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The Relevance of Mass Spectrometry Analysis for Personalized Medicine through Its Successful Application in Cancer "Omics".

Mass spectrometry (MS) is an essential analytical technology on which the emerging omics domains; such as genomics; transcriptomics; proteomics and metabolomics; are based. This quantifiable technique allows for the identification of thousands of proteins from cell culture; bodily fluids or tissue using either global or targeted strategies; or detection of biologically active metabolites in ultra amounts. The routine performance of MS technology in the oncological field provides a better understanding of human diseases in terms of pathophysiology; prevention; diagnosis and treatment; as well a

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… Sirolimus is one such immunosuppressive drug which is used to prevent transplant rejection and to treat immune mediated diseases [ 94 ]. … Firstly; to quantify the amount of Sirolimus from whole blood LC-tandem mass spectrometry using solid-phase extraction was performed [ 102 ]. Secondly; HPLC/electrospray-mass spectrometry was used to quantify sirolimus and its metabolites from the blood of kidney graft patients [ 103 ]. …

Selected Abstracts from the 13th Annual Meeting of the Clinical Immunology Society: 2022 Annual Meeting: Immune Deficiency and Dysregulation North American Conference

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… The patient was subsequently started on sirolimus (rapamycin), which inhibits mTOR, a downstream effector of PI3K, and has previously been shown to decrease lymphoproliferation and improve clinical symptoms. The patient in this case has had an excellent clinical response to sirolimus. … Patients with gastrointestinal manifestations of APDS may benefit from targeted treatment with sirolimus, especially if there has been progression despite the use of other immunosuppressants. …

Доклад по делу: Синдром Рефрактора Эванса two Пациенты, страдающие спондилоэндродисплазией с иммунной дисрегуляцией, успешно лечились с ингибицией JAK1/JAK2.

Biallelic мутации в гене ACP5 вызывают спондилоэндхондрисплазию с иммунной дисрегуляцией (SPENCDI). Для СЕНКОДИ характерна фенотипическая триада скелетной дисфункции, врожденная и адаптивная иммунная дисфункция, а также переменные неврологические результаты, начиная от асимптоматических кальцинаций мозга и заканчивая сильной задержкой в развитии и прививкой. Регулирование иммунной дискриминации в СИННКДИ часто является отходом от стандартного иммунодепрессивного лечения. Здесь мы представляем примеры two :: пациенты, страдающие синдромом SNNCDI и аутоиммунной цитопенией, которые продемонстриро

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… Various other combinations of immunosuppressive therapies including immunoglobulins (IVIG), rituximab, sirolimus, bortezomib and mycophenolate mofetil (MMF) failed to improve his cytopenias or caused severe side effects, such as transaminitis (sirolimus) and anaphylaxis (bortezomib), ultimately necessitating … bilateral cerebellar calcifications Cytokine testing (Luminex) IFNa2 (pg/mL) | 136.8 | 224.69 IL-1Ralpha (pg/mL) | 17008398.6 | 521.06 IL-6 (pg/mL) | 3421.89 | 9.38 IL-18 (pg/mL) | NA | 490.84 TNF-alpha (pg/mL) | 1052.83 | 25.93 Therapy prior to ruxolitinib treatment | Prolonged therapy with steroids, sirolimus …

Adverse Effects of Virus-Specific T-Cell Therapy: An Integrative Review.

Allogeneic hematopoietic stem cell transplant (HSCT) remains the mainstay in treating many hematologic malignancies. T-cell-depleted grafts designed to reduce graft-vs.-host disease (GVHD) may be complicated by severe viral infections that increase morbidity and mortality. Despite the use of antiviral pharmacologic therapy, challenges in controlling viral infections include drug resistance and/or side-effect intolerability. Virus-specific T-cell (VST) therapy is a promising targeted therapy for treating severe or drug-refractory viral infections after HSCT. An integrative review was conducted

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… This complication is primarily treated with supportive care, which includes the elimination of toxic agents, such as calcineurin inhibitors and sirolimus (two commonly used immunosuppressive medications), as well as preservation of renal function and adequate antimicrobial treatment ( Ho et al., 2005 … Leen and colleagues ( 2013 ) also reported that TA-TMA is a complication that occurs in allogeneic HSCT recipients, particularly in those receiving sirolimus. The authors reported two patients who developed TA-TMA (n = 50), both of whom were receiving sirolimus ( Leen et al., 2013 ). …

Safety and efficacy of daratumumab in immune thrombocytopenia.

