Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative therapy for hematological malignancies, due to graft-versus-leukemia (GVL) activity mediated by alloreactive donor ...T cells. However, graft-versus-host disease (GVHD) is also mediated by these cells. Here, we assessed the effect of attenuating TCR-mediated SLP76:ITK interaction in GVL vs. GVHD effects after allo-HSCT. CD8+ and CD4+ donor T cells from mice expressing a Y145F mutation in SLP-76 did not cause GVHD but preserved GVL effects against B-ALL cells. SLP76Y145FKI CD8+ and CD4+ donor T cells also showed less inflammatory cytokine production and migration to GVHD target organs. We developed a novel peptide to specifically inhibit SLP76:ITK interactions, resulting in decreased phosphorylation of PLCγ1 and ERK, decreased cytokine production in human T cells, and separation of GVHD from GVL effects. Altogether, our data suggest that inhibiting SLP76:ITK interaction could be a therapeutic strategy to separate GVHD from GVL effects after allo-HSCT treatment.
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For a Figure360 author presentation of this figure, see https://doi.org/10.1016/j.isci.2021.102286.
•SLP76Y145FKI donor T cells exhibit minimal GVHD but maintain GVL activity•Inhibiting SLP76:ITK signaling by a novel peptide reduces GVHD while retaining GVL
Molecular Biology; Immunology
The crucial role of integrin in pathological processes such as tumor progression and metastasis formation has inspired intense efforts to design novel pharmaceutical agents modulating integrin ...functions in order to provide new tools for potential therapies. In the past decade, we have investigated the biological proprieties of the chimeric peptide RGDechi, containing a cyclic RGD motif linked to an echistatin C-terminal fragment, able to specifically recognize αvβ3 without cross reacting with αvβ5 and αIIbβ3 integrin. Additionally, we have demonstrated using two RGDechi-derived peptides, called RGDechi1-14 and ψRGDechi, that chemical modifications introduced in the C-terminal part of the peptide alter or abolish the binding to the αvβ3 integrin. Here, to shed light on the structural and dynamical determinants involved in the integrin recognition mechanism, we investigate the effects of the chemical modifications by exploring the conformational space sampled by RGDechi1-14 and ψRGDechi using an integrated natural-abundance NMR/MD approach. Our data demonstrate that the flexibility of the RGD-containing cycle is driven by the echistatin C-terminal region of the RGDechi peptide through a coupling mechanism between the N- and C-terminal regions.
Astrocyte Maria Teresa Gentile, Luca Colucci D'Amato
2018
eBook
Odprti dostop
A team of authors from prestigious academic schools contributed to draw up a project that would give a detailed account of astrocyte's morphology and physiology, examining thoroughly all the ...astrocyte's types; giving an accurate description of their morphology, location, function in the brain; and illustrating their physiology and pathology in terms of dealing with neurons through "gliotransmitters," ionic channels, and membrane receptors expression. This book gives an overview of the crucial role of astrocytes in the physiology of the CNS and in the pathogenesis of several CNS disorders suggesting that the shift from a neurocentric view to one that incorporates astrocytes in disease models for drug discovery is a critical step in renewing drug development strategies to treat neurodegenerative diseases.
The brain, composed of billions of neurons, is a complex network of interacting dynamical systems controlling all body functions. Neurons are the building blocks of the nervous system and their ...impairment of their functions could result in neurodegenerative disorders. Accumulating evidence shows an increase of brain-affecting disorders, still today characterized by poor therapeutic options. There is a strong urgency to find new alternative strategies to prevent progressive neuronal loss. Polyphenols, a wide family of plant compounds with an equally wide range of biological activities, are suitable candidates to counteract chronic degenerative disease in the central nervous system. Herein, we will review their role in human healthcare and highlight their: antioxidant activities in reactive oxygen species-producing neurodegenerative pathologies; putative role as anti-acetylcholinesterase inhibitors; and protective activity in Alzheimer's disease by preventing Aβ aggregation and tau hyperphosphorylation. Moreover, the pathology of these multifactorial diseases is also characterized by metal dyshomeostasis, specifically copper (Cu), zinc (Zn), and iron (Fe), most important for cellular function. In this scenario, polyphenols' action as natural chelators is also discussed. Furthermore, the critical importance of the role exerted by polyphenols on microbiota is assumed, since there is a growing body of evidence for the role of the intestinal microbiota in the gut-brain axis, giving new opportunities to study molecular mechanisms and to find novel strategies in neurological diseases.
