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β-adrenergic signaling is known to be involved in cancer progression; in particular, beta3-adrenoreceptor (β3-AR) is associated with different tumor conditions. Currently, there are few data concerning β3-AR in myeloid malignancies. Here, we evaluated β3-AR in myeloid leukemia cell lines and the effect of β3-AR antagonist SR59230A. In addition, we investigated the potential role of β3-AR blockade in doxorubicin resistance. Using flow cytometry, we assessed cell death in different in vitro myeloid leukemia cell lines (K562, KCL22, HEL, HL60) treated with SR59230A in hypoxia and normoxia; furthermore, we analyzed β3-AR expression. We used healthy bone marrow cells (BMCs), peripheral blood mononuclear cells (PBMCs) and cord blood as control samples. Finally, we evaluated the effect of SR59230A plus doxorubicin on K562 and K562/DOX cell lines; K562/DOX cells are resistant to doxorubicin and show P-glycoprotein (P-gp) overexpression. We found that SR59230A increased cancer cell lines apoptosis especially in hypoxia, resulting in selective activity for cancer cells; moreover, β3-AR expression was higher in malignancies, particularly under hypoxic condition. Finally, we observed that SR59230A plus doxorubicin increased doxorubicin resistance reversion mainly in hypoxia, probably acting on P-gp. Together, these data point to β3-AR as a new target and β3-AR blockade as a potential approach in myeloid leukemias.

The majority of breast cancers express the estrogen receptor (ER) and are dependent on estrogen for their growth and survival. Endocrine therapy (ET) is the standard of care for these tumors. However, a superior outcome is achieved in a subset of ER positive (ER+)/human epidermal growth factor receptor 2 negative (HER2−) metastatic breast cancer patients when ET is administrated in combination with a cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitor, such as palbociclib. Moreover, CDK4/6 inhibitors are currently being tested in ER+/HER2+ breast cancer and reported encouraging results. Despite the clinical advances of a combinatorial therapy using ET plus CDK4/6 inhibitors, potential limitations (i.e., resistance) could emerge and the metabolic adaptations underlying such resistance warrant further elucidation. Here we investigate the glucose-dependent catabolism in a series of isogenic ER+ breast cancer cell lines sensitive to palbociclib and in their derivatives with acquired resistance to the drug. Importantly, ER+/HER2− and ER+/HER2+ cell lines show a different degree of glucose dependency. While ER+/HER2− breast cancer cells are characterized by enhanced aerobic glycolysis at the time of palbociclib sensitivity, ER+/HER2+ cells enhance their glycolytic catabolism at resistance. This metabolic phenotype was shown to have prognostic value and was targeted with multiple approaches offering a series of potential scenarios that could be of clinical relevance.

Sarcomas are rare and heterogeneous malignant tumors relatively resistant to radio- and chemotherapy. Sarcoma progression is deeply dependent on environmental conditions that sustain both cancer growth and invasive abilities. Sarcoma microenvironment is composed of different stromal cell types and extracellular proteins. In this context, cancer cells may cooperate or compete with stromal cells for metabolic nutrients to sustain their survival and to adapt to environmental changes. The strict interplay between stromal and sarcoma cells deeply affects the extracellular metabolic milieu, thus altering the behavior of both cancer cells and other non-tumor cells, including immune cells. Cancer cells are typically dependent on glucose fermentation for growth and lactate is one of the most heavily increased metabolites in the tumor bulk. Currently, lactate is no longer considered a waste product of the Warburg metabolism, but novel signaling molecules able to regulate the behavior of tumor cells, tumor-stroma interactions and the immune response. In this review, we illustrate the role of lactate in the strong acidity microenvironment of sarcoma. Really, in the biological context of sarcoma, where novel targeted therapies are needed to improve patient outcomes in combination with current therapies or as an alternative treatment, lactate targeting could be a promising approach to future clinical trials.

