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Insulin Resistance at the Crossroads of Metabolic Inflammation, Cardiovascular Disease, Organ Failure and Cancer.

Insulin resistance (IR) describes impaired hormone signaling that triggers compensatory homeostatic responses resulting in hyperinsulinemia, increased accumulation of fatty substrates, lipotoxicity, oxidative stress, inflammation, cell death and fibrosis in target tissues. These processes ultimately lead to organ dysfunction and predispose certain individuals to various types of cancer. In this context, we will review the molecular pathogenesis and clinical significance of IR, its role in 'metaflammation', and the damage caused by IR in the pancreas, cardiovascular system, liver, and kidneys.

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… . | Cyclosporin A and sirolimus are immunosuppressive agents that have been linked to the development of dyslipidemia, IR, and new-onset diabetes following transplantation. | [ 44 ] | Maintaining a healthy lifestyle, avoiding high-risk medications, and controlling glucose early help preserve insulin … Molecular mechanisms underlying the effects of cyclosporin A and sirolimus on glucose and lipid metabolism in liver, skeletal muscle and adipose tissue in an in vivo rat model. Biochem. Pharmacol. 2014;88:216–228. doi: 10.1016/j.bcp.2014.01.020. 45. Kang I., Kim S.-W., Youn J.H. …

Defibrotide for Protecting Against and Managing Endothelial Injury in Hematologic Malignancies and COVID-19.

Defibrotide, which is approved for treating hepatic veno-occlusive disease (VOD)/sinusoidal obstruction syndrome (SOS), exhibits pleiotropic anti-inflammatory, anti-thrombotic, and fibrinolytic properties, conferring broad endothelial protective effects. Given these mechanisms, defibrotide has potential utility in various conditions involving endothelial injury or activation. In this review we outline the endothelial-protective mechanisms of defibrotide and comprehensively summarize current evidence supporting its applications in hematologic malignancies, including the prevention and treatment

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… DF has been shown to have a protective effect against the proinflammatory and prothrombotic effects of cyclosporine A and tacrolimus plus sirolimus on microvascular endothelial cells, attenuating the increased expression of ICAM-1 and elevated extracellular matrix reactivity [ 22 ]. … Distinct deleterious effects of cyclosporine and tacrolimus and combined tacrolimus-sirolimus on endothelial cells: Protective effect of defibrotide. Biol. Blood Marrow Transplant. 2013;19:1439–1445. doi: 10.1016/j.bbmt.2013.07.001. 23. …

Assessing Recurrent Acute Rhinosinusitis Development in Posttransplant Patients: A Study on Sinus Surgery Necessity.

OBJECTIVE: Recurrent acute rhinosinusitis (RARS) significantly decreases quality of life. Transplant recipients (TR) are particularly vulnerable to rhinologic conditions. There is a lack of guidelines for managing RARS in this population. Our study aims to determine the prevalence of and risk factors for RARS among TR and assess the need for sinus surgery within this group. STUDY DESIGN: Retrospective cohort. SETTING: Mayo Clinic between 2017 and 2022. METHODS: A total of 1116 patients met the inclusion criteria and were divided based on the presence or absence of a new incident RARS diagno

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… 692 (68.9%) | 81 (73.0%) | .295 | 1.26 | 0.80 | 2.03 Mycophenolate mofetil | 620 (55.6%) | 563 (56.0%) | 57 (51.4%) | .414 | 0.84 | 0.56 | 1.28 Prednisone | 843 (75.5%) | 765 (76.1%) | 78 (70.3%) | .247 | 0.77 | 0.49 | 1.23 Azathioprine | 58 (5.2%) | 52 (5.2%) | 6 (5.4%) | .897 | 1.05 | 0.36 | 2.54 Sirolimus …

Isolation of a Highly Purified HSC-enriched CD34+CD90+CD45RA- Cell Subset for Allogeneic Transplantation in the Nonhuman Primate Large-animal Model.

