176 research outputs found
Whole-exome analysis in osteosarcoma to identify a personalized therapy
Osteosarcoma is the most common pediatric primary non-hematopoietic bone
tumor. Survival of these young patients is related to the response to chemotherapy and
development of metastases. Despite many advances in cancer research, chemotherapy
regimens for osteosarcoma are still based on non-selective cytotoxic drugs. It is essential
to investigate new specific molecular therapies for osteosarcoma to increase the survival
rate of these patients. We performed exomic sequence analyses of 8 diagnostic biopsies
of patients with conventional high grade osteosarcoma to advance our understanding
of their genetic underpinnings and to correlate the genetic alteration with the clinical
and pathological features of each patient to identify a personalized therapy.
We identified 18,275 somatic variations in 8,247 genes and we found three
mutated genes in 7/8 (87%) samples (KIF1B, NEB and KMT2C). KMT2C showed the
highest number of variations; it is an important component of a histone H3 lysine 4
methyltransferase complex and it is one of the histone modifiers previously implicated
in carcinogenesis, never studied in osteosarcoma. Moreover, we found a group of 15
genes that showed variations only in patients that did not respond to therapy and
developed metastasis and some of these genes are involved in carcinogenesis and
tumor progression in other tumors.
These data could offer the opportunity to get a key molecular target to identify
possible new strategies for early diagnosis and new therapeutic approaches for
osteosarcoma and to provide a tailored treatment for each patient based on their
genetic profile
Autohydrolysis pretreatment of Arundo donax: a comparison between microwave-assisted batch and fast heating rate flow-through reaction systems
Background: Autohydrolysis of lignocellulosic biomass in liquid hot water has been widely studied owing to its
high efficiency and relatively low cost. In the perspective of industrial applications, continuous or semi-continuous
processes are more interesting than batch systems. Moreover, microwave heating of pretreatment systems has been
proposed to intensify the kinetics of the process. In this study, the autohydrolysis of Arundo donax was performed in
pure liquid hot water using a microwave-heated batch reactor and a semi-continuous flow-through reaction system
with fast heating rate at the same operating conditions with the aim of performing a systematic comparison between
the two different experimental apparatuses.
Results: The effect of process temperature and time, biomass to water mass to volume ratio and water flow rate on
the concentration and yield of hydrolysis products was investigated. The flow-through set-up allowed us to reach
biomass solubilization up to 44.5 wt% on dry basis, while the batch system stopped at 34.5 wt% suggesting that the
mass transfer could be the rate-determining step in the solubilization of the constituting biopolymers. For example,
in the flow-through layout, using a flow rate of 3.5 mL/min at 200 °C with 20 min of processing time, quantitative
recovery of hemicellulose was obtained with limited formation of degradation products. Interestingly, higher cellulose/
hemicellulose extraction ratios were found using the microwave-assisted batch reactor. FTIR analyses of the solid
residues recovered after the pretreatment offered independent information on the fractions of liquefied biopolymers
complementary to those derived from HPLC and UVâVis spectroscopy.
Conclusions: Collected experimental results indicated that the flow-through system can be adopted to obtain complete
solubilization of the hemicellulose fraction of Arundo donax addressing the product distribution in soluble compounds
towards fermentable sugars with limited formation of sugar degradation products and with limited penalty in
terms of dilution of the hydrolysate solution. It was also found that microwaves can promote cellulose depolymerization
and solubilization, thus allowing a more comprehensive utilization of the biomass and that infrared spectroscopy
can be a useful technique to estimate the effect of the pretreatment
CXCL12/SDF-1 from perisynaptic Schwann cells promotes regeneration of injured motor axonterminals
The neuromuscular junction has retained through evolution the capacity to regenerate after damage, but little is known on the inter-cellular signals involved in its functional recovery from trauma, autoimmune attacks, or neurotoxins. We report here that CXCL12, also abbreviated as stromal-derived factor-1 (SDF-1), is produced specifically by perisynaptic Schwann cells following motor axon terminal degeneration induced by -latrotoxin. CXCL12 acts via binding to the neuronal CXCR4 receptor. A CXCL12-neutralizing antibody or a specific CXCR4 inhibitor strongly delays recovery from motor neuron degeneration invivo. Recombinant CXCL12 invivo accelerates neurotransmission rescue upon damage and very effectively stimulates the axon growth of spinal cord motor neurons invitro. These findings indicate that the CXCL12-CXCR4 axis plays an important role in the regeneration of the neuromuscular junction after motor axon injury. The present results have important implications in the effort to find therapeutics and protocols to improve recovery of function after different forms of motor axon terminal damage