Endo-, phyto- and synthetic cannabinoids have been proposed as promising anti-cancer agents able to impair cancer cells’ behavior without affecting their non-transformed counterparts. However, cancer outcome depends not only on cancer cells’ activity, but also on the stromal cells, which coevolve with cancer cells to sustain tumor progression. Here, we show for the first time that cannabinoid treatment impairs the activation and the reactivity of cancer-associated fibroblasts (CAFs), the most represented stromal component of prostate tumor microenvironment. Using prostate cancer-derived CAFs, we demonstrated that WIN 55-212.2 mesylate, a synthetic full agonist of cannabinoid receptors (CBs) 1 and 2, downregulates α-smooth muscle actin and matrix metalloprotease-2 expression, and it inhibits CAF migration, essential features to ensure the activated and reactive CAF phenotype. Furthermore, by impairing stromal reactivity, WIN 55-212.2 mesylate also negatively affects CAF-mediated cancer cells’ invasiveness. Using selective antagonists of CBs, we proved that CAFs response to WIN 55-212.2 mesylate is mainly mediated by CB2. Finally, we suggest that endocannabinoids self-sustain both prostate tumor cells migration and CAFs phenotype by an autocrine loop. Overall, our data strongly support the use of cannabinoids as anti-tumor agents in prostate cancer, since they are able to simultaneously strike both cancer and stromal cells.

Few reports have been published on the correlation between plasma concentrations of rivaroxaban and clinical outcome in patients who have experienced venous thromboembolism. This article describes the case of a 44-year-old woman who experienced deep vein thrombosis during anticoagulation therapy with rivaroxaban, with evidence of repeated low plasma levels of the drug. We postulate that the determination of plasma rivaroxaban anti-Xa activity can be useful in the evaluation of anticoagulation therapy in selected cases.

Inflammation has been suggested to play an important role in onset and progression of prostate cancer (PCa). Histological analysis of prostatectomy specimens has revealed focal inflammation in early stage lesions of this malignancy. We addressed the role of inflammatory stimuli in the release of PCa-specific, tumor-derived soluble factors (PCa-TDSFs) already reported to be mediators of PCa morbidity, such as indoleamine 2,3-dioxygenase (IDO) and interleukin (IL)-6. Inflammation-driven production and functions of PCa-TDFSs were tested “in vitro” by stimulating established cell lines (CA-HPV-10 and PC3) with IFN-γ or TNF-α. Expression of genes encoding IDO, IL-6, IFN-γ, TNF-α, and their receptors was investigated in tumor tissues of PCa patients undergoing radical prostatectomy, in comparison with benign prostatic hyperplasia (BPH) specimens. IFN-γ and TNF-α-treatment resulted in the induction of IDO and IL-6 gene expression and release in established cell lines, suggesting that the elicitation of PCa-TDSFs by these cytokines might contribute to progression of cancer into an untreatable phenotype. An analysis based on timing of biochemical recurrence revealed the prognostic value of IDO but not IL-6 gene expression in predicting recurrence-free survival in patients (RFS) with PCa. In addition, a urine-based mRNA biomarker study revealed the diagnostic potential of IDO gene expression in urines of men at risk of PCa development.

ObjectivesThe nuclear protein high mobility group protein box 1 (HMGB1) is a proinflammatory mediator that belongs to the alarmin family of proinflammatory mediators, and it has recently emerged as a key player in different acute and chronic immune disorders. Several lines of evidence demonstrate that HMGB1 is actively released extracellularly from immune cells or passively released from necrotic cells. Because of the ability of HMGB1 to sustain chronic inflammation, we investigated whether the protein is present in nasal fluids of patients with different forms of rhinitis.MethodsHMGB1 levels were evaluated in nasal fluids of healthy subjects or rhinitis patients who were treated or not treated with different treatments.ResultsWe report that the level of HMGB1 was significantly increased in nasal fluids of patients with allergic rhinitis, patients with NARES (nonallergic rhinitis with eosinophiliac syndrome), as well as patients with polyps. We also found that a formulation containing the HMGB1-binding compound glycyrrhizin (GLT) reduced the HMGB1 content in nasal fluids of rhinitis patients to an extent similar to that with nasal budesonide treatment. We also found that among the cultured human leukocyte populations, eosinophils released higher amounts of HMGB1. Based on the ability of HMGB1 to sustain eosinophil survival and the ability of GLT to inactivate HMGB1, we report that GLT selectively killed cultured eosinophils and had no effect on neutrophils, macrophages, and lymphocytes.ConclusionCollectively, these data underscore the role of HMGB1 in rhinitis pathogenesis and the therapeutic potential of GLT formulations in treatment of chronic inflammatory disorders of the nasal mucosa.

