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Journal of the American College of... Nov 2022
Topics: Humans; Sirolimus; Myocardial Infarction; Drug-Eluting Stents; Percutaneous Coronary Intervention; Treatment Outcome; ST Elevation Myocardial Infarction
PubMed: 36328692
DOI: 10.1016/j.jacc.2022.08.796 -
Frontiers in Bioscience (Landmark... Jan 2022Local treatment of the airways and lung parenchyma has been used in clinical practice for several years for a variety of diseases. (Review)
Review
INTRODUCTION
Local treatment of the airways and lung parenchyma has been used in clinical practice for several years for a variety of diseases.
METHODS
A variety of endoscopic tools for local treatment exist, especially for treating malignancies. Using these endoscopic tools, one can administer drugs specifically designed for the airways.
DISCUSSION
This article presents all locally administered treatment options and provides useful insights for future local endoscopically applied treatments.
Topics: Drug-Eluting Stents; Everolimus; Sirolimus; Treatment Outcome
PubMed: 35090341
DOI: 10.31083/j.fbl2701036 -
Blood Jan 2023mTOR inhibitors such as sirolimus are increasingly used in the management of multilineage immune cytopenia (m-IC) in children. Although sirolimus is effective in...
mTOR inhibitors such as sirolimus are increasingly used in the management of multilineage immune cytopenia (m-IC) in children. Although sirolimus is effective in improving IC, it is unclear how sirolimus affects the broader immune dysregulation associated with m-IC. We profiled T- and B-cell subsets longitudinally and measured cytokines and chemokines before and after sirolimus treatment. Eleven of the 12 patients with m-IC who tolerated sirolimus were followed for a median duration of 17 months. All patients had an improvement in IC, and sirolimus therapy did not result in significant decreases in T-, B- and NK-cell numbers. However, the expansion and activation of circulating T follicular helper and the Th1 bias noted before the initiation of sirolimus were significantly decreased. Features of chronic T-cell activation and exhaustion within effector memory compartments of CD4+ and CD8+ T cells decreased with sirolimus therapy. Corresponding to these changes, plasma levels of CXCL9 and CXCL10 also decreased. Interestingly, no significant improvement in the proportion of class-switched memory B cells or frequencies of CD4+ naive T cells were noted. Longer follow-up and additional studies are needed to validate these findings and evaluate the effect of sirolimus on B-cell maturation.
Topics: Child; Humans; CD4-Positive T-Lymphocytes; Sirolimus; TOR Serine-Threonine Kinases; B-Lymphocyte Subsets; CD8-Positive T-Lymphocytes
PubMed: 36206504
DOI: 10.1182/blood.2022015966 -
Orphanet Journal of Rare Diseases Feb 2019The treatment of tuberous sclerosis complex (TSC) using mammalian target of rapamycin (mTOR) inhibitors is clinically promising. The aim of the present study was to... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
The treatment of tuberous sclerosis complex (TSC) using mammalian target of rapamycin (mTOR) inhibitors is clinically promising. The aim of the present study was to evaluate the efficacy and safety of mTOR inhibitors for improving the clinical symptoms of TSC.
METHODS
We performed a systematic search of major electronic databases (PubMed, EMBASE, Cochrane Library and WanFang, CNKI, and VIP databases) to identify randomized controlled trials (RCTs) and quasi-randomized studies from the date of database inception to November 2017; the Chinese Food and Drug Administration and clinicaltrials.gov were also searched for unpublished studies. The endpoints of the study were the tumor response rate and seizure frequency response rate (the proportion of patients achieving a ≥ 50% reduction relative to the baseline). Two researchers screened articles, assessed the risk of bias and extracted data independently. The included RCTs were analyzed using RevMan 5.3, which was provided by the Cochrane Collaboration.
