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Three-month dual antiplatelet therapy after implantation of zotarolimus-eluting stents: the DATE (Duration of Dual Antiplatelet Therapy AfterImplantation of Endeavor Stent) registry.

BACKGROUND: The optimal duration of dual antiplatelet therapy remains controversial. METHODS AND RESULTS: Between December 2006 and March 2008, 823 patients were enrolled in a prospective multicenter registry for 3-month dual antiplatelet therapy (aspirin 100-200mg+clopidogrel 75 mg daily) followed by aspirin mono-therapy after zotarolimus-eluting stents (ZES). Major exclusion criteria were: cardiogenic shock, stent thrombosis (ST)-segment elevation myocardial infarction (MI) within 48h, previous drug-eluting stent implantation, severe left ventricular dysfunction, bifurcation lesions requiri

Survival benefit with proapoptotic molecular and pathologic responses from dual targeting of mammalian target of rapamycin and epidermal growth factor receptor in a preclinical model of pancreatic neuroendocrine carcinogenesis.

PURPOSE: Pancreatic neuroendocrine tumors (PNETs), although rare, often metastasize, such that surgery, the only potentially curative therapy, is not possible. There is no effective systemic therapy for patients with advanced PNETs. Therefore, new strategies are needed. Toward that end, we investigated the potential benefit of dual therapeutic targeting of the epidermal growth factor receptor (EGFR) and mammalian target of rapamycin (mTOR) kinases, using a preclinical mouse model of PNET. MATERIALS AND METHODS: Rapamycin and erlotinib, inhibitors of mTOR and EGFR, respectively, were used to t

Rapamycin-insensitive up-regulation of MMP2 and other genes in tuberous sclerosis complex 2-deficient lymphangioleiomyomatosis-like cells.

Increased matrix metalloproteinase (MMP) activity has been implicated in the pathogenesis of lymphangioleiomyomatosis (LAM). The objective of this study was to investigate how tuberous sclerosis complex (TSC) 1 or TSC2 deficiency alters MMP expression and regulation. We studied immortalized cells that lack TSC2 derived from an angiomyolipoma of a patient with LAM, a TSC2 addback derivative, and murine embryonic fibroblast cells that lack Tsc1 or -2 and respective controls. Global gene expression analysis was performed in the angiomyolipoma and derivative cell lines. MMP levels in the condition

The Rheb-mTOR pathway is upregulated in reactive astrocytes of the injured spinal cord.

Astrocytes in the CNS respond to tissue damage by becoming reactive. They migrate, undergo hypertrophy, and form a glial scar that inhibits axon regeneration. Therefore, limiting astrocytic responses represents a potential therapeutic strategy to improve functional recovery. It was recently shown that the epidermal growth factor (EGF) receptor is upregulated in astrocytes after injury and promotes their transformation into reactive astrocytes. Furthermore, EGF receptor inhibitors were shown to enhance axon regeneration in the injured optic nerve and promote recovery after spinal cord injury. H

Activation or inactivation of cardiac Akt/mTOR signaling diverges physiological from pathological hypertrophy.

Cardiomyocyte hypertrophy differs according to the stress exerted on the myocardium. While pressure overload-induced cardiomyocyte hypertrophy is associated with depressed contractile function, physiological hypertrophy after exercise training associates with preserved or increased inotropy. We determined the activation state of myocardial Akt signaling with downstream substrates and fetal gene reactivation in exercise-induced physiological and pressure overload-induced pathological hypertrophies. C57BL/6J mice were either treadmill trained for 6 weeks, 5 days/week, at 85-90% of maximal oxygen

Kidney-targeted Birt-Hogg-Dube gene inactivation in a mouse model: Erk1/2 and Akt-mTOR activation, cell hyperproliferation, and polycystic kidneys.

BACKGROUND: Patients with Birt-Hogg-Dubé (BHD) syndrome harbor germline mutations in the BHD tumor suppressor gene that are associated with an increased risk for kidney cancer. BHD encodes folliculin, a protein that may interact with the energy- and nutrient-sensing 5'-AMP-activated protein kinase-mammalian target of rapamycin (AMPK-mTOR) signaling pathways. METHODS: We used recombineering methods to generate mice with a conditional BHD allele and introduced the cadherin 16 (KSP)-Cre transgene to target BHD inactivation to the kidney. Kidney cell proliferation was measured by BrdU incorporati

A plant triterpenoid, avicin D, induces autophagy by activation of AMP-activated protein kinase.