The link-calculus has been recently proposed as a process calculus for representing interactions that are open (i.e., that the number of processes may vary), and multiparty (i.e., that may involve more than two processes). Here, we apply the link-calculus for expressing, possibly hierarchical and non dyadic, biological interactions. In particular, we provide a natural encoding of Cardelli's Brane calculus, a compartment-based calculus, introduced to model the behaviour of nested membranes. Notably, the link-calculus is flat, but we can model membranes just as special processes taking part in the biological reaction. Moreover, we give evidence that the link-calculus allows one to directly model biological phenomena at the more appropriate level of abstraction.

The struggle to find novel efficacious pharmacological approaches for cancer treatment has ledto the identification of several kinases involved in neoplastic genesis and cell development. [...]

Incidence distribution of cutaneous melanoma depends on phenotypic characteristics of population and geographic location. In Italy, in the period 1999-2003 Friuli Venezia Giulia (FVG) region had the second highest incidence rates for males and the third for females. We analysed melanoma and lip cancer incidence data of the FVG cancer registry for the period 1995-2005. We used Bayesian hierarchical spatial models to describe the spatial pattern by gender. We decomposed the geographical distribution of the risk in two parts: a component linked to chronic exposure and a component related to intermittent exposure. In order to model the chronic component we considered the geographical distribution of incidence cases of lip cancer, for which chronic occupational solar radiation exposure is a documented risk factor. We also analysed the distribution by site and we calculated standardised rates for body surface area. This study documents a significant gradient in the incidence of cutaneous melanoma in FVG. Highstandardisedincidence rates are present in the area of Trieste and in the coastal area. The descriptive analysis by age group and by site, showed risks associated with intermittent exposures in both genders. For the coastal area the risk is especially high for sites traditionally linked to high cumulative exposures (face and neck), especially among men. The results suggest diagnostic preventive interventions in the populations living in the area of Trieste, given the high rates observed in the young age groups.

Pulse-chase experiments are often used to study the degradation of macromolecules such as proteins or mRNA. Considerations for the choice of pulse length include the toxicity of the pulse to the cell and maximization of labeling. In the general case of non-exponential decay, varying the length of the pulse results in decay patterns that look different. Analysis of these patterns without consideration to pulse length would yield incorrect degradation parameters. Here we propose a method that constructively includes pulse length in the analysis of decay patterns and extracts the parameters of the underlying degradation process. We also show how to extract decay parameters reliably from measurements taken during the pulse phase.

Trace gas concentration measurements in the stratosphere and troposphere are critically required as inputs to constrain climate models. For this purpose, measurement campaigns on stratospheric aircraft and balloons are being carried out all over the world, each one involving sensors which are tailored for the specific gas and environmental conditions. This paper describes an automated, portable, mid-infrared quantum cascade laser spectrometer, for in situ carbon monoxide mixing ratio measurements in the stratosphere and troposphere. The instrument was designed to be versatile, suitable for easy installation on different platforms and capable of operating completely unattended, without the presence of an operator, not only during one flight but for the whole period of a campaign. The spectrometer features a small size (80 × 25 × 41 cm3), light weight (23 kg) and low power consumption (85 W typical), without being pressurized and without the need of calibration on the ground or during in-flight operation. The device was tested in the laboratory and in-field during a research campaign carried out in Nepal in summer 2017, onboard the stratospheric aircraft M55 Geophysica. The instrument worked extremely well, without external maintenance during all flights, proving an in-flight sensitivity of 1–2 ppbV with a time resolution of 1 s.

