) is a heterodimeric protein, first recovered from EBV-transformed B cell lines.It is a multifunctional cytokine, the properties of which bridge innate and adaptive immunity, acting as a key regulator of cell-mediated immune responses through the induction of T helper 1 differentiation. By promoting IFN-g production, proliferation, and cytolytic activity of natural killer and T cells, IL-12 induces cellular immunity. In addition, IL-12 induces an antiangiogenic program mediated by IFN-g^inducible genes and by lymphocyte-endothelial cell cross-talk. The immunomodulating and antiangiogenic functions of IL-12 have provided the rationale for exploiting this cytokine as an anticancer agent. In contrast with the significant antitumor and antimetastatic activity of IL-12, documented in several preclinical studies, clinical trials with IL-12, used as a single agent, or as a vaccine adjuvant, have shown limited efficacy in most instances. More effective application of this cytokine, and of newly identified IL-12 family members (IL-23 and IL-27), should be evaluated as therapeutic agents with considerable potential in cancer patients.Interleukin-12 (IL-12) is recognized as a master regulator of adaptive type 1, cell-mediated immunity, the critical pathway involved in protection against neoplasia and many viruses. This is supported by the analysis of numerous animal (1, 2) and human clinical studies that attribute improved clinical outcome (3) and mechanisms of IL-12 -based therapy (4) to strong type 1 responses in situ. Since the initial preclinical and clinical studies of IL-12, done over a decade ago, basic and translational science studies have contributed to the greater understanding of IL-12 immunobiology. In addition to its noted effects in the priming of T helper 1 (TH1) cell responses and IFN-g production by T and natural killer (NK) cells, more recent studies support its critical role as a third signal for CD8 + T cell differentiation (5, 6), and its ability to serve as an important factor in the reactivation and survival of memory CD4 + T cells (7). This is particularly relevant in the repolarization of CD4 + T cells from dysfunctional antitumor TH2 into TH1 cells in the cancer setting (8). Here, we review the immunomodulatory and antiangiogenic functions of IL-12, as well as the results of preclinical and clinical studies in which IL-12 was used as an anticancer agent.

No abstract

Lung cancer is the most common malignancy worldwide. Despite significant advances in diagnosis and treatment, mortality rates remain extremely high, close to incidence rates. Several targeted therapies have been recently introduced for the treatment of non-small cell lung cancer (NSCLC), the most common type of lung cancer. Nivolumab, a monoclonal antibody that targets programmed death-1 (PD-1), was the first immune checkpoint inhibitor approved for the treatment of patients with advanced/metastatic NSCLC not responding to platinum-based chemotherapy. Biomarkers predicting response to these therapies would allow early identification of non-responders and timely implementation of appropriate combination strategies, avoiding inadequate and expensive therapies. The role of the neutrophil to lymphocyte ratio and other blood cell count indexes as possible biomarkers of response has been recently investigated. We discuss the encouraging results reported on the topic, provide new data from our personal experience, and discuss opportunities for further research.

We herein report an uncommon association of intimately admixed atypical carcinoid (AC) and large cell neuroendocrine (NE) carcinoma (LCNEC) of the thymus, occurring in two 20- and 39-year-old Caucasian males. Both tumors were treated by maximal thymectomy. The younger patient presented with a synchronous lesion and died of disease after 9 months, while the other patient was associated with a recurrent ectopic adrenocorticotropic hormone Cushing's syndrome and is alive with disease at the 2-year follow-up. MEN1 syndrome was excluded in either case. Immunohistochemically, disarrayed cytoplasmic and nuclear ß-catenin expression was seen alongside an intra-tumor Ki-67 antigen labeling index (LI) ranging from 2 to 80% in the younger patient's tumor and from 3 to 45% in the other. Both exhibited upregulated cyclin D1 and retinoblastoma, while vimentin was overexpressed in the recurrent LCNEC only. Next-generation sequencing revealed CTNNB1, TP53, and JAK3 mutations in the synchronous tumor and CTNNB1 mutation alone in the metachronous tumor (the latter with the same mutation as the first tumor of 17 years prior). None of the 23 T-NET controls exhibited this hallmarking triple alteration (p = 0.003). These findings suggested that LCNEC components developed from pre-existing CTNNB1-mutated AC upon loss-of-function TP53 and gain-of-function JAK3 mutations in one case and an epithelial-mesenchymal transition upon vimentin overexpression in the other case. Both tumors maintained intact cyclin D1-retinoblastoma machinery. Our report challenges the concept of secondary LCNEC as an entity that develops from pre-existing AC as a result of tumor progression, suggesting a paradigm shift to the current pathogenesis of NET.

We report on experiences at the Software Sustainability Institute (SSI) in customizing and using the Trac system to provide a single platform for recording, managing and tracking a wide range of community interactions. We note the essential requirement of a lightweight, easy-to-use system for recording 'community metadata' and discuss the pros and cons of using Trac in this way for day-to-day operations within SSI, and more generally as a means to record and track interactions with a wide and potentially very large community.

No abstract

Non-small-cell lung cancer is still considered a difficult disease to manage because of its aggressiveness and resistance to common therapies. Chemotherapy remains the gold standard in nearly 80% of lung cancers, but clinical outcomes are discouraging, and the impact on median overall survival (OS) barely reaches 12 months.At the end of the last century, the discovery of oncogene-driven tumours completely changed the therapeutic landscape in lung cancers, harbouring specific gene mutations/translocations. Epidermal growth factors receptor (EGFR) common mutations first and anaplastic lymphoma kinase (ALK) translocations later led new insights in lung cancer biology knowledge. The use of specific tyrosine kinases inhibitors overturned the biological behaviour of EGFR mutation positive tumours and became a preclinical model to understand the heterogeneity of lung cancers and the mechanisms of drug resistance. In this review, we summarise the employment of targeted agents against the most representative biomolecular alterations and provide some criticisms of the therapeutic strategies.

Obstructive Sleep Apnea Syndrome (OSAS) is a recognized risk factor for cardiovascular disorders and in some cases is complicated with Pulmonary Arterial Hypertension (PAH), as the endothelium is affected. Recent studies provide strong evidence for endothelial dysfunction in obstructive sleep apnea. The resultant vasoconstriction, abnormal cell proliferation and hyper-coagulability may lead to the initiation or progression of atherosclerotic cardiovascular and cerebrovascular disorders, which are frequently encountered in OSA patients. While the currently available therapies for OSAS, such as Continuous Positive Airway Pressure therapy (CPAP therapy), improve endothelial dysfunction, they are not well-tolerated by patients. CPAP therapy can reduce nocturnal hypoxemias and decrease noradrenaline circulating levels, but does not affect ET-1 plasma levels. Potent and selective Endothelin-1 receptor antagonists have been developed and have shown promising results in the treatment of cardiovascular diseases such as pulmonary arterial hypertension, acute and chronic heart failure, hypertension, renal failure, and atherosclerosis. However, results are often contrasting and complicated because of the tissue-specific vasoconstrictor actions of Endothelin-B receptors and the fact that endothelin is an autocrine and paracrine factor whose activity is difficult to measure in vivo.