Avicins, a family of plant triterpene electrophiles, can trigger apoptosis-associated tumor cell death, and suppress chemical-induced carcinogenesis by its anti-inflammatory, anti-mutagenic, and antioxidant properties. Here, we show that tumor cells treated with benzyloxycarbonylvalyl-alanyl-aspartic acid (O-methyl)-fluoro-methylketone, an apoptosis inhibitor, and Bax(-/-)Bak(-/-) apoptosis-resistant cells can still undergo cell death in response to avicin D treatment. We demonstrate that this non-apoptotic cell death is mediated by autophagy, which can be suppressed by chloroquine, an autopha

Mind the GAP: Wnt steps onto the mTORC1 train.

The TSC1/2 tumor-suppressor complex controls protein synthesis through the regulation of mTOR. In this issue of Cell, Inoki et al. (2006) report that the kinases GSK3 and AMPK cooperate in the activation of TSC2 to inhibit mTOR activity. Surprisingly, the phosphorylation of TSC2 by GSK3 is markedly suppressed by Wnt signaling. This suggests that components of the mTOR pathway may be therapeutic targets for diseases linked to hyperactive Wnt signaling.

A pivotal role of cyclin D3 and cyclin-dependent kinase inhibitor p27 in the regulation of IL-2-, IL-4-, or IL-10-mediated human B cell proliferation.

The functional differences between IgDhighCD38- naive and IgD-CD38- memory (M) or IgDlowCD38+ germinal center (GC) B cells may stem from their variable response to signals that regulate activation, proliferation, and differentiation. In this report, we provide evidence for differential induction of cell cycle regulators in tonsillar human B cell subpopulations that were activated with anti-IgM and anti-CD40 in the presence or absence of IL-2, IL-4, or IL-10. Naive (IgDhigh) B cells exhibited a significant proliferative response to IL-4, but not to IL-2 or IL-10, whereas these cytokines trigger

Mice lacking p27(Kip1) display increased body size, multiple organ hyperplasia, retinal dysplasia, and pituitary tumors.

Mice lacking p27(Kip1) have been created by gene targeting in embryonic stem cells. These mice are larger than the control animals, with thymus, pituitary, and adrenal glands and gonadal organs exhibiting striking enlargement. CDK2 activity is elevated about 10-fold in p27(-/-) thymocytes. Development of ovarian follicles seems to be impaired, resulting in female sterility. Similar to mice with the Rb mutation, the p27(-/-) mice often develop pituitary tumors spontaneously. The retinas of the mutant mice show a disturbed organization of the normal cellular layer pattern. These findings indicat

Treatment of chronic GvHD with mesenchymal stromal cells induces durable responses: A phase II study.

Steroid-refractory chronic graft-vs-host disease (cGvHD) contributes to morbidity after allogeneic hematopoietic stem cell transplantation. Here, we report on 11 patients with severe, refractory cGvHD treated with repeated infusions of allogeneic bone marrow-derived mesenchymal stromal cells (MSC) over a 6- to 12-month period. Six patients responded to MSC treatment following National Institutes of Health response criteria, accompanied by improvement in GvHD-related symptoms and quality of life. This response was durable, with systemic immunosuppressive therapy withdrawn from two responders, a

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… , imatinib, ECP | 50 3 | 56 | CLL | Flu+Cy+TBI | Tacrolimus+sirolimus | — | — | 9 | 18 | Tacrolimus+ prednisone, Rituximab | 7.5 4 | 50 | AML | Bu+Cy | CyA+Mtx | — | — | 7 | 6 | CyA+ prednisone | 50 5 | 38 | AML | Bu+Cy | CyA+Mtx | Yes | Yes | 11 | 37 | CyA+ prednisone, Mtx | 15 6 | 30 | HL | Flu+Cy+ … TBI | CyA+Mtx | Yes | No | 8 | 34 | CyA+ prednisone, Mtx, rituximab, ECP, MMF | 3.75 7 | 41 | MM | Flu+TBI | CyA+Mtx | No | No | 3 | 9 | CyA+prednisone, infliximab | 30 8 | 20 | AML | Bu+Cy | CyA+Mtx | Yes | Yes | 7 | 57 | CyA+ prednisone, sirolimus, MMF, infliximab, rituximab, tacrolimus, ECP, imatinib …

Management of Immunosuppression in Kidney Transplant Recipients Who Develop Malignancy.