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare aggressive malignancy with poor outcomes. Although novel options like tagraxofusp, a CD123-directed cytotoxin, has emerged and is ...promising, treatment options are very limited in the relapsed and recurrent setting. We present a case of refractory BPDCN in a 62-year-old man who showed a complete bone marrow response to liposomal daunorubicin and cytarabine (vyxeos).
Neurofibromatosis type 1 (NF1) is one of the most common genetic tumor predisposition syndrome, caused by mutations in the NF1. To date, few genotype-phenotype correlations have been discerned in ...NF1, due to a highly variable clinical presentation. We aimed to study the molecular spectrum of NF1 and genotype-phenotype correlations in a monocentric study cohort of 85 NF1 patients (20 relatives, 65 sporadic cases). Clinical data were collected at the time of the mutation analysis and reviewed for accuracy in this investigation. An internal phenotypic categorization was applied. The 94% of the patients enrolled showed a severe phenotype with at least one systemic complication and a wide range of associated malignancies. Spine deformities were the most common complications in this cohort. We also reported 66 different NF1 mutations, of which 7 are novel mutations. Correlation analysis identified a slight significant inverse correlation between age at diagnosis and delayed acquisition of psychomotor skills with residual multi-domain cognitive impairment. Odds ratio with 95% confidence interval showed a higher prevalence of learning disabilities in patients carrying frameshift mutations. Overall, our results aim to offer an interesting contribution to studies on the genotype–phenotype of NF1 and in genetic management and counselling.
Differential DNA methylation defects of H19/IGF2 are associated with congenital growth disorders characterized by opposite clinical pictures. Due to structural differences between human and mouse, ...the mechanisms by which mutations of the H19/IGF2 Imprinting Control region (IC1) result in these diseases are undefined. To address this issue, we previously generated a mouse line carrying a humanized IC1 (hIC1) and now replaced the wildtype with a mutant IC1 identified in the overgrowth-associated Beckwith-Wiedemann syndrome. The new humanized mouse line shows pre/post-natal overgrowth on maternal transmission and pre/post-natal undergrowth on paternal transmission of the mutation. The mutant hIC1 acquires abnormal methylation during development causing opposite H19/Igf2 imprinting defects on maternal and paternal chromosomes. Differential and possibly mosaic Igf2 expression and imprinting is associated with asymmetric growth of bilateral organs. Furthermore, tissue-specific imprinting defects result in deficient liver- and placenta-derived Igf2 on paternal transmission and excessive Igf2 in peripheral tissues on maternal transmission, providing a possible molecular explanation for imprinting-associated and phenotypically contrasting growth disorders.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Introduction:
Catastrophic antiphospholipid syndrome (CAPS) is characterized by multiple intravascular thrombotic events occurring over a short time period in the presence of persistently detectable ...antiphospholipid antibodies (APLA). Despite its clinical significance with mortality rate of 40-50%, the underlying pathophysiology remains somewhat enigmatic. More recent focus on the complement system as it interacts with the coagulation cascade has led to off-label use of eculizumab, a humanized monoclonal antibody against C5, in the treatment of CAPS.
Consequently, monitoring of disease status with complement levels is an area of interest. We report complement levels in four patients with CAPS who had various clinical outcomes.
Methods:
Four patients admitted to SUNY Upstate Medical University with CAPS between February and May 2019 were included in this case series. All patients had APS with prior history of refractory CAPS (persistent disease despite standard therapy with steroids, rituximab, and therapeutic plasma exchange TPEX). Antiphospholipid antibodies (APLA) and complement (C3 and C4) levels were monitored during admission until discharge or death.
Results:
Patient characteristics are summarized in Table 1.