AbstractResistance to B-cell-targeted therapies in immune thrombocytopenia (ITP) has been linked to persistence of autoantibody-producing CD38+ long-lived plasma cells. CD38 antibody daratumumab has been proposed as a potential therapy for ITP. This multicenter, open-label, phase 2 study evaluated safety and efficacy of daratumumab in 21 patients with previously treated ITP. Following a safety run-in, 2 dosing cohorts received 8 and 10 subcutaneous injections of 1800 mg daratumumab weekly, respectively. Primary end points were safety and response (2 consecutive platelet counts ≥50 × 109/L at w

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… At the point of evaluation of response, concomitant therapy was administered to 8 of 21 patients, including TPO-RA only (n = 1), corticosteroids (n = 2), both (n = 4), and TPO-RA with sirolimus (n = 1). … At the point of evaluation of response, concomitant therapy was administered to 8 of 21 patients, including TPO-RA only (n = 1), corticosteroids (n = 2), both (n = 4), and TPO-RA with sirolimus (n = 1). …

History of hematopoietic cell transplantation: challenges and progress.

After more than 60 years of research in allogeneic hematopoietic cell transplantation (HCT), this therapy has advanced from one that was declared dead in the 1960s to a standard treatment of otherwise fatal malignant and non-malignant blood diseases. To date, close to 1.5 million hematopoietic cell transplants have been performed in more than 1,500 transplantation centers worldwide. This review will highlight the enormous efforts by numerous investigators throughout the world who have brought the experimental field of HCT to clinical reality, examine ongoing challenges, and provide insights fo

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… The addition of sirolimus to the graft-versus-host disease prophylaxis regimen in reduced intensity allogeneic stem cell transplantation for lymphoma: a multicentre randomized trial. Br J Haematol. 2016;173(1):96-104. 84. Sandmaier BM, Kornblit B, Storer BE, et al. … A randomized phase II trial of tacrolimus, mycophenolate mofetil and sirolimus after non-myeloablative unrelated donor transplantation. Haematologica. 2014;99(10): 1624-1631. 86. Hogan WJ, Little MT, Zellmer E, et al. …

A case report on the treatment of autoimmune hemolytic anemia after CBT by daratumumab in a mucopolysaccharidosis type III patient.

RATIONALE: Mucopolysaccharidosis type III, also referred to as Sanfilippo disease, is a rare hereditary lysosomal storage illness and one of the more common variants. The illness can affect all tissues and organs of the body, with the central nervous system being the most profoundly impacted. Autoimmune hemolytic anemia (AIHA) is a rare, diverse, antibody-mediated disorder characterized by the production of antibodies that target and destroy red blood cells, leading to their rapid destruction. AIHA is a prevalent and notable complication in recipients following umbilical cord blood stem cell t

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… | 20 | 16 mg/kg/dose | 16 mg/kg/dose | 16 mg/kg/dose | 16 mg/kg/dose | 16 mg/kg/dose Diagnosis by AIHA for the initial daratumumab | 8 | 7 | 3 | 5 | 9 | 3 | 17 | 9 | 11 Joint therapy | Prednisone | Prednisone | Eltrombopag | Prednisone | Corticosteroids | Deferoxamine, corticosteroids | Bortezomib, sirolimus … , MMF, ibrutinib, Cy, ATG | MMF, plasmapheresis | MMF, sirolimus, eculizumab Uses of daratumumab (n) | 6 | 3 | 6 | 6 | 6 | 8 | 11 | 4 | 7 Post daratumumab RBC transfusions following the initial/final daratumumab dosage (n/n) | 3/1 | 1/0 | 0/0 | 0/0 | 0/0 | 0/1 | – | – | – Duration from the last daratumumab …

Elevated Galectin-3 Plasma Concentrations in Recipients of Allogeneic Hematopoietic Cell Transplantation.

