1,721,092 research outputs found
TRANSCRIPTIONAL LANDSCAPE OF NEURONAL and CANCER STEM CELLS
Get PDFTumor mass is composed by heterogeneous cell population including a subset of “cancer stem cells” (CSC).
Oncogenic signals foster CSC by transforming tissue stem cells or by reprogramming progenitor/differentiated
cells towards stemness. Thus, CSC share features with cancer and stem cells (e.g. self-renewal, hierarchical
developmental program leading to differentiated cells, epithelial/mesenchimal transition) and these latter are
maintained by the constitutive activation of stemness-promoting signals. CSC could trigger tumor formation,
drive to resistance to conventional therapeutics and underlie patients’ relapse. Indeed, stem cell signatures
have been associated with poor prognosis in various.
This background makes the identification of CSC molecular features mandatory to highlight the survival inner
working and to design novel CSC specific therapeutic strategies.
Medulloblastoma (MB) is the most common childhood malignant brain tumor and a leading cause of cancerrelated
morbidity and mortality. Current multimodal therapies are effective in about 50% of patients but often
cause long-term side effects, i.e. developmental, neurological, neuroendocrine and psychosocial deficits
(Northcott PA Nature Rev cancer 2012). For many years, MB treated as a single tumor entity despite the
divergent tumor histology, patients’ outcome and drug sensitivity, and also by the diversity of the stem cell of
origin. Very recently the scenario of human MB has dramatically changed since its heterogeneous biology has
been addressed by high-throughput gene expression analysis (oligonucleotide microarrays) or by the powerful
genomic next-generation sequencing. These led to the identification of four tumor subgroups (WNT, SHH,
Group 3 and Group 4) uncovering the existence of a highly diverse mutational spectra and gene expression.
However a quantitative approach has not yet been applied to the transcriptional landscape of Medulloblastoma
stem cells (MbSC) through RNA Next Generation Sequencing (RNA-Seq) technology. This is a relevant issue,
since RNA-Seq is able to interrogate the genome wide global transcriptome including new transcripts,
alternative spliced isoforms and non-coding RNAs.
Lower rhombic lip progenitors of the dorsal brainstem are considered the trigger cells in WNT tumors; in SHH
subgroup initiation cells are Prominin1+ CD15+ stem cells from the subventricular zone requiring the
commitment to Math1+ granule cell progenitors [GCP] of the external granule cell layer [EGL]; while Math1+ or
Math1- EGL-GCP or Prominin1+/lineage-negative stem cells sustain the MYC driven Group 3.
MbSC derived from SHH tumors and postnatal normal cerebellar stem cells (NcSC) have been reported to
share several features. A key signal for both of them is Hedgehog. Furthermore, both NcSC and MbSC display
up-regulation of stemness genes (e.g Sox2, Nestin, Nanog, Prom1). Finally, constitutive activation of the Shh
pathway by conditional deletion of Ptch1 inhibitory receptor in NcSC, promote medulloblastoma in vivo,
producing a mouse model of the human SHH tumor. Acquisition of stemness features may therefore represent
the first step of oncogenic conversion. Cooperation with additional oncogenic signals is however needed to
enhance MbSC tumorigenicity.
In order to understand the MbSCs transcriptional programs, we analyze by RNA-Seq, MbSC derived from
Ptch1+/- tumors (Ptch1+/- MbSC). This choice, of a genetically determined model of MB, has allowed us to
work with Ptch1+/- MbSC together with appropriate NcSC counterpart, and to analyze biological replicates
doing statistical analysis.
