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Interventional radiology in the elderly.

Interventional radiological percutaneous procedures are becoming all the more important in the curative or palliative management of elderly frail patients with multiple underlying comorbidities. They may serve either as alternative primary minimally invasive therapies or adjuncts to traditional surgical treatments. The present report provides a concise review of the most important interventional radiological procedures with a special focus on the treatment of the primary debilitating pathologies of the elderly population. The authors elaborate on the scientific evidence and latest developments

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… Comparison of sirolimus-eluting vs bare-metal stents for the treatment of infrapopliteal obstructions. EuroIntervention. 2006;2(2):169–174. 79. Bosiers M, Hart JP, Deloose K, Verbist J, Peeters P. … Sirolimus for below the knee lesions: mid-term results of SiroBTK study. Catheter Cardiovasc Interv. 2006;68(5):793–798. doi: 10.1002/ccd.20893. 81. Bosiers M, Deloose K, Verbist J, Peeters P. …

Pathogenesis of Oral Toxicities Associated with Targeted Therapy and Immunotherapy.

Targeted therapy and immunotherapy have redefined cancer treatment. While they have enhanced tumor response and improved survival rates in many cancer types, toxicities continue to occur, and these often involve the oral cavity. Broadly reported as "mucositis" or "stomatitis," oral toxicities induced by targeted therapies differ clinically and mechanistically from those associated with conventional chemotherapy. Manifesting primarily as mucosal lesions, salivary gland hypofunction, or orofacial neuropathies, these oral toxicities may nonetheless lead to significant morbidity and impact patient

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… Everolimus, sirolimus, and temsirolimus are the mTORis currently approved by the Food and Drug Administration (FDA) in the Unites States. Both sirolimus and everolimus bind to the FK binding protein to moderate the mTOR activity and subsequently inhibit the PTEN/PI3K/Akt and JAK pathways [ 12 ]. … Mammalian target of rapamycin inhibitor-associated stomatitis in hematopoietic stem cell transplantation patients receiving sirolimus prophylaxis for graft-versus-host disease. Biol. …

Defining the Role of Oral Pathway Inhibitors as Targeted Therapeutics in Arteriovenous Malformation Care.

Arteriovenous malformations (AVMs) are vascular malformations that are prone to rupturing and can cause significant morbidity and mortality in relatively young patients. Conventional treatment options such as surgery and endovascular therapy often are insufficient for cure. There is a growing body of knowledge on the genetic and molecular underpinnings of AVM development and maintenance, making the future of precision medicine a real possibility for AVM management. Here, we review the pathophysiology of AVM development across various cell types, with a focus on current and potential druggable

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… Lastly, a study on 10 patients with extracranial AVMs treated with sirolimus also demonstrated its poor efficacy in this population [ 43 ]. … Combining the mTOR inhibitor sirolimus with the VEGFR2 inhibitor nintedanib had a synergistic effect on blocking and reverting AVM morphology and improved clinical pathology such as anemia, CBC markers, and bleeding in two HHT mouse models [ 65 ]. …

PTEN protects kidney against acute kidney injury by alleviating apoptosis and promoting autophagy via regulating HIF1-α and mTOR through PI3K/Akt pathway.

Phosphatase and tensin homolog (PTEN) deleted on human chromosome 10 is a tumor suppressor with bispecific phosphatase activity, which is often involved in the study of energy metabolism and tumorigenesis. PTEN is recently reported to participate in the process of acute injury. However, the mechanism of PTEN in Ischemia-Reperfusion Injury (IRI) has not yet been clearly elucidated. In this study, mice with bilateral renal artery ischemia-reperfusion and HK-2 cells with hypoxia/reoxygenation (H/R) were used as acute kidney injury models. We demonstrated that PTEN was downregulated in IRI-induced

A molecular cascade modulates MAP1B and confers resistance to mTOR inhibition in human glioblastoma.

BACKGROUND: Clinical trials of therapies directed against nodes of the signaling axis of phosphatidylinositol-3 kinase/Akt/mammalian target of rapamycin (mTOR) in glioblastoma (GBM) have had disappointing results. Resistance to mTOR inhibitors limits their efficacy. METHODS: To determine mechanisms of resistance to chronic mTOR inhibition, we performed tandem screens on patient-derived GBM cultures. RESULTS: An unbiased phosphoproteomic screen quantified phosphorylation changes associated with chronic exposure to the mTOR inhibitor rapamycin, and our analysis implicated a role for glycogen s

Effect of Optimal Medical Therapy Before Procedures on Outcomes in Coronary Patients Treated With Drug-Eluting Stents.

It has not been established whether the achievement of optimal medical therapy (OMT) before implantation of a drug-eluting stent has a clinical benefit for patients with stable coronary artery disease (CAD). This study included 3,004 patients with CAD treated with drug-eluting stent from 123 Japanese participating centers. The achievement of OMT was defined as control of blood pressure <130/80 mm Hg, hemoglobin A1c <7.0%, and low-density lipoprotein cholesterol <100 mg/dl. The primary end point was target vessel failure, a composite of death related to the target vessel, myocardial infarction,

Early Tumour Shrinkage: A Tool for the Detection of Early Clinical Activity in Metastatic Renal Cell Carcinoma.