The risk of cancer increases after transplantation. However, the consensus on immunosuppression (IS) adjustment after diagnosis of malignancy is lacking. Our study aims to assess the impact of IS adjustment on mortality of post-kidney transplant patients and allograft outcomes. We retrospectively reviewed the data in our center of 110 subjects. Our results showed IS dose adjustment was not statistically associated with mortality risk (HR 1.94, 95%CI 0.85-4.41, p = 0.12), and chemotherapy was the only factor that was significantly related to mortality (HR 2.3, 95%CI 1.21-4.35, p = 0.01). IS red

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… Previous studies showed that sirolimus was associated with reduction in the risk of malignancy and nonmelanoma skin cancer in kidney transplant recipients; however, it was associated with increased mortality risk [ 9 ]. … Lastly, we disregarded the effect of sirolimus and steroid adjustment since both drugs are not part of the standard immunosuppressive regimen at our transplant center. 5. …

Systemic Sclerosis: From Pathophysiology to Novel Therapeutic Approaches.

Systemic sclerosis (SSc) is a systemic, immune-mediated chronic disorder characterized by small vessel alterations and progressive fibrosis of the skin and internal organs. The combination of a predisposing genetic background and triggering factors that causes a persistent activation of immune system at microvascular and tissue level is thought to be the pathogenetic driver of SSc. Endothelial alterations with subsequent myofibroblast activation, excessive extracellular matrix (ECM) deposition, and unrestrained tissue fibrosis are the pathogenetic steps responsible for the clinical manifestati

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… In addition, sirolimus treatment inhibited proliferation and collagen production of mouse fibroblasts in a dose-dependent manner [ 106 ]. In a small pilot study, sirolimus and MTX were compared in SSc patients. … Another phase II study of sirolimus treatment in SSc was planned and registered but the current status is unknown ( NCT03365869 ). …

Immunosuppression in Glomerular Diseases: Implications for SARS-CoV-2 Vaccines and COVID-19.

BackgroundGlomerular diseases (GD) are chronic conditions that often involve immune dysfunction and require immunosuppressive therapy (IST) to control underlying pathogenesis. Unfortunately, such diseases appear to heighten risks of severe outcomes in COVID-19 and predispose to other infections that may be life-threatening. Thus, averting preventable infections is imperative in GD patients.SummaryThe advent of vaccines demonstrated to be safe and efficacious against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has favorably impacted the COVID-19 pandemic epidemiology. However,

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… Of note, these classes of compounds derive from microorganisms (e.g., cyclosporin(e) from the fungus Tolypocladium inflatum ; tacrolimus from the bacterium Streptomyces tsukubaensis ; and sirolimus from the bacterium Streptomyces hygroscopicus ) that apparently evolved them to modulate the immune system … Interestingly, data from vaccine studies in rhesus macaques indicate that mTOR inhibitors such as sirolimus may enhance viral-specific CD8+ Tc responses [ 64 ]. …

Transfusion Burden in Allogeneic Hematopoietic Stem Cell Transplantation over Time: Experience from a Single Institution.

IntroductionTransfusion plays a main role in supportive treatment for patients who receive an allogeneic hematopoietic stem cell transplantation (HSCT). In this study, we compare the transfusion requirements of patients undergoing different modalities of HSCT according to different time periods. The objective is to assess the evolution of HSCT transfusion requirements over time, from a single institution.MethodsThe clinical charts and transfusion records of patients who underwent HSCT of different modalities at La Fe University Hospital during a twelve-year period were reviewed (2009-2020). Fo

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… Uniform graft-versus-host disease prophylaxis with posttransplant cyclophosphamide, sirolimus, and mycophenolate mofetil following hematopoietic stem cell transplantation from haploidentical, matched sibling and unrelated donors. … Post-transplant cyclophosphamide and sirolimus based graft-versus-host disease prophylaxis after allogeneic stem cell transplantation for acute myeloid leukemia. Bone Marrow Transpl. 2022;57:1389–1398. doi: 10.1038/s41409-022-01725-3. 13. …

Successful treatment of an adult with Kasabach-Merritt syndrome using thalidomide, vincristine, and prednisone.

