Cyclosporine A and tacrolimus reduce the amount of GLUT4 at the cell-surface in human adipocytes: increased endocytosis as a potential mechanism for the diabetogenic effects of immunosuppressive agents

Context:Immunosuppressive agentes are associated with profound metabolic side effects including new-onset diabetes and dyslipidemia after organ transplantation. Objective: Toi nvestigated the effects of the cyclosporine A(CsA)or tacrolimus ong lucose uptake and insulin signalling in human adipocytes and their impact on the regulation of celular trafficking of the glucose transporter 4 (GLUT4). Design:Human isolated adipocytes were incubated with therapeutic concentrations of either CsA or tacrolimus, and glucose uptake and expression of insulin signaling proteins were assessed. Furthermore,we studied effects of CsA and tacrolimus on the regulation of celular trafficking of the GLUT4 in differentiated human pre-adipocytes and L6 cells. Results:CsA and tacrolimus had a concentration-dependent inhibitory effect on basal and insulin stimulated 14C-glucose uptake in adipocytes. Although phosphorylation at Tyr1146 of insulin receptor (IR) was inhibited by tacrolimus, the phosphorylation and/or protein levels of the insulin signalling proteinsIRS1/2,p85-PI3K,PKB,AS160 and mTORC1,as well as GLUT4 and GLUT1,were unchanged by CsA or tacrolimus. Furthermore, CsA and tacrolimus reduced the GLUT4 amount localized at the cell surfasse of differentiated human pre-adipocytes and L6 cells in the presence of insulin.This occurred by na increased rate of GLUT4 endocytosis,with no change in the exocytosis rate. Conclusions: These results suggest that therapeutic concentrations of CsA and tacrolimus can inhibit glucose uptake independente of insulin signalling by removing GLUT4 from the cell surface via na increased rate of endocytosis.Such mechanisms can contribute to the development of insulin resistance and diabetes associated with immunosuppressive therapy.In addition,they may provide novel pharmacological approaches for treatment of diabetes

The Minimal Length of a Lagrangian Cobordism between Legendrians

To investigate the rigidity and flexibility of Lagrangian cobordisms between Legendrian submanifolds, we investigate the minimal length of such a cobordism, which is a $1$-dimensional measurement of the non-cylindrical portion of the cobordism. Our primary tool is a set of real-valued capacities for a Legendrian submanifold, which are derived from a filtered version of Legendrian Contact Homology. Relationships between capacities of Legendrians at the ends of a Lagrangian cobordism yield lower bounds on the length of the cobordism. We apply the capacities to Lagrangian cobordisms realizing vertical dilations (which may be arbitrarily short) and contractions (whose lengths are bounded below). We also study the interaction between length and the linking of multiple cobordisms as well as the lengths of cobordisms derived from non-trivial loops of Legendrian isotopies.Comment: 33 pages, 9 figures. v2: Minor corrections in response to referee comments. More general statement in Proposition 3.3 and some reorganization at the end of Section

Honeycomb layered oxides: Structure, energy storage, transport, topology and relevant insights

The advent of nanotechnology has hurtled the discovery and development of nanostructured materials with stellar chemical and physical functionalities in a bid to address issues in energy, environment, telecommunications and healthcare. In this quest, a class of two-dimensional layered materials consisting of alkali or coinage metal atoms sandwiched between slabs exclusively made of transition metal and chalcogen (or pnictogen) atoms arranged in a honeycomb fashion have emerged as materials exhibiting fascinatingly rich crystal chemistry, high-voltage electrochemistry, fast cation diffusion besides playing host to varied exotic electromagnetic and topological phenomena. Currently, with a niche application in energy storage as high-voltage materials, this class of honeycomb layered oxides serves as ideal pedagogical exemplars of the innumerable capabilities of nanomaterials drawing immense interest in multiple fields ranging from materials science, solid-state chemistry, electrochemistry and condensed matter physics. In this review, we delineate the relevant chemistry and physics of honeycomb layered oxides, and discuss their functionalities for tunable electrochemistry, superfast ionic conduction, electromagnetism and topology. Moreover, we elucidate the unexplored albeit vastly promising crystal chemistry space whilst outlining effective ways to identify regions within this compositional space, particularly where interesting electromagnetic and topological properties could be lurking within the aforementioned alkali and coinage-metal honeycomb layered oxide structures. We conclude by pointing towards possible future research directions, particularly the prospective realisation of Kitaev-Heisenberg-Dzyaloshinskii-Moriya interactions with single crystals and Floquet theory in closely-related honeycomb layered oxide materials. This journal i