Allogeneic hematopoietic stem cell transplantation (allo-HCT) is a common treatment for patients suffering from different hematological disorders. Allo-HCT in combination with hematopoietic stem cell (HSC) gene therapy is considered a promising treatment option for millions of patients with HIV+ and acute myeloid leukemia. Most currently available HSC gene therapy approaches target CD34-enriched cell fractions, a heterogeneous mix of mostly progenitor cells and only very few HSCs with long-term multilineage engraftment potential. As a consequence, gene therapy approaches are currently limited

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… Graft versus host disease/rejection prophylaxis starting the day of cell infusion included tacrolimus alone (0.025 mg/kg twice daily, with a target serum level of 5–10 ng/mL) for the first transplant recipient ID A17230, and tacrolimus combined with sirolimus (target serum level of 5–15 ng/mL) for the …

Epidemiologic and Clinical Characteristics of Coronavirus and Bocavirus Respiratory Infections after Allogeneic Stem Cell Transplantation: A Prospective Single-Center Study.

Epidemiologic data about coronaviruses (CoVs) and human bocavirus (HBoV) in the setting of allogeneic hematopoietic stem cell transplantation (allo-HSCT) are scarce. We conducted a prospective longitudinal study on respiratory viral infections (RVIs) in allo-HSCT recipients with respiratory symptoms from December 2013 until June 2016. Respiratory virus in upper and/or lower respiratory tract (URT and LRT) specimens were tested using Luminex xTAG RVP Fast v1 assay. Seventy-nine consecutive allo-HSCT recipients developed a total of 192 virologically documented RVI episodes over 30 months. The me

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… chronic lymphocytic leukemia; MM, multiple myeloma; CR, complete remission; PR, partial remission; ASCT, autologous stem cell transplantation; RIC, reduced-intensity conditioning; Flu, fludarabine; Mel, melphalan; Bu, busulfan; Thio, thiotepa; CFM, cyclophosphamide; ATG, antithymocyte globulin; Siro, sirolimus …

A defective lysophosphatidic acid-autophagy axis increases miscarriage risk by restricting decidual macrophage residence.

Massive infiltrated and enriched decidual macrophages (dMφ) have been widely regarded as important regulators of maternal-fetal immune tolerance and trophoblast invasion, contributing to normal pregnancy. However, the characteristics of metabolic profile and the underlying mechanism of dMφ residence remain largely unknown. Here, we observe that dMφ display an active glycerophospholipid metabolism. The activation of ENPP2-lysophosphatidic acid (LPA) facilitates the adhesion and retention, and M2 differentiation of dMφ during normal pregnancy. Mechanistically, this process is mediated through ac

Antiaging Strategies and Remedies: A Landscape of Research Progress and Promise.

Aging is typified by a gradual loss of physiological fitness and accumulation of cellular damage, leading to deteriorated functions and enhanced vulnerability to diseases. Antiaging research has a long history throughout civilization, with many efforts put forth to understand and prevent the effects of aging. Multiple strategies aiming to promote healthy aging and extend the lifespan have been developed including lifestyle adjustments, medical treatments, and social programs. A multitude of antiaging medicines and remedies have also been explored. Here, we use data from the CAS Content Collect

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… Six participants with bilateral GA were enrolled and received intravitreal sirolimus, but no benefit was detected. 412 A following phase II study NCT01675947 enrolled 52 participants with GA for monthly intravitreal sirolimus treatment. …

Targeting Autophagy with Natural Products as a Potential Therapeutic Approach for Cancer.

Macro-autophagy (autophagy) is a highly conserved eukaryotic intracellular process of self-digestion caused by lysosomes on demand, which is upregulated as a survival strategy upon exposure to various stressors, such as metabolic insults, cytotoxic drugs, and alcohol abuse. Paradoxically, autophagy dysfunction also contributes to cancer and aging. It is well known that regulating autophagy by targeting specific regulatory molecules in its machinery can modulate multiple disease processes. Therefore, autophagy represents a significant pharmacological target for drug development and therapeutic

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… Cetuximab | Colorectal Carcinoma | 1/2/C | NCT01252628 | Cascadian Therapeutics Inc - | Glioblastoma | 2/C | NCT01259869 | NCIC Clinical Trials Group Vinblastine | Sirolimus | CNS Tumors | 1/C | NCT01135563 | The Hospital for Sick Children CyP, Cape, Nivolumab | Childhood Lymphoma | 1/2/R | NCT03585465 … While the inhibitor mTOR rapamycin (sirolimus) is known to be a powerful autophagy inducer that extends the lifespan of various organisms, from flies to mammals [ 106 , 107 , 108 ], it has serious adverse effects, including insulin resistance [ 106 ]. …

Роль микроглии в синаптогенезе, синаптической и синаптической пластичности в физиологических условиях и в нарушениях центральной нервной системы.

