ATP-binding cassette transporters in progression and clinical outcome of pancreatic cancer: What is the way forward?

© The Author(s) 2018. Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive diseases and is characterized by high chemoresistance, leading to the lack of effective therapeutic approaches and grim prognosis. Despite increasing understanding of the mechanisms of chemoresistance in cancer and the role of ATPbinding cassette (ABC) transporters in this resistance, the therapeutic potential of their pharmacological inhibition has not been successfully exploited yet. In spite of the discovery of potent pharmacological modulators of ABC transporters, the results obtained in clinical trials have been so far disappointing, with high toxicity levels impairing their successful administration to the patients. Critically, although ABC transporters have been mostly studied for their involvement in development of multidrug resistance (MDR), in recent years the contribution of ABC transporters to cancer initiation and progression has emerged as an important area of research, the understanding of which could significantly influence the development of more specific and efficient therapies. In this review, we explore the role of ABC transporters in the development and progression of malignancies, with focus on PDAC. Their established involvement in development of MDR will be also presented. Moreover, an emerging role for ABC transporters as prognostic tools for patients' survival will be discussed, demonstrating the therapeutic potential of ABC transporters in cancer therapy

Emerging role of the KRAS-PDK1 axis in pancreatic cancer

Pancreatic cancer is a highly aggressive tumour that is very resistant to treatments and it is rarely diagnosed early because of absence of specific symptoms. Therefore, the prognosis for this disease is very poor and it has the grim supremacy in terms of unfavourable survival rates. There have been great advances in survival rates for many types of cancers over the past few decades but hardly any change for pancreatic cancer. Mutations of the Ras oncogene are the most frequent oncogenic alterations in human cancers. The frequency of KRAS mutations in pancreatic cancer is around 90%. Given the well-established role of KRAS in cancer it is not surprising that it is one of the most attractive targets for cancer therapy. Nevertheless, during the last thirty years all attempts to target directly KRAS protein have failed. Therefore, it is crucial to identify downstream KRAS effectors in order to develop specific drugs able to counteract activation of this pathway. Among the different signalling pathways activated by oncogenic KRAS, the phosphoinositide 3-Kinase (PI3K) pathway is emerging as one of the most critical KRAS effector. In turn, PI3K activates several parallel pathways making the identification of the precise effectors activated by KRAS/PI3K more difficult. Recent data identify 3-phosphoinositide-dependent protein kinase 1 as a key tumour-initiating event downstream KRAS interaction with PI3K in pancreatic cancer

Properties and prospects for rhenium(i) tricarbonyl N-heterocyclic carbene complexes

Re(i) complexes bound to p-conjugated bidentate N-heterocyclic carbene ligands with formulation Re(CO)3(N^NHC)L (where N^NHC represents an imidazole or benzimidazole carbene ligand conjugated to a N-based heterocycle such as pyridine, pyrimidine, quinoline or quinoxaline) are a relatively new class of complexes belonging to the archetypal family of well known luminescent Re(CO)3(diim)X species (where diim is a conjugated diimine ligand and X is a halogen anion). The complexes Re(CO)3(N^NHC)L are characterised by blue-shifted emission compared to Re(CO)3(diim)X, but with shorter excited state lifetime decays and lower quantum yields, in contrast to trends expected by the energy gap law. Detailed investigations elucidated that these complexes are photochemically active and undergo ligand exchange reactions when excited to their lowest metal-to-ligand charge transfer excited states. This mechanism is entirely different from previously known mechanisms of photoactivated ligand substitution reactions in Re(i) tricarbonyl complexes. Therefore, the species Re(CO)3(N^NHC)L represent a new and unique class of photoactive Re(i) complexes. This feature article illustrates the research effort dedicated to the design and synthesis of Re(CO)3(N^NHC)L complexes and the elucidation of their photophysical and photochemical behaviour by means of a variety of spectroscopic techniques. Furthermore, for their unique characteristics, these new complexes have demonstrated potential value in several applications including catalysis, diagnosis and therapy. These studies will also be illustrated herein

Nasal manifestations in granulomatosis with polyangiitis: a case report and review of the literature