Mitochondrial enzyme GLUD2 plays a critical role in glioblastoma progression
Background: Glioblastoma (GBM) is the most frequent and malignant primary brain tumor in adults and despite the progress in surgical procedures and therapy options, the overall survival remains very poor. Glutamate and α-KG are fundamental elements necessary to support the growth and proliferation of GBM cells. Glutamate oxidative deamination, catalyzed by GLUD2, is the predominant pathway for the production of α-KG. Methods: GLUD2 emerged from the RNA-seq analysis of 13 GBM patients, performed in our laboratory and a microarray analysis of 77 high-grade gliomas available on the Geo database. Thereafter, we investigated GLUD2 relevance in cancer cell behavior by GLUD2 overexpression and silencing in two different human GBM cell lines. Finally, we overexpressed GLUD2 in-vivo by using zebrafish embryos and monitored the developing central nervous system. Findings: GLUD2 expression was found associated to the histopathological classification, prognosis and survival of GBM patients. Moreover, through in-vitro functional studies, we showed that differences in GLUD2 expression level affected cell proliferation, migration, invasion, colony formation abilities, cell cycle phases, mitochondrial function and ROS production. In support of these findings, we also demonstrated, with in-vivo studies, that GLUD2 overexpression affects glial cell proliferation without affecting neuronal development in zebrafish embryos. Interpretation: We concluded that GLUD2 overexpression inhibited GBM cell growth suggesting a novel potential drug target for control of GBM progression. The possibility to enhance GLUD2 activity in GBM could result in a blocked/reduced proliferation of GBM cells without affecting the survival of the surrounding neurons
A mouse mammary tumor virus env-like exogenous sequence is strictly related to progression of human sporadic breast carcinoma
A viral etiology of human breast cancer (HBC) has been postulated for decades since the identification of mouse mammary tumor virus (MMTV). The detection of MMTV env-like exogenous sequences (MMTVels) in 30% to 40% of invasive HBCs increased attention to this hypothesis. Looking for MMTVels during cancer progression may contribute to a better understanding of their role in HBC. Herein, we analyzed HBC preinvasive lesions for the presence of MMTVels. Samples were obtained by laser microdissection of FFPE tissues: 20 usual-type ductal hyperplasias, 22 atypical ductal hyperplasias (ADHs), 49 ductal carcinomas in situ (DCISs), 20 infiltrating ductal carcinomas (IDCs), and 26 normal epithelial cells collateral to a DCIS or an IDC. Controls included reductive mammoplastic tissue, thyroid and colon carcinoma, and blood samples from healthy donors. MMTVels were detected by fluorescence-nested PCR. DNA samples from the tissues of nine patients were analyzed by real-time quantitative PCR, revealing a different viral load correlated with stage of progression. Furthermore, as never previously described, the presence of MMTVels was investigated by chromogenic in situ hybridization. MMTVels were found in 19% of normal epithelial cells collateral to a DCIS or an IDC, 27% of ADHs, 82% of DCISs, and 35% of IDCs. No MMTVels were found in the control samples. Quantitative PCR and chromogenic in situ hybridization confirmed these results. These data could contribute to our understanding of the role of MMTVels in HBC. (Am J Pathol 2011, 179:2083-2090; DOI: 10.1016/j.ajpath.2011.06.046
Pathological features and molecular phenotype of mmtv likeâpositive feline mammary carcinomas
In the last few years MMTVâlike nucleotide sequences were detected in some feline and canine mammary tumours. Due to the confirmed role of cats in the epidemiology of the MMTVâlike virus, the aim of this study was to investigate the main pathological features of positive feline mammary carcinomas (FMCs). Twentyâfour FMCs were collected at the University of Bologna, submitted to laser microdissection and analysed by nested fluorescenceâPCR using primer sets specific for MMTV env sequence. For immunohistochemistry, an antibody against MMTV protein 14 (p14) was used. MMTVâlike sequences were detected in three out of 24 FMCs (12.5%), one tubular carcinoma, one tubulopapillary carcinoma and one ductal carcinoma. All PCRâpositive tumours were also positive for p14. Multiple nucleotide alignment has shown similarity to MMTV ranging from 98% to 100%. All the 102 examined FMCs were submitted to immunohistochemistry for molecular pheno-typing. Of the nine MMTVâlike positive FMCs, six were basalâlike and three luminalâlike. Our results demonstrate MMTVâlike sequences and protein in FMCs of different geographic areas. Molecular phenotyping could contribute to understand the possible role of MMTVâlike virus in FMC tumor biology
Satisfaction with chronic obstructive pulmonary disease treatment: results from a multicenter, observational study