We identify a number of transcripts, annotated ones, novel isoforms, and long non-coding RNAs,
characterizing MbSC and/or NcSC. Some of these genes control stemness or are cancer related and
conserved in human medulloblastomas. Interestingly a subset of them, belonging to cell stress response, are
of prognostic relevance being significantly related to clinical outcome. Correlation of genes expression
characterizing MbSC with survival information from our human medulloblastomas database further
demonstrates the significance of these findings. Our data suggest that the modulation of normal and cancer
stem cell functions observed in vitro is effective in dissecting the transcriptional programs underlying the in
vivo behavior of human medulloblastomas
Solitary subependymal giant cell astrocytoma lacking TSC1/2 mutations and TTF-1 expression: A potential diagnostic pitfall
No full text: Subependymal giant cell astrocytoma (SEGA) is a rare, low-grade glioma typically associated with tuberous sclerosis (TS) and mutations in the TSC1 or TSC2 genes. It is characterized by an intraventricular location, an expansive growth pattern, and the expression of glial and neural markers. TTF-1 expression is considered a sensitive marker of SEGA, likely reflecting its origin from progenitor cells in the caudothalamic groove. We report a case of SEGA with unusual immunohistochemical and molecular features in a 20-year-old man with no signs or family history of TS. The tumor was located in the anterior horn of the right ventricle and obstructed the foramen of Monro. Histologically, it exhibited an expansive growth pattern and was composed of cells with ovoid nuclei and abundant eosinophilic cytoplasm. Immunohistochemically, the tumor cells were positive for GFAP and S-100 protein, weakly positive for SOX2, focally positive for synaptophysin, and negative for TTF-1, neurofilament protein, NeuN, EMA, chromogranin, and BCOR. Scattered OLIG2-positive neoplastic cells were also observed. Molecular analysis revealed no pathogenic mutations or copy number variations in the analyzed 174 genes, including TSC1/2, except for a variant of unknown significance in BAP1. The histopathological features and immunohistochemical profile suggested SEGA, despite the absence of TTF-1 expression and TSC1/2 mutations. The diagnosis was confirmed by DNA methylation profiling, which assigned the tumor to the methylation class "subependymal giant cell astrocytoma with TSC1/TSC2 alterations" with a calibrated score of 0.95. This case highlights the potential diagnostic pitfall of SEGA lacking TTF-1 expression and emphasizes the importance of considering this entity in the differential diagnosis of intraventricular tumors, even in the absence of TS and characteristic molecular alterations. The existence of TTF-1 negative SEGAs reveals that these tumors might also derive from TTF-1 negative cells in the subpendymal region
Cardiotossicità dei farmaci chemioterapici nella paziente anziana
No full textAn adverse reaction is defined such as treatment response which
caused toxic effects with a normal dose. The most important pharmaceutic agents with cardiotoxic effects are: anthracycline,
ciclophosphamide, Fluorouracil and many others.C a r d i o - t o x i c i t y , associated to chemotherapy with this agents can be divided in acute one and cronic one. Moreover there are very
important risk factors, such as cumulative dose, pre-existent cardiac diseases, age of patients and the eventual use of cardio-pro tective agents
[Aromatase inhibitors in advanced breast cancer].
No full textBenefits from hormonal therapy in patients with hormon-sensitive breast cancers are widely and well known. A great challenge for clinicians is represented by the possibility to use citoreductive primary hormonal therapy in patients with locally advanced breast carcinoma. Five-year treatment with tamoxifen has been for long time the gold standard in adjuvant settings. In post-menopausal women affected by breast cancer larger than 3 cm and expressing estrogen receptors (ER+), clinical trials have shown that few months treatment with aromatase inhibitors can downsizing tumors. This citoreduction is greater than the one obtained with tamoxifen and it makes conservative surgery possible in most part of cases
Nanoparticle-based delivery of small interfering RNA: challenges for cancer therapy
No full textDuring recent decades there have been remarkable advances and profound changes in cancer therapy. Many therapeutic strategies learned at the bench, including monoclonal antibodies and small molecule inhibitors, have been used at the bedside, leading to important successes. One of the most important advances in biology has been the discovery that small interfering RNA (siRNA) is able to regulate the expression of genes, by a phenomenon known as RNA interference (RNAi). RNAi is one of the most rapidly growing fields of research in biology and therapeutics. Much research effort has gone into the application of this new discovery in the treatment of various diseases, including cancer. However, even though these molecules may have potential and strong utility, some limitations make their clinical application difficult, including delivery problems, side effects due to off-target