Granulomatosis with polyangiitis (GPA) is an anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides of medium and small arteries, characterized by necrotizing granulomatous inflammation of the upper and lower respiratory tract with coexist- ing glomerulonephritis. We report a case of GPA in a patient presenting with a six-month history of spontaneous epistaxis, nasal obstruction and frontal headache. Nasal endoscopy showed a large nasal septum perforation and an anterior translucid mass in the right nasal fossa. Findings were confirmed by computed tomography (CT) scan with contrast. The patient underwent func- tional transnasal endoscopic removal of the mass; histological examination showed tissue features suggestive of GPA; dosage of c-ANCA e p-ANCA antibodies confirmed GPA diagnosis. Nasal septum perforation has long been recognized as a feature of GPA, in which granulomatous destruction of nasal cartilage can result in perforation and saddle-nose deformity. Prompt diagno- sis of GPA is important to initiate therapy which may be life-saving and organ sparing

Backbone switch to abacavir/lamivudine fixed-dose combination: implications for antiretroviral therapy optimization

Current guidelines recommend treatment optimization in virologically suppressed patients through switching/ simplification strategies to minimize long-term toxicities and improve adherence. The assessment of inflammation/ coagulation profiles may support therapeutic decisions. We undertook a prospective, non-randomized study to evaluate the efficacy and safety of switching to ABC/3TC from ZDV/3TC or TDF/FTC backbones, in 40 HIV-1 infected patients with HIV-RNA levels 24 months). Main endpoints were viral load levels, CD4+ T cells and toxicities after 48 weeks. Serum inflammation/coagulation markers (ESR, CRP, D-dimer and fibrinogen) and pro-inflammatory cytokines (IL-6, TNF-α, adiponectin, resistin) were evaluated. Baseline characteristics were similar in the two arms, with significantly lower values of e-GFR in patients on TDF/FTC. Markers of inflammation/ coagulation and cytokine profile were also similar, except for higher values of resistin in patients on TDF/ FTC. During follow up, CD4+ T cells increased and viral load remained undetectable in both groups. Patient from ZDV/3TC had significantly greater changes in total cholesterol and serum creatinine. Markers of inflammation/ coagulation remained unchanged. Adiponectin significantly increased in patients from ZDV/3TC. Switching to ABC/3TC was effective and safe. Inflammatory markers remained low in both groups. Some changes in metabolic, kidney and cytokine profiles were apparently specific for baseline cART treatment

Glycerophosphoinositol 4-phosphate, a putative endogenous inhibitor of adenylylcyclase.

In a continuous line of rat thyroid cells transformed by the k-ras oncogene (KiKi), the expression of ras-p21 correlates with an increased activity of a phosphoinositide-specific phospholipase A2, which leads to elevated levels of glycerophosphoinositols. In this study we have characterized the biological activities of these compounds. Growth and differentiation in thyroid cells are mainly regulated by the activation of adenylylcyclase. Therefore, we have studied the effects of glycerophosphoinositols on the activity of this enzyme using a normal thyroid cell line (FRTL5). Micromolar concentrations of glycerophosphoinositol 4-phosphate (GroPIns-4-P) caused a approximately 50% inhibition of the adenylylcyclase activity in FRTL5 membranes stimulated by the GTP-binding protein activator fluoroaluminate. Similar concentrations of GroPIns-4-P were detected in KiKi cells but not in the normal FRTL5 line. Micromolar GroPIns-4-P was found to be taken up by intact FRTL5 cells and to induce nearly 50% inhibition of the thyrotropin- and cholera toxin-induced increase in cAMP levels. Similar results were also observed in other cell lines (smooth muscle, pituitary cells, and pneumocytes). GroPIns-4-P inhibited cAMP-dependent cellular functions such as iodide uptake and thymidine incorporation in FRTL5 cells when stimulated by thyrotropin and cholera toxin but not when induced by forskolin. These results are consistent with GroPIns-4-P exerting an inhibitory effect on the GTP-binding protein that stimulates adenylycyclase. We propose that GroPIns-4-P might mediate a mechanism of cross-talk between adenylylcyclase and phospholipase A2 in thyroid as well as in other cell systems

Recovery from repeated sudden hearing loss in a patient with Takayasu’s arteritis treated with hyperbaric oxygen therapy: the first report in the literature

Hearing loss has been rarely reported in Takayasu's arteritis, presents as sudden sensorineural hearing loss and usually responds well to corticosteroid therapy. Hyperbaric Oxygen Therapy is commonly used as a supplementary treatment to corticosteroids for sudden hearing loss. We present the case of a woman with Takayasu's arteritis who had two episodes of hearing loss involving one ear at a time with a 11-month delay between each episode. During the first episode, the patient was treated with high-dose intramuscular corticosteroids with a temporary improvement of auditory threshold, that deteriorated close to previous level 14 days after cessation of therapy. In the second episode, Hyperbaric Oxygen Therapy was associated to corticosteroids, with a significant, longer term improvement in both ears, including the one that had shown to be unresponsive to previous pharmacologic therapy. Oxygen therapy could have played a role in hearing restoration in this patient, as it could have acted synergically with corticosteroids amplifying their effect