Galectin-3 is a beta-galactoside-binding lectin with an established association to inflammatory and fibrotic conditions. We investigated galectin-3 levels in 68 recipients of allogeneic hematopoietic cell transplantation (HCT) to look for associations with chronic graft-versus-host disease (cGVHD). Plasma galectin-3 concentrations were measured at 1 year post-HCT and correlated with clinical data collected from individual medical records. The median serum galectin-3 level at that time point was 14.9 ng/mL (range, 5.5-61.6), which was significantly higher than that among healthy controls (14.9

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… Tacrolimus/sirolimus-based strategies ( n = 61, 90%) were primarily used for GVHD prophylaxis. Four patients (6%) received anti-thymocyte globulin as part of their GVHD prophylaxis. Thirteen patients (19%) had previous acute GVHD. Table 1 Patient demographics and transplant characteristics. … Mismatched unrelated donor | 6 (9) Umbilical cord blood | 1 (1) Graft source, n (%) | Peripheral blood | 63 (93) Bone marrow | 4 (6) Umbilical cord | 1 (1) Conditioning intensity, n (%) | Myeloablative | 7 (10) Reduced intensity or non-myeloablative | 61 (90) GVHD prophylaxis, n (%) | Tacrolimus/sirolimus …

A prospective clinical trial of GVHD prophylaxis with posttransplant cyclophosphamide and abatacept.

AbstractWe conducted a prospective randomized clinical trial to investigate the combination of posttransplant cyclophosphamide (PTCy) and abatacept (Aba) for graft-versus-host disease (GVHD) prophylaxis. Patients with hematologic malignancies undergoing an allogeneic transplant from an 8/8 matched related or unrelated donor were randomized 1:1 to tacrolimus and methotrexate (standard-of-care arm [SOC]) or PTCy on days +3 and +4, followed by Aba on an extended schedule: days +5, +14, and +28, and every 4 weeks up to day +168 (PTCy+Aba). All patients received peripherally collected stem cells. T

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… For instance, long-term follow-up of a phase 2 study in pediatric patients undergoing haploidentical HSCT for nonmalignant diseases showed reduced chronic GVHD when PTCy was combined with extended-dose Aba (starting day 0 and continued until 6 months after HSCT) and sirolimus. 23 Similarly, a phase 1b … successful novel solution: cytotoxic T-lymphocyte-associated protein 4-immunoglobulin blockade for GVHD prophylaxis Cell Transpl 33 2024 9636897241265249 10.1177/09636897241265249 PMC11289812 39076086 25 Jaiswal SR Bhakuni P Aiyer HM Soni M Bansal S Chakrabarti S CTLA4Ig in an extended schedule along with sirolimus …

Clinical Outcomes and Treatment Strategies of Adult Transplant-Associated Thrombotic Microangiopathy: External Validation of Harmonizing Definitions and High-Risk Criteria.

Transplant-associated thrombotic microangiopathy (TA-TMA) is an endothelial dysfunction syndrome observed after allogeneic hematopoietic cell transplant (alloHCT). Our aim was to externally validate the impact of high-risk features on the clinical outcomes of adult patients meeting the updated TA-TMA harmonizing criteria. Between 2005 and 2022, 99 patients were diagnosed with TA-TMA at Mayo Clinic Rochester (incidence 6.2%) after a median of 137 days post alloHCT (IQR: 34-283 days). The development of TA-TMA was associated with an inferior overall survival posttransplant (HR: 3.8, 95% CI: 2.97

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… Abbreviations: alloHCT, allogeneic transplant; CNI, calcineurin inhibitor (tacrolimus/cyclosporine A); GVHD, graft‐versus‐host disease; mTOR, mechanistic target of rapamycin (sirolimus); PTCy, posttransplant cyclophosphamide. a Myelomonocytic ( n = 4), myeloid ( n = 3), and lymphoid ( n = 1). b B‐cell … Shayani S., Palmer J., Stiller T., et al., “Thrombotic Microangiopathy Associated With Sirolimus Level After Allogeneic Hematopoietic Cell Transplantation With Tacrolimus/Sirolimus‐Based Graft‐Versus‐Host Disease Prophylaxis,” Biology of Blood and Marrow Transplantation 19, no. 2 (2013): 298–304, 10.1016 …

Outpatient Rescue With Stem Cells Boost for Refractory Hematotoxicity Following anti-BCMA CAR T-Cell Therapy: A Case Report.