ObjectiveKasabach-Merritt syndrome is a rare disease that mainly occurs in infants and adolescents. It usually manifests as disseminated intravascular coagulation and severe bleeding, and is associated with high mortality. However, its low incidence and clinical rarity in adults mean that there is currently no well-verified treatment regimen for this disease. We report on an effective novel therapeutic regimen in a patient with Kasabach-Merritt syndrome.MethodsA woman with Kasabach-Merritt syndrome presented with a recurrent subcutaneous mass and disseminated intravascular coagulation, and was

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… If regression cannot be achieved by the above treatments, cytotoxic drugs, interferon, and mTOR inhibitors such as sirolimus may also be used. 22 In summary, KMS is a rare cause of DIC in adults. … J Pediatr 2013 ; 163 : 285 – 291 . 23796341 10.1016/j.jpeds.2013.03.080 22 Wang Z Li K Dong K et al Refractory Kasabach-Merritt phenomenon successfully treated with sirolimus, and a mini-review of the published work. J Dermatol 2015 ; 42 : 401 – 404 . 25728547 10.1111/1346-8138.12797 …

Endothelial cell function and endothelial-related disorders following haematopoietic cell transplantation.

Use of haematopoietic cell transplantation (HCT) in the treatment of haematologic and neoplastic diseases may lead to life-threatening complications that cause substantial morbidity and mortality if untreated. In addition to patient- and disease-related factors, toxicity associated with HCT puts patients at risk for complications that share a similar pathophysiology involving endothelial cells (ECs). Normally, the endothelium plays a role in maintaining homeostasis, including regulation of coagulation, vascular tone, permeability and inflammatory processes. When activated, ECs acquire cellular

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… While sirolimus worsens the effect of CNIs, it has not been shown to damage ECs. … Sirolimus is associated with veno‐occlusive disease of the liver after myeloablative allogeneic stem cell transplantation. Blood. 2008;112:4425–31. 70. Roeker LE, Kim HT, Glotzbecker B, Nageshwar P, Nikiforow S, Koreth J, et al. …

Classic Kaposi Sarcoma: Current Treatment Strategies and Emerging Therapeutic Approaches.

Classic Kaposi sarcoma (CKS) is a rare vascular neoplasm driven by infection with Kaposi sarcoma-associated herpesvirus (KSHV) and characterized by a heterogeneous geographic distribution. While the etiology of other Kaposi's sarcoma (KS) variants is well established, the underlying mechanisms of CKS appear multifactorial, with several risk factors, among which advanced age and male sex are most significant. Due to the rarity of CKS and its often indolent clinical course, clinical trials are sparse, and current knowledge of therapeutic approaches remains limited. Most available clinical trials

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… mTOR inhibitors, such as sirolimus and temsirolimus, reduce VEGF secretion [ 66 ] and are effective in post-transplant KS, where switching from calcineurin inhibitors to sirolimus is common [ 67 ]. … However, sirolimus has not demonstrated meaningful benefit in classic KS, as its immunosuppressive effects may outweigh its antitumor activity [ 68 ]. …

An Update in Drug-Induced Thrombotic Microangiopathy.

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… The inhibitors of the mechanistic target of rapamycin (mTOR), can also cause DITMA, most frequently associated with sirolimus or tacrolimus administration, than everolimus ( 60 – 62 ). … Thrombotic microangiopathy associated with sirolimus level after allogeneic hematopoietic cell transplantation with tacrolimus/sirolimus-based graft-versus-host disease prophylaxis . Biol Blood Marrow Transpl . ( 2013 ) 19 : 298 – 304 . 10.1016/j.bbmt.2012.10.006 23078784 PMC3589900 63. …