Background: Understanding the level of patients' satisfaction with treatment and its determinants have the potential to impact therapeutic management and clinical outcome in chronic conditions such as chronic obstructive pulmonary disease (COPD). Methods: A national, multicenter, longitudinal, observational study of COPD from 20 Italian pulmonary centers to explore patients' satisfaction to treatment [assessed by the Treatment Satisfaction Questionnaire, 9 items (TSQM-9)] and association with clinical parameters [including dyspnea score, COPD Assessment Test (CAT) score, exacerbation rate], adherence to treatment [Morisky Medication-Taking Adherence Scale (MMAS-4)], illness perception [evaluated by Brief Illness Perception Questionnaire (B-IPQ)] in a 1-year follow up. Results: A total of 401 COPD patients were enrolled [69.4% group B Global Initiative for COPD (GOLD), considering 366 patients with available GOLD 2017 classification at enrollment]. At enrollment, satisfaction with treatment was moderate, being TSQM-9 mean scores for effectiveness 64.2 [95% confidence interval (CI) 62.5-65.9], for convenience 75.8 (95% CI 74.2-77.3), and for global satisfaction 65.7 (95% CI 64.0-67.4). Global satisfaction was negatively associated with disease perception (beta = -0.4709, p < 0.0001), and grade of dyspnea (beta = -4.2564, p = 0.009). Satisfaction with treatment was lower in patients with poor compared with optimal adherence to treatment (beta = -4.5608, p = 0.002). Changes in inhalation regimens during follow up did not modify the satisfaction with treatment. Conclusions: The results of this real-life study showed that the patients' satisfaction with treatments is only moderate in COPD. A high grade of patients' satisfaction is associated mainly with a low perception of the disease, high adherence to treatment and lower level of dyspnea
VHL and HIF-1α: gene variations and prognosis in early-stage clear cell renal cell carcinoma.
A human MMTV-like betaretrovirus linked to breast cancer has been present in humans at least since the Copper Age
The betaretrovirus Mouse Mammary Tumor Virus (MMTV) is the well characterized etiological agent of mammary tumors in mice. In contrast, the etiology of sporadic human breast cancer (BC) is unknown, but accumulating data indicate a possible viral origin also for these malignancies. The presence of MMTVenv-like sequences (MMTVels) in the human salivary glands and saliva supports the latter as possible route of interhuman dissemination. In the absence of the demonstration of a mouse-man transmission of MMTV, we considered the possibility that a cross-species transmission could have occurred in ancient times. Therefore, we investigated MMTVels in the ancient dental calculus, which originates from saliva and is an excellent material for paleovirology. The calculus was collected from 36 ancient human skulls, excluding any possible mouse contamination. MMTV-like sequences were identified in the calculus of 6 individuals dated from the Copper Age to the 17th century. The MMTV-like sequences were compared with known human endogenous betaretroviruses and with animal exogenous betaretroviruses, confirming their exogenous origin and relation to MMTV. These data reveal that a human exogenous betaretrovirus similar to MMTV has existed at least since 4,500 years ago and indirectly support the hypothesis that it could play a role in human breast cancer
Systemic antifungal treatment after posaconazole prophylaxis: results from the SEIFEM 2010-C survey.
OBJECTIVES:
To investigate the incidence, treatment and outcome of breakthrough invasive fungal infections (IFIs) in adult acute myeloid leukaemia (AML) patients after posaconazole prophylaxis.
METHODS:
From January 2010 to April 2012, all consecutive patients with newly diagnosed AML were prospectively registered at 33 participating Italian centres. All cases of IFIs occurring within 30 days after the end of the first induction chemotherapy were recorded. The strategy of antifungal treatment (empirical, pre-emptive or targeted) and the drugs used were analysed. ClinicalTrials.gov code: NCT01315925.
RESULTS:
In total, 1192 patients with newly diagnosed AML were enrolled in the study, of whom 510 received posaconazole prophylaxis and were included in the present analysis. Of these patients, 140 (27%) needed systemic antifungal treatment. Among the 127 evaluable cases, an empirical approach was utilized in 102 patients (80%), a pre-emptive approach in 19 patients (15%) and targeted therapy in 6 patients (5%). Only five patients died of IFIs (three in the empirical group and two in the targeted group; 4%). A critical review of IFI diagnoses at 30 days demonstrated that among the patients treated empirically, âŒ30% were not affected by IFIs but rather only by fever of unidentified origin. A comparison between the empirical and the pre-emptive groups showed no significant differences regarding the attributable and overall mortalities.
CONCLUSIONS:
This study confirms that posaconazole prophylaxis reduces the incidence of breakthrough IFIs and does not modify the efficacy of subsequent systemic antifungal treatment, regardless of the approach (empirical or pre-emptive) or the antifungal drug used
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