The Role of the Pleckstrin Homology Domain in Membrane Targeting and Activation of Phospholipase Cβ1

Current studies involve an investigation of the role of the pleckstrin homology (PH) domain in membrane targeting and activation of phospholipase Cbeta(1) (PLCbeta(1)). Here we report studies on the membrane localization of the isolated PH domain from the amino terminus of PLCbeta(1) (PLCbeta(1)-PH) using fluorescence microscopy of a green fluorescent protein fusion protein. Whereas PLCbeta(1)-PH does not localize to the plasma membrane in serum-starved cells, it undergoes a rapid but transient migration to the plasma membrane upon stimulation of cells with serum or lysophosphatidic acid (LPA). Regulation of the plasma membrane localization of PLCbeta(1)-PH by phosphoinositides was also investigated. PLCbeta(1)-PH was found to bind phosphatidylinositol 3-phosphate most strongly, whereas other phosphoinositides were bound with lower affinity. The plasma membrane localization of PLCbeta(1)-PH induced by serum and LPA was blocked by wortmannin pretreatment and by LY294002. In parallel, activation of PLCbeta by LPA was inhibited by wortmannin, by LY294002, or by the overexpression of PLCbeta(1)-PH. Microinjection of betagamma subunits of G proteins in serum-starved cells induced the translocation of PLCbeta(1)-PH to the plasma membrane. These results demonstrate that a cooperative mechanism involving phosphatidylinositol 3-phosphate and the Gbetagamma subunit regulates the plasma membrane localization and activation of PLCbeta(1)-PH

Defining the Anti-Cancer Activity of Tricarbonyl Rhenium Complexes: Induction of G2/M Cell Cycle Arrest and Blockade of Aurora-A Kinase Phosphorylation

Rhenium and ruthenium complexes containing N-heterocylic carbene (NHC) ligands and conjugated to indomethacin were prepared. The anticancer properties were probed against pancreatic cell lines, revealing a remarkable activity of the rhenium fragment as anticancer agent. The ruthenium complexes were found to be inactive against the same pancreatic cancer cell lines, either alone or in conjugation with indomethacin. An in-depth biological study revealed the origin of the anticancer properties of the rhenium tricarbonyl fragment, of which a complete elucidation had yet to be achieved. It was found that the rhenium complexes induce cell cycle arrest at the G2/M phase by inhibiting the phosphorylation of Aurora-A kinase. A preliminary study on the structure-activity relationship on a large family of these complexes revealed that the anticancer properties are mainly associated with the lability of the ancillary ligand, with inert complexes showing limited to no anticancer properties

Subtyping patients with somatic tinnitus: modulation of tinnitus and history for somatic dysfunction help identify tinnitus patients with temporomandibular joint disorders

Objective: Determine in a cohort of patients with normal hearing and chronic tinnitus if self-reported history for temporomandibular joint (TMJ) dysfunction and a positive modulation of tinnitus in the TMJ region could be suggestive of an underlying TMJ disorder. Patients and Methods: The study included 226 patients presenting to the Head and Neck Service of our University Hospital. Following audiological and somatic tinnitus evaluation, patients were divided into two groups. The study group (n= 134) included subjects that met both the following criteria: A) a self-reported history for TMJ dysfunction and B) a positive modulation of tinnitus following somatic maneuvers in the TMJ region. The control group (n=92) included patients with similar demographic and tinnitus characteristics that did not meet the proposed criteria for somatic tinnitus. Afterwards, patients underwent clinical TMJ evaluation in the Service of Clinical Gnathology of our University. Results: One hundred thirty-one patients (57.9%) received a clinical diagnosis of TMJ disorder according to DC/TMD Axis I; 79.1% in the study group and 27.2% in the control group. Ninety-five (42.1%) patients were negative for TMJ disorders; 20.9% in the study group and 72.8% in the control group. A significantly higher number of TMJ disorders was found in patients in the study group compared to the control group (p<0.0001). Most patients had joint disorders (67.2%), followed by other (29.8%) and pain disorders (29%). Logistic regression analysis in the study group showed that female gender was more prevalent in patients with TMJ disorders. Conclusion: Our findings in patients with chronic tinnitus and normal hearing suggest that self-reported history for somatic dysfunction and modulation of tinnitus, when occurring simultaneously in the TMJ region, can be useful to preliminarily identify patients with TMJ disorders