BACKGROUND: The predictive role of objective remission remains undefined for targeted agents in metastatic renal cell carcinoma (mRCC); howe … aplan-Meier method. INTERVENTION: Axitinib, bevacizumab, interferon α, sorafenib, sunitinib, or temsirolimus. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We measured optimal thresholds of eTS and eTS as a predictor of OS or PFS. RESULTS AND LIMITATIONS: Optimal threshold of eTS for the prediction of OS and PFS was determined to be approximately 10%. I …

Mitochondrial Dysfunction in the Liver and Antiphospholipid Antibody Production Precede Disease Onset and Respond to Rapamycin in Lupus-Prone Mice.

OBJECTIVE: Antiphospholipid antibodies (aPL) constitute a diagnostic criterion of systemic lupus erythematosus (SLE), and aPL have been functionally linked to liver disease in patients with SLE. Since the mechanistic target of rapamycin (mTOR) is a regulator of oxidative stress, a pathophysiologic process that contributes to the development of aPL, this study was undertaken in a mouse model of SLE to examine the involvement of liver mitochondria in lupus pathogenesis. METHODS: Mitochondria were isolated from lupus-prone MRL/lpr, C57BL/6.lpr, and MRL mice, age-matched autoimmunity-resistant C5

Endothelial Cell mTOR Complex-2 Regulates Sprouting Angiogenesis.

Tumor neovascularization is targeted by inhibition of vascular endothelial growth factor (VEGF) or the receptor to prevent tumor growth, but drug resistance to angiogenesis inhibition limits clinical efficacy. Inhibition of the phosphoinositide 3 kinase pathway intermediate, mammalian target of rapamycin (mTOR), also inhibits tumor growth and may prevent escape from VEGF receptor inhibitors. mTOR is assembled into two separate multi-molecular complexes, mTORC1 and mTORC2. The direct effect of mTORC2 inhibition on the endothelium and tumor angiogenesis is poorly defined. We used pharmacological

Ndfip1 represses cell proliferation by controlling Pten localization and signaling specificity.

Pten controls a signaling axis that is implicated to regulate cell proliferation, growth, survival, migration, and metabolism. The molecular mechanisms underlying the specificity of Pten responses to such diverse cellular functions are currently poorly understood. Here we report the control of Pten activity and signaling specificity during the cell cycle by Ndfip1 regulation of Pten spatial distribution. Genetic deletion of Ndfip1 resulted in a loss of Pten nuclear compartmentalization and increased cell proliferation, despite cytoplasmic Pten remaining active in regulating PI3K/Akt signaling.

Impact of dual mTORC1/2 mTOR kinase inhibitor AZD8055 on acquired endocrine resistance in breast cancer in vitro.

INTRODUCTION: Upregulation of PI3K/Akt/mTOR signalling in endocrine-resistant breast cancer (BC) has identified mTOR as an attractive target alongside anti-hormones to control resistance. RAD001 (everolimus/Afinitor®), an allosteric mTOR inhibitor, is proving valuable in this setting; however, some patients are inherently refractory or relapse during treatment requiring alternative strategies. Here we evaluate the potential for novel dual mTORC1/2 mTOR kinase inhibitors, exemplified by AZD8055, by comparison with RAD001 in ER + endocrine resistant BC cells. METHODS: In vitro models of tamoxif

Liver damage, inflammation, and enhanced tumorigenesis after persistent mTORC1 inhibition.

Obesity can result in insulin resistance, hepatosteatosis, and nonalcoholic steatohepatitis (NASH) and increases liver cancer risk. Obesity-induced insulin resistance depends, in part, on chronic activation of mammalian target of rapamycin complex 1 (mTORC1), which also occurs in human and mouse hepatocellular carcinoma (HCC), a frequently fatal liver cancer. Correspondingly, mTORC1 inhibitors have been considered as potential NASH and HCC treatments. Using a mouse model in which high-fat diet enhances HCC induction by the hepatic carcinogen DEN, we examined whether mTORC1 inhibition attenuate

Everolimus-eluting Xience v/Promus versus zotarolimus-eluting resolute stents in patients with diabetes mellitus.

OBJECTIVES: This study sought to compare everolimus-eluting stents (EES) versus Resolute zotarolimus-eluting stents (ZES) in terms of patient- or stent-related clinical outcomes in an "all-comer" group of patients with diabetes mellitus (DM) who underwent percutaneous coronary intervention. BACKGROUND: DM significantly increases the risk of adverse events after percutaneous coronary intervention. The efficacy and safety of second-generation drug-eluting stents, in particular EES versus ZES, in patients with DM have not been extensively evaluated. METHODS: Patients with DM (1,855 of 5,054 pat

The transcription factor FoxO1 sustains expression of the inhibitory receptor PD-1 and survival of antiviral CD8(+) T cells during chronic infection.

