibit the growth of hematological malignancies. However, the advancement of knowledge in this area has been slowed down by the lack of in vitro models to facilitate the screening of potential candidate agents. The rare cases of acute lymphoblastic leukemia (ALL) in children presenting with extensive bone involvement may represent an exaggerated form of some aspects of the normal tumor-bone interactions. Thus, these cases can provide insight into processes that are otherwise challenging to uncover. The authors describe the case of a 6-year-old child who presented with severe osteopenia that resolved at the time of leukemic remission. Compared to control sera, serum taken at disease presentation contained increased levels of a group of osteolytic cytokines and was effective in activating preosteoclast cells in culture. Based on these findings, the authors describe an experimental model to identify agents that would interfere with leukemia mediated osteolytic process.