Prolonged and refractory hematotoxicity is a severe complication of anti-BCMA CAR-T cell therapy, associated with substantial morbidity. When conventional supportive measures (transfusions and hematopoietic growth factors) fail, alternative strategies are urgently needed. We report the case of a 55-year-old man who developed persistent cytopenias after idecabtagene vicleucel. Reinfusion of cryopreserved autologous stem cells (stem cell boost), administered without conditioning chemotherapy, resulted in rapid and complete hematopoietic recovery after 14 days. This case highlights the potential

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… Sirolimus has been reported to improve cytopenia in a single case [ 11 ]. However, SCB is increasingly considered when supportive care fails [ 4 – 6 , 8 ]. … De Guibert S. , Manson G. , and Houot R. , Prolonged Thrombocytopenia After CAR T-cell Therapy: The Role of Thrombopoietin Receptor Agonists , Blood Advances . ( 2023 ) 7 , no. 4, 537 – 540 , 10.1182/bloodadvances.2022008066 . 35930692 PMC9979763 11 Xing L. , Wang Y. , Liu H. et al., Case Report: Sirolimus …

Protection by mTOR Inhibition on Zymosan-Induced Systemic Inflammatory Response and Oxidative/Nitrosative Stress: Contribution of mTOR/MEK1/ERK1/2/IKKβ/IκB-α/NF-κB Signalling Pathway.

Mammalian target of rapamycin (mTOR), a serine/threonine kinase regulate variety of cellular functions including cell growth, differentiation, cell survival, metabolism, and stress response, is now appreciated to be a central regulator of immune responses. Because mTOR inhibitors enhanced the anti-inflammatory activities of regulatory T cells and decreased the production of proinflammatory cytokines by macrophages, mTOR has been a pharmacological target for inflammatory diseases. In this study, we examined the role of mTOR in the production of proinflammatory and vasodilator mediators in zymos

Rapamycin-Induced Hypoxia Inducible Factor 2A Is Essential for Chondrogenic Differentiation of Amniotic Fluid Stem Cells.

UNLABELLED: Amniotic fluid stem (AFS) cells represent a major source of donor cells for cartilage repair. Recently, it became clear that mammalian target of rapamycin (mTOR) inhibition has beneficial effects on cartilage homeostasis, but the effect of mTOR on chondrogenic differentiation is still elusive. Therefore, the objectives of this study were to investigate the effects of mammalian target of rapamycin complex 1 (mTORC1) modulation on the expression of SOX9 and on its downstream targets during chondrogenic differentiation of AFS cells. We performed three-dimensional pellet culturing of A

TSC1/2 mutations define a molecular subset of HCC with aggressive behaviour and treatment implication.

OBJECTIVE: We investigated the mutational landscape of mammalian target of rapamycin (mTOR) signalling cascade in hepatocellular carcinomas (HCCs) with chronic HBV background, aiming to evaluate and delineate mutation-dependent mechanism of mTOR hyperactivation in hepatocarcinogenesis. DESIGN: We performed next-generation sequencing on human HCC samples and cell line panel. Systematic mutational screening of mTOR pathway-related genes was undertaken and mutant genes were evaluated based on their recurrence. Protein expressions of tuberous sclerosis complex (TSC)1, TSC2 and pRPS6 were assessed

CD4+ T cell STAT3 phosphorylation precedes acute GVHD, and subsequent Th17 tissue invasion correlates with GVHD severity and therapeutic response.