Protein kinase B (also known as AKT) and the mechanistic target of rapamycin (mTOR) are central regulators of T cell differentiation, proliferation, metabolism, and survival. Here, we show that during chronic murine lymphocytic choriomeningitis virus infection, activation of AKT and mTOR are impaired in antiviral cytotoxic T lymphocytes (CTLs), resulting in enhanced activity of the transcription factor FoxO1. Blockade of inhibitory receptor programmed cell death protein 1 (PD-1) in vivo increased mTOR activity in virus-specific CTLs, and its therapeutic effects were abrogated by the mTOR inhib

The Combination of Sorafenib and Everolimus Abrogates mTORC1 and mTORC2 upregulation in osteosarcoma preclinical models.

PURPOSE: The multikinase inhibitor sorafenib displays antitumor activity in preclinical models of osteosarcoma. However, in sorafenib-treated patients with metastatic-relapsed osteosarcoma, disease stabilization and tumor shrinkage were short-lived and drug resistance occurred. We explored the sorafenib treatment escape mechanisms to overcome their drawbacks. EXPERIMENTAL DESIGN: Immunoprecipitation, Western blotting, and immunohistochemistry were used to analyze the mTOR pathway [mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2)]. Cell viability, colony growth, and cell migration were eval

Combination of zoledronic Acid and targeted therapy is active but may induce osteonecrosis of the jaw in patients with metastatic renal cell carcinoma.

PURPOSE: To investigate the efficacy and safety of zoledronic acid (ZA) combined with targeted therapy (TT). MATERIALS AND METHODS: A retrospective study was performed in patients with metastatic renal cell carcinoma treated with ZA and TT. RESULTS: Twenty-one patients received ZA and TT to prevent skeletal-related events and no pretherapy oral and maxillofacial (OM) examination (cohort A). Six patients (29%) developed osteonecrosis of the jaw (ONJ), which was observed only in patients receiving sunitinib and ZA. Sixteen patients received TT and ZA for hypercalcemia and no pretherapy OM exam

Autophagy modulators sensitize prostate epithelial cancer cell lines to TNF-alpha-dependent apoptosis.

TNF-alpha levels in prostate cancer correlate with the extent of disease and are significantly elevated in the metastatic stage. TNF receptor superfamily controls two distinct signalling cascades, leading to opposite effects, i.e. apoptosis and survival; in prostate cancer TNF-alpha-mediated signalling induces cell survival and resistance to therapy. The apoptosis of prostate epithelial cancer cells LNCaP and PC3 was investigated upon treatment with the autophagy inhibitor 3-methyladenine and the autophagy inducer rapamycin, in combination with TNF-alpha. Cells were exposed to these molecules

mTOR-dependent modulation of gastric nesfatin-1/NUCB2.

BACKGROUND: Nesfatin-1, an 82 amino acid peptide derived from the prohormone nucleobindin-2 (NUCB2), is a novel satiety hormone acting through a leptin-independent mechanism in the hypothalamus. The mechanisms by which production of nesfatin-1/NUCB2 is regulated remain unknown. METHODS: Nesfatin-1/NUCB2 mRNA and immunoreactivity were examined in gastric tissue and Min-6 cells by RT-PCR and immunofluorescent staining or Western blotting. RESULTS: Nesfatin-1/NUCB2 is co-localized with pS6K1, the downstream target of mammalian target of rapamycin (mTOR), in gastric X/A like cells. A parallel re

Innate and adaptive immune responses are tolerized in chimeras prepared with nonmyeloablative conditioning.

BACKGROUND: Mixed chimerism is an effective approach for tolerance induction in transplantation. Strategies to achieve mixed chimerism with relatively low toxicity have significantly expanded the clinical use of chimerism. METHODS: Allogeneic bone marrow transplants were performed between B6 (H2(b)) and BALB/c (H2(d)) mice. Recipient B6 mice were nonmyeloablatively conditioned with anti-αβ-T-cell receptor, anti-CD154, or rapamycin alone or in different combinations. A total of 15 × 10(6) BALB/c bone marrow cells were transplanted after varying doses of cGy of total body irradiation. RESULTS:

Randomized comparison of cost-saving and effectiveness of oral rapamycin plus bare-metal stents with drug-eluting stents: three-year outcome from the randomized oral rapamycin in Argentina (ORAR) III trial.

OBJECTIVES: The Oral Rapamycin in ARgentina (ORAR) III trial is a randomized study comparing a strategy of oral rapamycin (OR) plus bare-metal stent (BMS) versus a strategy of drug-eluting stents (DES) in patients with de novo coronary lesions. The purpose of this study was to assess the 3 years cost-effectiveness outcome of each strategy. BACKGROUND: OR after BMS has been associated with reduction of target vessel revascularization (TVR) although its value in long-term efficacy in comparison with DES is unknown. METHODS: In three hospitals in Buenos Aires, Argentina, 200 patients were rando