RESULTS
Compared with the placebo, mTOR inhibitors significantly reduced tumor volume in both angiomyolipoma (AML) (RR = 24.69, 95% CI = 3.51,173.41, P = 0.001) and subependymal giant cell astrocytoma (SEGA) (RR = 27.85, 95% CI = 1.74,444.82, P = 0.02). Compared with the placebo, mTOR inhibitors significantly reduced seizure frequency (RR = 2.12, 95% CI = 1.41,3.19, P = 0.0003). Regarding safety, compared with patients who did not receive mTOR inhibitors, those who did had a higher risk of suffering stomatitis (RR = 3.20, 95% CI = 1.49,6.86, P = 0.003). In contrast, patients who did and did not receive mTOR inhibitors experienced similar adverse events, such as upper respiratory tract infections (RR = 1.08, 95% CI = 0.81,1.45, P = 0.59) and nasopharyngitis (RR = 0.86, 95% CI = 0.60,1.21, P = 0.38).
CONCLUSION
In view of the efficacy and safety associated with tumor and seizure frequency in the TSC patients, mTOR inhibitors is a good therapeutic choice. Unlike the risks of upper respiratory tract infections and nasopharyngitis, mTOR inhibitors seem to increase the risk of stomatitis, mostly grade 1 and 2.
Topics: Humans; Sirolimus; TOR Serine-Threonine Kinases; Tuberous Sclerosis
PubMed: 30760308
DOI: 10.1186/s13023-019-1012-x -
Frontiers in Immunology 2022Immunocompromised (IC) patients show diminished immune response to COVID-19 mRNA vaccines (Co-mV). To date, there is no 'empirical' evidence to link the perturbation of...
BACKGROUND
Immunocompromised (IC) patients show diminished immune response to COVID-19 mRNA vaccines (Co-mV). To date, there is no 'empirical' evidence to link the perturbation of translation, a rate-limiting step for mRNA vaccine efficiency (VE), to the dampened response of Co-mV.
MATERIALS AND METHODS
Impact of immunosuppressants (ISs), tacrolimus (T), mycophenolate (M), rapamycin/sirolimus (S), and their combinations on Pfizer Co-mV translation were determined by the Spike (Sp) protein expression following Co-mV transfection in HEK293 cells. impact of ISs on SARS-CoV-2 spike specific antigen (SpAg) and associated antibody levels (IgG) in serum were assessed in Balb/c mice after two doses (2D) of the Pfizer vaccine. Spike Ag and IgG levels were assessed in 259 IC patients and 50 healthy controls (HC) who received 2D of Pfizer or Moderna Co-mV as well as in 67 immunosuppressed solid organ transplant (SOT) patients and 843 non-transplanted (NT) subjects following three doses (3D) of Co-mV. Higher Co-mV concentrations and transient drug holidays were evaluated.
RESULTS
We observed significantly lower IgG response in IC patients (p<0.0001) compared to their matched controls in 2D and 3D Co-mV groups. IC patients on M or S showed a profound dampening of IgG response relative to those that were not on these drugs. M and S, when used individually or in combination, significantly attenuated the Co-mV-induced Sp expression, whereas T did not exert significant influence. Sirolimus combo pretreatment significantly attenuated the Co-mV induced IgM and IgG production, which correlated with a decreasing trend in the early levels (after day 1) of Co-mV induced Sp immunogen levels. Neither higher Co-mV concentrations (6μg) nor withholding S for 1-day could overcome the inhibition of Sp protein levels. Interestingly, 3-days S holiday or using T alone rescued Sp levels
CONCLUSIONS
This is the first study to demonstrate that ISs, sirolimus and mycophenolate inhibited Co-mV-induced Sp protein synthesis translation repression. Selective use of tacrolimus or drug holiday of sirolimus can be a potential means to rescue translation-dependent Sp protein production. These findings lay a strong foundation for guiding future studies aimed at improving Co-mV responses in high-risk IC patients.
Topics: Mice; Animals; Humans; COVID-19 Vaccines; Tacrolimus; HEK293 Cells; COVID-19; SARS-CoV-2; Immunoglobulin G; Sirolimus; mRNA Vaccines
PubMed: 36389788
DOI: 10.3389/fimmu.2022.1020165 -
Transplantation and Cellular Therapy Jun 2023Sirolimus is an inhibitor of the mammalian target of rapamycin (mTOR) and is emerging as a promising component of graft-versus-host disease (GVHD) prophylaxis regimens...