Th17 cells contribute to severe GVHD in murine bone marrow transplantation. Targeted deletion of the RORγt transcription factor or blockade of the JAK2-STAT3 axis suppresses IL-17 production and alloreactivity by Th17 cells. Here, we show that pSTAT3 Y705 is increased significantly in CD4(+) T cells among human recipients of allogeneic HCT before the onset of Grade II-IV acute GVHD. Examination of target-organ tissues at the time of GVHD diagnosis indicates that the amount of RORγt + Th17 cells is significantly higher in severe GVHD. Greater accumulation of tissue-resident Th17 cells also corr

Targeting Focal Adhesion Kinase and Resistance to mTOR Inhibition in Pancreatic Neuroendocrine Tumors.

BACKGROUND: Focal adhesion kinase (FAK) mediates survival of normal pancreatic islets through activation of AKT. Upon malignant transformation of islet cells into pancreatic neuroendocrine tumors (PanNETs), AKT is frequently overexpressed and mutations in the AKT/mTOR pathway are detected. Because mTOR inhibitors rarely induce PanNET tumor regression, partly because of feedback activation of AKT, novel combination strategies are needed to target FAK/AKT/mTOR signaling. METHODS: We characterized the activation of FAK in PanNETs using immunohistochemistry and Western blot analysis and tested th

Hepatitis C virus inhibits AKT-tuberous sclerosis complex (TSC), the mechanistic target of rapamycin (MTOR) pathway, through endoplasmic reticulum stress to induce autophagy.

Hepatitis C virus (HCV) is able to induce autophagy via endoplasmic reticulum (ER) stress, but the exact molecular signaling pathway is not well understood. We found that the activity of the mechanistic target of rapamycin complex 1 (MTORC1) was inhibited in Huh7 cells either harboring HCV-N (genotype 1b) full-genomic replicon or infected with JFH1 (genotype 2a) virus, which led to the activation of UNC-51-like kinase 1 (ULK1) and thus to autophagy. We then analyzed activity upstream of MTORC1, and found that both protein kinase, AMP-activated, α (PRKAA, including PRKAA1 and PRKAA2, also known

Potential anti-aging agents suppress the level of constitutive mTOR- and DNA damage- signaling.

Two different mechanisms are considered to be the primary cause of aging. Cumulative DNA damage caused by reactive oxygen species (ROS), the by-products of oxidative phosphorylation, is one of these mechanisms (ROS concept). Constitutive stimulation of mitogen- and nutrient-sensing mTOR/S6 signaling is the second mechanism (TOR concept). The flow- and laser scanning- cytometric methods were developed to measure the level of the constitutive DNA damage/ROS- as well as of mTOR/S6- signaling in individual cells. Specifically, persistent activation of ATM and expression of γH2AX in untreated cells

Sequence therapy in patients with metastatic renal cell carcinoma: comparison of common targeted treatment options following failure of receptor tyrosine kinase inhibitors.

BACKGROUND: The best sequence of targeted therapy in patients with metastatic renal cell carcinoma (mRCC) has not been sufficiently defined. OBJECTIVE: To describe the efficacy and toxicity of sequential everolimus (EV) versus receptor tyrosine kinase inhibitor (rTKI) following failure of first rTKI treatment. DESIGN, SETTING, AND PARTICIPANTS: Retrospective study of 108 patients receiving rTKI or EV after progression on rTKI therapy at two German academic centres. INTERVENTION: Sequence of systemic targeted treatment with sunitinib (n=85) or sorafenib (n=23) followed by EV (n=62) or anothe

Aberrant CD8+ T-cell responses and memory differentiation upon viral infection of an ataxia-telangiectasia mouse model driven by hyper-activated Akt and mTORC1 signaling.

Immune system-related pathology is common in ataxia-telangiectasia (A-T) patients and mice that lack the protein kinase, A-T mutated (ATM). However, it has not been studied how ATM influences immune responses to a viral infection. Using the lymphocytic choriomeningitis virus (LCMV) infection model, we show that ATM(-/-) mice, despite having fewer naïve CD8⁺ T cells, effectively clear the virus. However, aberrant CD8⁺ T-cell responses are observed, including defective expansion and contraction, effector-to-memory differentiation, and a switch in viral-epitope immunodominance. T-cell receptor-ac