Микроглии являются постоянными иммунными клетками мозга, которые были широко изучены для их иммунного наблюдения и фагоцитоза. В последние годы постепенно признается важная роль микроглии в синапсовом образовании, ликвидации и пластичности. Синапсы являются основным режимом связи между нейронами. Они постоянно меняются в количестве и пластичности на протяжении всего жизненного цикла, который является основой обучения и памяти. Микроглии являются сильно мотилированными, ветковыми формами, которые осуществляют мониторинг микроокружающей среды центральной нервной системы (КНС) и поощряют синапсов

Natural products as metabolic modulators to enhance cancer immunotherapy: reprogramming the tumor microenvironment.

Cancer remains a major global health challenge, and although immunotherapy has achieved remarkable breakthroughs, its efficacy is often limited by tumor-induced immunosuppression within the tumor microenvironment (TME). Emerging evidence indicates that metabolic reprogramming plays a pivotal role in shaping the TME and regulating antitumor immune responses. Targeting tumor and immune cell metabolism has therefore become a promising strategy to enhance the effectiveness of cancer immunotherapy. This review first summarizes the metabolic reprogramming that occurs within the TME, including altera

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… in Preventing Cancer in Healthy Participants | COMPL-ETED | Unspecified Adult Solid Tumor, Protocol Specific | DRUG: resveratrol NCT02261844 | Resveratrol and Human Hepatocyte Function in Cancer | WITHD-RAWN | Liver Cancer | DIETARY_SUPPLEMENT: Resveratrol|DRUG: Placebo NCT03253913 | Resveratrol and Sirolimus … in Lymphangioleiomyomatosis Trial | COMPL-ETED | Lymphangioleiomyomatosis | DRUG: Sirolimus|DRUG: Resveratrol NCT00920556 | A Clinical Study to Assess the Safety and Activity of SRT501 Alone or in Combination With Bortezomib in Patients With Multiple Myeloma | TERMI-NATED | Multiple Myeloma | DRUG: …

What nature has to offer: Opportunities for immuno-oncology.

Recent rapid development of cancer therapy has come about with the paradigm shift from the traditional goal of targeting cancer cells themselves, to reprograming the immune tumor microenvironment. Accumulating evidence shows that compounds that target epigenetic regulation, called epidrugs, play a crucial role in mediating the immunogenicity of cancer cells and in reshaping antitumor immunity. A large body of literature has recognized natural compounds as epigenetic modulators for their immunomodulatory effects and anticancer potential. Unifying our understanding of the role of these biologica

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… Similarly, resveratrol alone or in combination with rapamycin induced cell death in human bladder cancer cell lines | [ 100 ] Sirolimus (Rapamune, Rapamycin) | Thyroid cancer: in vitro and in vivo | In vitro : compared to single use of rapamycin or resveratrol, co-administration had a synergistic effect … Resveratrol is sensitizing the anti-tumor effects of rapamycin; In vivo : co-administration significantly enhanced the anti-tumor effects than use of any one drug, as shown by the reduction of the tumor growth rate in the xenograft model | [ 101 ] Sirolimus (Rapamune, Rapamycin) | Lymphoma: in vivo | …

Disease-Modifying Therapies for Multiple System Atrophy: Where Are We in 2022?

Multiple system atrophy is a rapidly progressive and fatal neurodegenerative disorder. While numerous preclinical studies suggested efficacy of potentially disease modifying agents, none of those were proven to be effective in large-scale clinical trials. Three major strategies are currently pursued in preclinical and clinical studies attempting to slow down disease progression. These target α-synuclein, neuroinflammation, and restoration of neurotrophic support. This review provides a comprehensive overview on ongoing preclinical and clinical developments of disease modifying therapies. Furth

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… Rapamycin, also known as sirolimus, is an immunosuppressant that specifically inhibits actions of mTOR by allosterically modulating access to the catalytic site of mTOR [ 76 ]. … A phase II randomized controlled study in patients with MSA assessing efficacy of oral sirolimus on slowing disease progression was recently prematurely terminated because meeting the futility criteria ( NCT03589976 ). …

Cancer and the kidney: dangereoux liasons or price paid for the progress in medicine?