Sirolimus is an inhibitor of the mammalian target of rapamycin (mTOR) and is emerging as a promising component of graft-versus-host disease (GVHD) prophylaxis regimens in the context of allogeneic hematopoietic stem cell transplantation (HSCT). Multiple studies have explored the clinical benefits of adding sirolimus to GVHD prophylaxis; however, detailed immunologic studies have not yet been carried out in this context. Mechanistically, mTOR is at the center of metabolic regulation in T cells and natural killer (NK) cells and is critical for their differentiation to mature effector cells. Therefore, close evaluation of the inhibition of mTOR in the context of immune reconstitution post-HSCT is warranted. In this work, we studied the effect of sirolimus on immune reconstitution using a biobank of longitudinal samples from patients receiving either tacrolimus/sirolimus (TAC/SIR) or cyclosporin A/methotrexate (CSA/MTX) as conventional GVHD prophylaxis. Healthy donor controls, donor graft material, and samples from 28 patients (14 with TAC/SIR, 14 with CSA/MTX) at 3 to 4 weeks and 34 to 39 weeks post- HSCT were collected. Multicolor flow cytometry was used to perform broad immune cell mapping, with a focus on NK cells. NK cell proliferation was evaluated over a 6-day in vitro homeostatic proliferation protocol. Furthermore, in vitro NK cell responses to cytokine stimulation or tumor cells were evaluated. Systems-level assessment of the immune repertoire revealed a deep and prolonged suppression (weeks 34 to 39 post-HSCT) of the naïve CD4 T cell compartment with relative sparing of regulatory T cells and enrichment of CD69Ki-67HLA-DR CD8 T cells, independent of the type of GVHD prophylaxis. Early after transplantation (weeks 3 to 4), while patients were still on TAC/SIR or CSA/MTX, we found a relative increase in less-differentiated CD56 NK cells and NKG2ACD57KIR CD56 NK cells and a distinct loss of CD16 and DNAM-1 expression. Both regimens led to suppressed proliferative responses ex vivo and functional impairment with preferential loss of cytokine responsiveness and IFN-γ production. Patients who received TAC/SIR as GVHD prophylaxis showed delayed NK cell reconstitution with lower overall NK cell counts and fewer CD56 and NKG2A CD56 NK cells. Treatment with sirolimus-containing regimens generated similar immune cell profiles as conventional prophylaxis; however, the NK cell compartment seemed to be composed of slightly more mature NK cells. These effects were also present after the completion of GVHD prophylaxis, suggesting that mTOR inhibition with sirolimus leaves a lasting imprint on homeostatic proliferation and NK cell reconstitution following HSCT.
Topics: Humans; Sirolimus; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Killer Cells, Natural; Methotrexate; Cytokines; TOR Serine-Threonine Kinases
PubMed: 36966873
DOI: 10.1016/j.jtct.2023.03.023 -
Journal of Hematology & Oncology Nov 2010Discovery of new treatments for lymphoma that prolong survival and are less toxic than currently available agents represents an urgent unmet need. We now have a better... (Review)
Review
Discovery of new treatments for lymphoma that prolong survival and are less toxic than currently available agents represents an urgent unmet need. We now have a better understanding of the molecular pathogenesis of lymphoma, such as aberrant signal transduction pathways, which have led to the discovery and development of targeted therapeutics. The ubiquitin-proteasome and the Akt/mammalian target of rapamycin (mTOR) pathways are examples of pathological mechanisms that are being targeted in drug development efforts. Bortezomib (a small molecule protease inhibitor) and the mTOR inhibitors temsirolimus, everolimus, and ridaforolimus are some of the targeted therapies currently being studied in the treatment of aggressive, relapsed/refractory lymphoma. This review will discuss the rationale for and summarize the reported findings of initial and ongoing investigations of mTOR inhibitors and other small molecule targeted therapies in the treatment of lymphoma.