We formally characterize a set of causality-based properties of metabolic networks. This set of properties aims at making precise several notions on the production of metabolites, which are familiar in the biologists' terminology. From a theoretical point of view, biochemical reactions are abstractly represented as causal implications and the produced metabolites as causal consequences of the implication representing the corresponding reaction. The fact that a reactant is produced is represented by means of the chain of reactions that have made it exist. Such representation abstracts away from quantities, stoichiometric and thermodynamic parameters and constitutes the basis for the characterization of our properties. Moreover, we propose an effective method for verifying our properties based on an abstract model of system dynamics. This consists of a new abstract semantics for the system seen as a concurrent network and expressed using the Chemical Ground Form calculus. We illustrate an application of this framework to a portion of a real metabolic pathway.

Histone deacetylase inhibitors (HDACi) are emerging tools for epigenetic modulation of gene expression and suppress the inflammatory response in models of systemic immune activation. Yet, their effects within the brain are still controversial. Also, whether HDACs are expressed in astrocytes or microglia is unclear. Here, we report the identification of transcripts for HDAC 1–11 in cultured mouse glial cells. Two HDACi such as SAHA and ITF2357 induce dramatic increase of histone acetylation without causing cytotoxicity of cultured cells. Of note, the two compounds inhibit expression of pro-inflammatory mediators by LPS-challenged glial cultures, and potentiate immunosuppression triggered by dexamethasone in vitro. The anti-inflammatory effect is not due to HDACi-induced transcription of immunosuppressant proteins, (including SOCS-1/3) or microRNA-146. Rather, it is accompanied by direct alteration of transcription factor DNA binding and ensuing transcriptional activation. Indeed, both HDACi impair NFκB-dependent IκBα resynthesis in glial cells exposed to LPS, and, among various AP1 subunits and NFκB p65, affect the DNA binding activity of c-FOS, c-JUN and FRA2. Importantly, ITF2357 reduces the expression of pro-inflammatory mediators in the striatum of mice iontophoretically injected with LPS. Data demonstrate that mouse glial cells have ongoing HDAC activity, and its inhibition suppresses the neuroinflammatory response because of a direct impairment of the transcriptional machinery.

Comparative genomics usually involves managing the functional aspects of genomes, by simply comparing gene-by-gene functions. Following this approach, Mushegian and Koonin proposed a hypothetical minimal genome, Minimal Gene Set (MGS), aiming for a possible oldest ancestor genome. They obtained MGS by comparing the genomes of two simple bacteria and eliminating duplicated or functionally identical genes. The authors raised the fundamental question of whether a hypothetical organism possessing MGS is able to live or not. We attacked this viability problem specifying in silico the metabolic pathways of the MGS-based prokaryote. We then performed a dynamic simulation of cellular metabolic activities in order to check whether the MGS-prokaryote reaches some equilibrium state and produces the necessary biomass. We assumed these two conditions to be necessary for a living organism. Our simulations clearly show that the MGS does not express an organism that is able to live. We then iteratively proceeded with functional replacements in order to obtain a genome composition that gives rise to equilibrium. We ruled out 76 of the original 254 genes in the MGS, because they resulted in duplication from a functional point of view. We also added seven genes not present in the MGS. These genes encode for enzymes involved in critical nodes of the metabolic network. These modifications led to a genome composed of 187 elements expressing a virtually living organism, Virtual Cell (ViCe), that exhibits homeostatic capabilities and produces biomass. Moreover, the steady-state distribution of the concentrations of virtual metabolites that resulted was similar to that experimentally measured in bacteria. We conclude then that ViCe is able to "live in silico."

We evaluated the role of COX-2 pathway in 35 head and neck cancers (HNCs) by analyzing COX-2 expression and prostaglandin E2 (PGE2) production in relation to tumor angiogenesis and lymph node metastasis. COX-2 activity was also correlated to vascular endothelial growth factor (VEGF) mRNA and protein expression. COX-2 mRNA and protein expression was higher in tumor samples than in normal mucosa. PGE2 levels were higher in the tumor front zone in comparison with tumor core and normal mucosa (P