A phase I dose-escalation study to evaluate safety and tolerability of sorafenib combined with sirolimus in patients with advanced solid cancer

Contains fulltext : 87630.pdf (publisher's version ) (Closed access)BACKGROUND: The combination of sorafenib (vascular endothelial growth factor receptor 2 inhibitor) and sirolimus (mammalian target of rapamycin inhibitor) might work synergistically. METHODS: A phase I dose-escalation study with sorafenib twice a day (b.i.d.) and sirolimus once daily (q.d.) was performed to determine the recommended dose of the combination in patients with solid tumours. Secondary objectives were to determine the safety profile and maximum tolerated dose (MTD), and to evaluate the pharmacokinetics (PK) of the combination. RESULTS: Dose-limiting toxicities were transaminitis and cutaneous toxicity. The most frequently reported adverse events were elevated transaminases, hypophosphatemia, fatigue, anorexia, diarrhoea, nausea, rash and palmar-plantar erythrodysaesthesia. Sirolimus did not change the PK of sorafenib; in contrast, sorafenib reduced the AUC(0-96) and C(max) of sirolimus. No objective responses were observed; eight patients showed stable disease for a median of 16.3 weeks (range 8-24). The MTD of the combination was sorafenib 200 mg b.i.d. with sirolimus 1 mg q.d. CONCLUSION: The combination of sorafenib and sirolimus showed enhanced toxicity, which could not be explained by the PK of both drugs. The relative low doses at the MTD, in combination with the PK results, do not warrant further development of this combination

HCC recurrence in HCV-infected patients after liver transplantation: SiLVER Study reveals benefits of sirolimus in combination with CNIs - a post-hoc analysis

Factors affecting outcomes in liver transplant (LTx) recipients with hepatocellular carcinoma (HCC) and hepatitis C viral (HCV) infection include the choice of immunosuppression. Here, we analyzed the HCV+ subgroup of patients from the randomized controlled, international SiLVER Study. We performed a post hoc analysis of 166 HCV+ SiLVER Study patients regarding HCC outcome after LTx. Control patients (group A: n = 88) received mTOR inhibitor (mTORi)-free, calcineurin inhibitor (CNI)-based versus sirolimus-based immunosuppression (group B: n = 78). We found no significant difference regarding HCV-RNA titers between group A and B. Since no effect in group B could be due to variable sirolimus dosing, we split group B into patients receiving sirolimus-based immunosuppression + CNIs for >50% (B1; n = 44) or <50% (B2; n = 34) of the time. While there remained no difference in HCV-RNA titer between groups, HCC recurrence-free survival in group B1 (81.8%) was markedly better versus both group A (62.7%; P = 0.0136) and group B2 (64.7%; P = 0.0326); Interestingly, further subgroup analysis revealed an increase (P = 0.0012) in liver enzyme values in group B2. Taken together, in HCV-infected patients with HCC and LTx, mTORi immunosuppression + CNIs yields excellent outcomes. Unexpectedly, higher levels of liver inflammation and poorer outcomes occur with mTORi monotherapy in the HCV+ subgroup

A prospective randomised, open-labeled, trial comparing sirolimus-containing versus mTOR-inhibitor-free immunosuppression in patients undergoing liver transplantation for hepatocellular carcinoma