Topics: Boronic Acids; Bortezomib; Everolimus; Humans; Lymphoma; Molecular Targeted Therapy; Pyrazines; Signal Transduction; Sirolimus; Survival Analysis
PubMed: 21092307
DOI: 10.1186/1756-8722-3-45 -
Molecular Systems Biology Dec 2010The mammalian target of rapamycin (mTOR) is a central regulator of cell growth and proliferation. mTOR signaling is frequently dysregulated in oncogenic cells, and thus... (Review)
Review
The mammalian target of rapamycin (mTOR) is a central regulator of cell growth and proliferation. mTOR signaling is frequently dysregulated in oncogenic cells, and thus an attractive target for anticancer therapy. Using CellDesigner, a modeling support software for graphical notation, we present herein a comprehensive map of the mTOR signaling network, which includes 964 species connected by 777 reactions. The map complies with both the systems biology markup language (SBML) and graphical notation (SBGN) for computational analysis and graphical representation, respectively. As captured in the mTOR map, we review and discuss our current understanding of the mTOR signaling network and highlight the impact of mTOR feedback and crosstalk regulations on drug-based cancer therapy. This map is available on the Payao platform, a Web 2.0 based community-wide interactive process for creating more accurate and information-rich databases. Thus, this comprehensive map of the mTOR network will serve as a tool to facilitate systems-level study of up-to-date mTOR network components and signaling events toward the discovery of novel regulatory processes and therapeutic strategies for cancer.
Topics: Antineoplastic Agents; Gene Regulatory Networks; Humans; Models, Biological; Neoplasms; Protein Interaction Mapping; Signal Transduction; Sirolimus; Systems Biology; TOR Serine-Threonine Kinases
PubMed: 21179025
DOI: 10.1038/msb.2010.108 -
Kidney International Aug 2009Posttransplant anemia is a common problem that may hinder patients' quality of life. It occurs in 12 to 76% of patients, and is most common in the immediate... (Review)
Review
Posttransplant anemia is a common problem that may hinder patients' quality of life. It occurs in 12 to 76% of patients, and is most common in the immediate posttransplant period. A variety of factors have been identified that increase the risk of posttransplant anemia, of which the level of renal function is most important. Sirolimus, a mammalian target of rapamycin inhibitor, has been implicated as playing a special role in posttransplant anemia. This review considers anemia associated with sirolimus, including its presentation, mechanisms, and management.
Topics: Anemia; Humans; Immunosuppressive Agents; Kidney Transplantation; Sirolimus
PubMed: 19553912
DOI: 10.1038/ki.2009.231 -
Oxidative Medicine and Cellular... 2017Tuberous sclerosis complex (TSC) is a genetic condition characterized by the presence of benign, noninvasive, and tumor-like lesions called hamartomas that can affect... (Review)
Review
Tuberous sclerosis complex (TSC) is a genetic condition characterized by the presence of benign, noninvasive, and tumor-like lesions called hamartomas that can affect multiple organ systems and are responsible for the clinical features of the disease. In the majority of cases, TSC results from mutations in the and genes, leading to the overactivation of the mammalian target of rapamycin (mTOR) signalling pathway, which controls several cell functions, including cell growth, proliferation, and survival. The establishment of a connection between TSC and mTOR led to the clinical use of drugs known as mTOR inhibitors (like rapamycin, also known as sirolimus and everolimus), which are becoming an increasingly interesting tool in the management of TSC-associated features, such as subependymal giant cell astrocytomas, renal angiomyolipomas, and also epilepsy. However, the intrinsic characteristics of these drugs and their systemic effects in such a heterogeneous condition pose many challenges in clinical practice, so that some questions remain unanswered. This article provides an overview of the pharmacological aspects of mTOR inhibitors about the clinical trials leading to their approval in TSC-related conditions and exposes current challenges and future directions associated with this promising therapeutic line.
Topics: Enzyme Inhibitors; Humans; Molecular Structure; Pharmacology; Sirolimus; TOR Serine-Threonine Kinases; Tuberous Sclerosis
PubMed: 28386314
DOI: 10.1155/2017/9820181