A long time ago, the links between renal disease and malignancy were observed, however, quite recently, their importance was recognized and 'new' subspecialty in nephrology, namely 'onconephrology' was established. In the XXI century, patients with malignancy make up the most growing number of the subjects seen for nephrology consult and/or critical care nephrology services. A plethora of renal problems may be found in patients with malignancy. They may influence not only their short-term outcomes but also the adequate therapy of the underlying oncological problem. Thus, all these kidney-relat

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… They also presented a novel strategy to prevent rejection in transplant recipients receiving PD-1 inhibitors using pre-emptive steroids and sirolimus. However, there is not enough data to give specific recommendations for oncology treatment in kidney transplant recipients. … 10.1111/ajt.13978 27575845 167 Wanchoo R Riella LV Uppal NN Lopez CA Nair V Devoe C Jhaveri KD Immune checkpoint inhibitors in the cancer patient with an organ transplant J Onconephrol 2017 1 42 8 10.5301/jo-n.5000006 168 Yanik EL Gustafson SK Kasiske BL Israni AK Snyder JJ Hess GP Engels EA Segev DL Sirolimus …

Current Approaches in the Treatment of Relapsed and Refractory Acute Myeloid Leukemia.

The limited sensitivity of the historical treatment response criteria for acute myeloid leukemia (AML) has resulted in a different paradigm for treatment compared with most other cancers presenting with widely disseminated disease. Initial cytotoxic induction chemotherapy is often able to reduce tumor burden to a level sufficient to meet the current criteria for "complete" remission. Nevertheless, most AML patients ultimately die from their disease, most commonly as clinically evident relapsed AML. Despite a variety of available salvage therapy options, prognosis in patients with relapsed or r

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… Notably, the addition of sirolimus to MEC was evaluated in an arm of the E1906 trial, a phase II study among patients with RR-AML, but closed to accrual early with 15% responses [ 30 ]. … This study randomized patients to either FLAM, carboplatin-topotecan (14% patients achieved CR or CRi), or sirolimus-MEC. …

A Systematic Review of Glioblastoma-Targeted Therapies in Phases II, III, IV Clinical Trials.

Glioblastoma (GBM), the most frequent and aggressive glial tumor, is currently treated as first line by the Stupp protocol, which combines, after surgery, radiotherapy and chemotherapy. For recurrent GBM, in absence of standard treatment or available clinical trials, various protocols including cytotoxic drugs and/or bevacizumab are currently applied. Despite these heavy treatments, the mean overall survival of patients is under 18 months. Many clinical studies are underway. Based on clinicaltrials.org and conducted up to 1 April 2020, this review lists, not only main, but all targeted therapi

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… Sirolimus (rapamycin) showed promising preclinical results by decreasing 95% tumor mass in vivo [ 189 ]. In addition, it also decreased the proliferation of GICs [ 190 ] and their differentiation [ 191 ]. … Despite these results, sirolimus combined with erlotinib is not effective in GBM recurrence ( NCT00672243 , Table 2 ) [ 116 ]. Similar results were observed with everolimus. …

Temsirolimus in the treatment of relapsed and/or refractory mantle cell lymphoma.

Patients with mantle cell lymphoma (MCL) have a poor prognosis; consequently, new therapeutic approaches, such as rapamycin and its derivates, mammalian target of rapamycin (mTOR) inhibitors, are warranted. Temsirolimus (also known as CCI-779), a dihydroester of rapamycin, in MCL cell lines inhibited mTOR, downregulated p21 and v-Raf, and induced autophagy. The first clinical trial in MCL patients was performed using 250 mg of temsirolimus weekly for 6-12 cycles. The overall response rate was 38%; the median time to progression was 6.5 months, median overall survival was 12 months, and the med…

Septic shock in the immunocompromised cancer patient: a narrative review.

Immunosuppressed patients, particularly those with cancer, represent a momentous and increasing portion of the population, especially as cancer incidence rises with population growth and aging. These patients are at a heightened risk of developing severe infections, including sepsis and septic shock, due to multiple immunologic defects such as neutropenia, lymphopenia, and T and B-cell impairment. The diverse and complex nature of these immunologic profiles, compounded by the concomitant use of immunosuppressive therapies (e.g., corticosteroids, cytotoxic drugs, and immunotherapy), superimpose

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… neutropenia Steroids; basiliximab; antithymocyte globulin; tacrolimus; mycophenolate mofetil; belatacept Chemotherapy; steroids; asplenia; rituximab; CAR-T cells; allogeneic bone marrow transplant Steroids;fludarabine; cyclophosphamide; methotrexate; azathioprine; alemtuzumab;; cyclosporine;mTOR inhibitors (sirolimus … Steroids; basiliximab; antithymocyte globulin; tacrolimus; mycophenolate mofetil; belatacept | Chemotherapy; steroids; asplenia; rituximab; CAR-T cells; allogeneic bone marrow transplant | Steroids;fludarabine; cyclophosphamide; methotrexate; azathioprine; alemtuzumab;; cyclosporine;mTOR inhibitors (sirolimus …

From HDAC to Voltage-Gated Ion Channels: What's Next? The Long Road of Antiepileptic Drugs Repositioning in Cancer.

Cancer is a major health burden worldwide. Although the plethora of molecular targets identified in the last decades and the deriving developed treatments, which significantly improved patients' outcome, the occurrence of resistance to therapies remains the major cause of relapse and mortality. Thus, efforts in identifying new markers to be exploited as molecular targets in cancer therapy are needed. This review will first give a glance on the diagnostic and therapeutic significance of histone deacetylase (HDAC) and voltage gated ion channels (VGICs) in cancer. Nevertheless, HDAC and VGICs hav

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… Despite this, a Phase II clinical trials sponsored by Georgetown University started in 2021 with the scope of evaluating the efficacy and safety of the mTOR inhibitor SM-88 (a modified dysfunctional tyrosine) in combination with three subtherapeutic conditioning agents (PHT, methoxsalen and sirolimus … In a recent Phase II trial on high-risk, biochemically recurrent, non-metastatic prostate cancer (BRPC), PHT was used only as an adjuvant, together with methoxsalen and sirolimus, to enhance the antineoplastic effects of the amino-acid analogue Racemetyrosine (SM-88). …

Incidence of malignancies after lung transplantation and their effect on the outcome. 26 years' experience.

BackgroundMalignancy is a significant, life-limiting complication after lung transplantation (LuTx) and the second common long-term cause of death. We aimed to investigate its incidence and effect on the outcome.MethodsThis is a retrospective observational study. Between 1996 and 2022, n = 627 lung transplantations (LuTx) were performed in our department. We used our institutional database to identify recipients with malignancies after LuTx and examined the malignancies' incidence and mortality.ResultsN = 59 malignancies occurred in n = 55 (8.8%) LuTx recipients. The post-LTx malignancies inci

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… In case of post-LuTx malignancy, a multidisiplinary approach through transplant team and oncological board was applied, an individualized reduction and adjustment of the immunosuppression, such as the use of Sirolimus-based immunosupression, as well as a multidisciplinary “case-by-cases” tumor treatment …

Third party, umbilical cord blood derived regulatory T-cells for prevention of graft versus host disease in allogeneic hematopoietic stem cell transplantation: feasibility, safety and immune reconstitution.

Incubation of umbilical cord blood (UCB) derived regulatory T-cells (Tregs) with fucosyltransferase enzyme improves their ability to home to the target tissue to prevent graft vs. host disease (GVHD). We report results of 5 patients (Double UCB Transplant, n=2; Peripheral Blood Matched Unrelated Donor Transplant, n=3) who received UCB-Tregs (Dose level = 1×106/kg), infused one day prior to the donor graft. All patients received their designated UCB-Treg dose without any infusion reaction. The ratio of conventional T-cells in donor graft was at least 10 times higher than infused UCB-Tregs (rati

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… GVHD prophylaxis included mycophenolate-mofetil 1.5 gram intravenously (IV) or orally (PO) twice daily from day −3 to +30 in combination with oral sirolimus with loading dose of 12 mg followed by 4 mg daily and target through level between 3-12 ug/mL from day −3 to day +100. …