<p>Abstract</p> <p>Background</p> <p>The potential anti-cancer effects of mammalian target of rapamycin (mTOR) inhibitors are being intensively studied. To date, however, few randomised clinical trials (RCT) have been performed to demonstrate anti-neoplastic effects in the pure oncology setting, and at present, no oncology endpoint-directed RCT has been reported in the high-malignancy risk population of immunosuppressed transplant recipients. Interestingly, since mTOR inhibitors have both immunosuppressive and anti-cancer effects, they have the potential to simultaneously protect against immunologic graft loss and tumour development. Therefore, we designed a prospective RCT to determine if the mTOR inhibitor sirolimus can improve hepatocellular carcinoma (HCC)-free patient survival in liver transplant (LT) recipients with a pre-transplant diagnosis of HCC.</p> <p>Methods/Design</p> <p>The study is an open-labelled, randomised, RCT comparing sirolimus-containing versus mTOR-inhibitor-free immunosuppression in patients undergoing LT for HCC. Patients with a histologically confirmed HCC diagnosis are randomised into 2 groups within 4-6 weeks after LT; one arm is maintained on a centre-specific mTOR-inhibitor-free immunosuppressive protocol and the second arm is maintained on a centre-specific mTOR-inhibitor-free immunosuppressive protocol for the first 4-6 weeks, at which time sirolimus is initiated. A 2^1/2 -year recruitment phase is planned with a 5-year follow-up, testing HCC-free survival as the primary endpoint. Our hypothesis is that sirolimus use in the second arm of the study will improve HCC-free survival. The study is a non-commercial investigator-initiated trial (IIT) sponsored by the University Hospital Regensburg and is endorsed by the European Liver and Intestine Transplant Association; 13 countries within Europe, Canada and Australia are participating.</p> <p>Discussion</p> <p>If our hypothesis is correct that mTOR inhibition can reduce HCC tumour growth while simultaneously providing immunosuppression to protect the liver allograft from rejection, patients should experience less post-transplant problems with HCC recurrence, and therefore could expect a longer and better quality of life. A positive outcome will likely change the standard of posttransplant immunosuppressive care for LT patients with HCC.</p> <p>Trial Register</p> <p>Trial registered at <url>http://www.clinicaltrials.gov</url>: NCT00355862</p> <p>(EudraCT Number: 2005-005362-36)</p

A prospective randomised, open-labeled, trial comparing sirolimus-containing versus mTOR-inhibitor-free immunosuppression in patients undergoing liver transplantation for hepatocellular carcinoma

Peer reviewe

Sirolimus Use in Liver Transplant Recipients With Hepatocellular Carcinoma : A Randomized, Multicenter, Open-Label Phase 3 Trial

Background We investigated whether sirolimus-based immunosuppression improves outcomes in liver transplantation (LTx) candidates with hepatocellular carcinoma (HCC). Methods In a prospective-randomized open-label international trial, 525 LTx recipients with HCC initially receiving mammalian target of rapamycin inhibitor-free immunosuppression were randomized 4 to 6 weeks after transplantation into a group on mammalian target of rapamycin inhibitor-free immunosuppression (group A: 264 patients) or a group incorporating sirolimus (group B: 261). The primary endpoint was recurrence-free survival (RFS); intention-to-treat (ITT) analysis was conducted after 8 years. Overall survival (OS) was a secondary endpoint. Results Recurrence-free survival was 64.5% in group A and 70.2% in group B at study end, this difference was not significant (P = 0.28; hazard ratio [HR], 0.84; 95% confidence interval [95% CI], 0.62; 1.15). In a planned analysis of RFS rates at yearly intervals, group B showed better outcomes 3 years after transplantation (HR, 0.7; 95% CI, 0.48-1.00). Similarly, OS (P = 0.21; HR, 0.81; 95% CI, 0.58-1.13) was not statistically better in group B at study end, but yearly analyses showed improvement out to 5 years (HR, 0.7; 95% CI, 0.49-1.00). Interestingly, subgroup (Milan Criteria-based) analyses revealed that low-risk, rather than high-risk, patients benefited most from sirolimus; furthermore, younger recipients (age 60) also benefited, as well sirolimus monotherapy patients. Serious adverse event numbers were alike in groups A (860) and B (874). Conclusions Sirolimus in LTx recipients with HCC does not improve long-term RFS beyond 5 years. However, a RFS and OS benefit is evident in the first 3 to 5 years, especially in low-risk patients. This trial provides the first high-level evidence base for selecting immunosuppression in LTx recipients with HCC.Peer reviewe

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival