Enzymatic Inactivation of Oxysterols in Breast Tumor Cells Constraints Metastasis Formation by Reprogramming the Metastatic Lung Microenvironment

Recent evidence indicates that immune cells contribute to the formation of tumor metastases by regulating the pre-metastatic niche. Whether tumor-derived factors involved in primary tumor formation play a role in metastasis formation is poorly characterized. Oxysterols act as endogenous regulators of lipid metabolism through the interaction with the nuclear Liver X Receptors-(LXR)alpha and LXR beta. In the context of tumor development, they establish a pro-tumor environment by dampening antitumor immune responses, and by recruiting pro-angiogenic and immunosuppressive neutrophils. However, the ability of LXR/oxysterol axis to promote tumor invasion and metastasis by exploiting immune cells, is still up to debate. In this study we provide evidence that oxysterols participate in the primary growth of orthotopically implanted 4T1 breast tumors by establishing a tumor-promoting microenvironment. Furthermore, we show that oxysterols are involved in the metastatic spread of 4T1 breast tumors, since their enzymatic inactivation mediated by the sulfotransferase 2B1b, reduces the number of metastatic cells in the lungs of tumor-bearing mice. Finally, we provide evidence that oxysterols support the metastatic cascade by modifying the lung metastatic niche, particularly allowing the recruitment of tumor-promoting neutrophils. These results identify a possible new metastatic pathway to target in order to prevent metastasis formation in breast cancer patients

Penile metastasis from primary cholangiocarcinoma: the first case report

BACKGROUND: Metastatic penile carcinoma derived from cholangiocarcinoma (CCA) has not been previously reported in the literature. Common metastatic sites for CCA include the regional lymph nodes and adjacent organs. CCAs are not highly vascularised tumours, making hematogenous metastases uncommon. Hematogenous CCA metastases commonly occur at distant organs such as the lungs, adrenal glands, and bones. Median survival for patients with metastatic disease is generally less than 1 year. CASE PRESENTATION: A 74-year-old Caucasian man consulted us after having undergone penile ultrasonography for pain and increased thickness at the base of the penis after self-examination. The patient presented with a history of hepatitis C-related cirrhosis and intrahepatic CCA, diagnosed 3 years previously. A biopsy of the corpora cavernosa on both sides revealed a carcinoma harbouring the same histological and immunophenotypical features as the primary hepatic lesion. CONCLUSIONS: To date, there is no case of penile or urogenital system metastasis from CCA described in the literature. Therefore, this article represents the first case report of penile metastasis from CCA

Harnessing the reverse cholesterol transport pathway to favor differentiation of monocyte-derived APCs and antitumor responses

Lipid and cholesterol metabolism play a crucial role in tumor cell behavior and in shaping the tumor microenvironment. In particular, enzymatic and non-enzymatic cholesterol metabolism, and derived metabolites control dendritic cell (DC) functions, ultimately impacting tumor antigen presentation within and outside the tumor mass, dampening tumor immunity and immunotherapeutic attempts. The mechanisms accounting for such events remain largely to be defined. Here we perturbed (oxy)sterol metabolism genetically and pharmacologically and analyzed the tumor lipidome landscape in relation to the tumor-infiltrating immune cells. We report that perturbing the lipidome of tumor microenvironment by the expression of sulfotransferase 2B1b crucial in cholesterol and oxysterol sulfate synthesis, favored intratumoral representation of monocyte-derived antigen-presenting cells, including monocyte-DCs. We also found that treating mice with a newly developed antagonist of the oxysterol receptors Liver X Receptors (LXRs), promoted intratumoral monocyte-DC differentiation, delayed tumor growth and synergized with anti-PD-1 immunotherapy and adoptive T cell therapy. Of note, looking at LXR/cholesterol gene signature in melanoma patients treated with anti-PD-1-based immunotherapy predicted diverse clinical outcomes. Indeed, patients whose tumors were poorly infiltrated by monocytes/macrophages expressing LXR target genes showed improved survival over the course of therapy. Thus, our data support a role for (oxy)sterol metabolism in shaping monocyte-to-DC differentiation, and in tumor antigen presentation critical for responsiveness to immunotherapy. The identification of a new LXR antagonist opens new treatment avenues for cancer patients

Epithelial ovarian cancer relapsing as isolated lymph node disease: natural history and clinical outcome

<p>Abstract</p> <p>Background</p> <p>Several evidences suggested that ovarian cancer (OC) patients showing isolated lymph node recurrence (ILNR) have an indolent evolution. The aim of the study was to retrospectively review ILNR observed in our Institution over the past 11 years in order to investigate: the pattern of disease progression after the first diagnosis of ILNR, and their clinical outcome.</p> <p>Methods</p> <p>Between September 1995 and September 2006, 523 epithelial OC were diagnosed in our centers, and 301 of these relapsed. Cases with a diagnosis of ILNR, and at least 12 months of follow up after the diagnosis of ILNR were included. Post-relapse survival (PRS) was recorded from the date of the diagnosis of ILNR to the date of death or date last seen. Survival probabilities were estimated according to the method of Kaplan and Meier and compared by the log rank test. Cox's regression model with stepwise variable selection was used to analyse the role of clinico-pathological parameters as prognostic factors for PRS.</p> <p>Results</p> <p>Thirty-two cases were identified as ILNR (10.6% of the recurrences, and 6.1% of the OC population). Most of the patients continued to exhibit the same pattern of progression during follow up, with 75% of the patients free from peritoneal disease after 2 years from the diagnosis of ILNR. Median Post-Relapse Survival (PRS) was 37 months, and median Overall Survival (OS) was 109 months, with all patients surviving more than 2 years after the initial diagnosis. In multivariate analysis only Platinum-Free Interval (PFI) retained a prognostic role for PRS (p value = 0.033).</p> <p>Conclusion</p> <p>ILNR represents a less aggressive pattern of OC relapse which keeps progressing in the lymph nodes in a relatively high percentage of cases. On the other hand, the occurrence of peritoneal spreading after ILNR is associated with a rapidly fatal outcome.</p

Migralepsy, hemicrania epileptica, post-ictal headache and “ictal epileptic headache”: a proposal for terminology and classification revision

Despite the fact that migraine and epilepsy are among the commoner brain diseases and that comorbidity of these conditions is well known, only few reports of migralepsy and hemicrania epileptica (HE) have been published according to the current ICHD-II criteria. Particularly, ICHD-II describes “migraine-triggered seizure” (i.e., migralepsy) among complications of migraine at “1.5.5” (as a rare event in which a seizure happens during migrainous aura), while hemicrania epileptica (coded at “7.6.1”) and post-ictal headache (coded at “7.6.2”) are described among headaches attributed to epileptic seizure. However, to date neither the International Headache Society nor the International League against Epilepsy mention that headache/migraine may be the sole ictal epileptic manifestation. Based on the current knowledge, migralepsy is highly unlikely to exist as such. We, therefore, propose to delete this term until clear evidence its existence is provided. Moreover, we herein propose a revision of terminology and classification criteria to properly represent the migraine/headache relationships. We suggest the term “ictal epileptic headache” in cases in which headache/migraine is the sole ictal epileptic manifestation

Evidence of Distinct Tumour-Propagating Cell Populations with Different Properties in Primary Human Hepatocellular Carcinoma

Increasing evidence that a number of malignancies are characterised by tumour cell heterogeneity has recently been published, but there is still a lack of data concerning liver cancers. The aim of this study was to investigate and characterise tumour-propagating cell (TPC) compartments within human hepatocellular carcinoma (HCC).After long-term culture, we identified three morphologically different tumour cell populations in a single HCC specimen, and extensively characterised them by means of flow cytometry, fluorescence microscopy, karyotyping and microarray analyses, single cell cloning, and xenotransplantation in NOD/SCID/IL2Rγ/⁻ mice.The primary cell populations (hcc-1, -2 and -3) and two clones generated by means of limiting dilutions from hcc-1 (clone-1/7 and -1/8) differently expressed a number of tumour-associated stem cell markers, including EpCAM, CD49f, CD44, CD133, CD56, Thy-1, ALDH and CK19, and also showed different doubling times, drug resistance and tumorigenic potential. Moreover, we found that ALDH expression, in combination with CD44 or Thy-1 negativity or CD56 positivity identified subpopulations with a higher clonogenic potential within hcc-1, hcc-2 and hcc-3 primary cell populations, respectively. Karyotyping revealed the clonal evolution of the cell populations and clones within the primary tumour. Importantly, the primary tumour cell population with the greatest tumorigenic potential and drug resistance showed more chromosomal alterations than the others and contained clones with epithelial and mesenchymal features.Individual HCCs can harbor different self-renewing tumorigenic cell types expressing a variety of morphological and phenotypical markers, karyotypic evolution and different gene expression profiles. This suggests that the models of hepatic carcinogenesis should take into account TPC heterogeneity due to intratumour clonal evolution

Ricreare Napoli: dalla crisi attuale allo sviluppo metropolitano

Il saggio analizza i fattori che rendono il territorio napoletano meno competitivo rispetto ad altre aree omogenee anche estere, evidenziando le criticità strutturali e congiunturali che influenzano le ridotte capacità economiche attuali. Le prospettive future vengono lette alla luce del ruolo che alcuni importanti asset strategici - quali, in primo luogo, la ricerca, il turismo e la logistica - potranno svolgere e degli ostacoli che occorrerà superare per ridare al territorio capacità attrattiva e competitiva

Ambiente - Azienda e strumenti finanziari di sostegno

L'impresa e l'ambiente fanno parte di un sistema integrato; un esempio evidente è costituito dal settore della produzione e trattamento dei rifiuti, in cui, accanto alle imprese, operano importanti stakeholders, quali i soggetti pubblici e le associazioni ambientalistiche. Rilevanti appaiono anche le dimensioni del mercato e le risorse finanziarie che, soprattutto da fonte pubblica, vengono destinate al settore