Patient 1 was a 42-year-old female with antiphospholipid syndrome (APS) on warfarin, ischemic stroke, and aortic valve replacement admitted on March 2019 with shortness of breath, hemoptysis and menorrhagia. She was found to have elevated APLA, thrombocytopenia, and acute renal failure with renal biopsy confirming APS nephropathy. Despite therapy with ongoing anticoagulation, steroids, rituximab, IVIG, and TPEX her clinical course continued to deteriorate. Hypocomplementemia was present (both low C3 and C4), with lowest C3 level on admission at 31 (Graph 1A). Decision was made to pursue eculizumab on 4/16/19 with continued clinical decline and no improvement in complement levels. She ultimately died on 4/24/19.
Patient 2 was a 35-year-old male with systemic lupus erythematosus (SLE), APS, end-stage renal disease, and Libman-Sacks endocarditis status post bioprosthetic aortic valve replacement admitted in February 2019 for worsening digital ischemia. Workup showed presence of lupus anticoagulant, thrombocytopenia, low C3 levels (Graph 1B), normal C4 levels, and arterial thrombi in the upper and lower extremities. Prior to initiation of treatment, respiratory status declined due to massive pulmonary embolus. He died after PEA arrest shortly thereafter.
Patient 3 is a 63-year-old male with chronic ITP and APS on warfarin, maintenance rituximab and intermittent apheresis admitted with worsening renal dysfunction in April 2019. Workup demonstrated acute on chronic thrombocytopenia, elevated APLA, and normal C3 and C4 levels (Graph 1C). Renal replacement therapy was commenced and he was discharged to receive ongoing outpatient therapy.
Patient 4 is a 35-year-old male with history of SLE and APS admitted in April 2019 with renal failure, anemia and thrombocytopenia. Workup showed presence of APLA. Despite therapy with steroids, IVIG, rituximab and TPEX he became anuric with renal biopsy showing thrombotic microangiopathy. He was also bacteremic with a mitral valve vegetation for which he underwent valve replacement. Hospital course was complicated by need respiratory failure necessitating intubation and ECMO. C3 levels were consistently low, but varied throughout his long admission (Graph 1D) and were not necessarily related to his clinical course (sepsis, ECMO, etc.). C4 levels were normal.
Conclusions:
Complement levels were variable among the patients in this case series. Three out of four patient had low C3, while only one patient had low C4. Further, complement levels did not improve in one patient after administration of eculizumab. Routine laboratory testing for C3 and C4 may not be optimal assays for monitoring disease status in CAPS. More specialized complement testing, such a C5 a/b, may be more appropriate especially in the setting of eculizumab use. While eculizumab is typically used in refractory disease, it may be pertinent to move this therapy into early line treatment to achieve better outcomes in certain clinical scenarios. Identification of a more specific biomarker to recognize cases in need of early therapy is warranted.
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No relevant conflicts of interest to declare.
Eculizumab, a humanized monoclonal IgG antibody that binds to complement protein C5, is discussed for its off-label use in the treatment of catastrophic antiphospholipid antibody syndrome.
Multiple myeloma is the second most common hematological malignancy. Ixazomib is the first oral proteasome inhibitor approved in the United States for the management of multiple myeloma who have ...received at least one prior treatment. The availability of oral chemotherapeutic agents for the management of multiple myeloma has made it easier for patients who do not have to come to the hospital for chemotherapy infusions. However, many barriers are associated with oral chemotherapy, and one of them is a misinterpretation of instruction which can have deleterious effects. In this case report, we present a case of a 69-year-old male with multiple myeloma who accidentally took ixazomib daily for 3 days instead of the weekly regimen and thus coming into the hospital with an overdose. In this report, we focus on the adverse effects associated with ixazomib toxicity and how to manage the adverse reactions. Although there is no antidote available for ixazomib, supportive care is very essential in these patients.
Abstract Chronic myelogenous leukemia (CML) is a myeloproliferative disorder where over a period of time 15–20% of patients show blastic transformation with majority transforming into acute myeloid ...leukemia, most of which are of granulocytic lineage. Erythroid blast phase of CML is relatively rare with the incidence ranging from 0–10%. Further the incidence of acute erythroid leukemia by itself is fairly low amongst all acute leukemias. We report a case of 41-year-old patient with CML who failed to achieve cytogenetic remission, transformed to acute erythroid leukemia and eventually succumbed to the disease over a short period of time. Related literature is also reviewed
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