actions, disturbance of physiological functions of the cellular machinery involved in gene silencing, and induction of the innate immune response. Many researchers have attempted to overcome these limitations and to improve the safety of potential RNAi-based therapeutics. Nanoparticles, which are nanostructured entities with tunable size, shape, and surface, as well as biological behavior, provide an ideal opportunity to modify current treatment regimens in a substantial way. These nanoparticles could be designed to surmount one or more of the barriers encountered by siRNA. Nanoparticle drug formulations afford the chance to improve drug bioavailability, exploiting superior tissue permeability, payload protection, and the "stealth" features of these entities. The main aims of this review are: to explain the siRNA mechanism with regard to potential applications in siRNA-based cancer therapy; to discuss the possible usefulness of nanoparticle-based delivery of certain molecules for overcoming present therapeutic limitations; to review the ongoing relevant clinical research with its pitfalls and promises; and to evaluate critically future perspectives and challenges in siRNA-based cancer therapy
Trastuzumab in metastatic breast cancer
No full textMetastatic breast cancer is an incurable disease in a very high percentage of patients. Despite new progress in endocrine and other systemic therapies, this evidence remains challenging for patients and clinicians. HER2 protein is a member of the epidermal growth factor family of transmembrane receptors. HER2 is overexpressed in approximately 20% to 30% of breast cancers. Overexpression of HER2 has been shown to be associated with increased tumor proliferation and relative resistance to some types of chemotherapy and hormonal therapies. Trastuzumab, a humanized monoclonal antibody directed against HER2 protein, has been shown to be an efficacious and well tolerated treatment for HER2-overexpressing metastatic breast cancer, both as a single agent and when it is used in combination with chemotherapy
CNS tumor with CREBBP::BCORL1 Fusion and pathogenic mutations in BCOR and CREBBP: expanding the spectrum of BCOR-altered tumors
No full text: The fifth edition of the World Health Organization (WHO) classification of central nervous system (CNS) tumors introduced the new tumor type CNS tumor with BCOR internal tandem duplication (ITD), characterized by a distinct DNA methylation profile and peculiar histopathological features, including a circumscribed growth pattern, ependymoma-like perivascular pseudorosettes, microcystic pattern, absent or focal GFAP immunostaining, OLIG2 positivity, and BCOR immunoreactivity. We describe a rare case of a CNS tumor in a 45-year-old man with histopathological and immunohistochemical features overlapping the CNS tumor with BCOR internal tandem duplication (ITD) but lacking BCOR immunostaining and BCOR ITD. Instead, the tumor showed CREBBP::BCORL1 fusion and pathogenic mutations in BCOR and CREBBP, along with a DNA methylation profile matching the "CNS tumor with EP300:BCOR(L1) fusion" methylation class. Two CNS tumors with fusions between CREBBP, or its paralog EP300, and BCORL1, and approximately twenty CNS tumors with CREBBP/EP300::BCOR fusions have been reported to date. They exhibited similar ependymoma-like features or a microcystic pattern, along with focal or absent GFAP immunostaining, and shared the same DNA methylation profile. Given their morphological and epigenetic similarities, circumscribed CNS tumors with EP300/CREBBP::BCOR(L1) fusions and CNS tumors with BCOR ITD may represent variants of the same tumor type. The ependymoma-like aspect coupled with the lack of diffuse GFAP immunostaining and the presence of OLIG2 positivity are useful clues for recognizing these tumors in histopathological practice. The diagnosis should be confirmed after testing for BCOR(L1) gene fusions and BCOR ITD
Albumin bound formulation of Paclitaxel (Abraxane ABI-007) in the treatment of breast cancer
No full textBreast cancer is the most common type of malignancy diagnosed in women. In the metastatic setting this disease is still uncurable. Taxanes represent an important class of antitumor agents which have proven to be fundamental in the treatment of advanced and early-stage breast cancer, but the clinical advances of taxanes have been limited by their highly hydrophobic molecular status. To overcome this poor water solubility, lipid-based solvents have been used as a vehicle, and new systemic formulations have been developed, mostly for paclitaxel, which are Cremophor-free and increase the circulation time of the drug. ABI-007 is a novel, albumin-bound, 130-nm particle formulation of paclitaxel, free from any kind of solvent. It has been demonstrated to be superior to an equitoxic dose of standard paclitaxel with a significantly lower incidence of toxicities in a large, international, randomized phase III trial. The availability of new drugs, such as Abraxane, in association with other traditional and non-traditional drugs (new antineoplastic agents and targeted molecules), will give the oncologist many different effective treatment options for patients in this setting
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