Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 20 de 56
Filter
1.
JAMA Netw Open ; 7(6): e2414122, 2024 Jun 03.
Article in English | MEDLINE | ID: mdl-38857050

ABSTRACT

Importance: Neurological manifestations during acute SARS-CoV-2-related multisystem inflammatory syndrome in children (MIS-C) are common in hospitalized patients younger than 18 years and may increase risk of new neurocognitive or functional morbidity. Objective: To assess the association of severe neurological manifestations during a SARS-CoV-2-related hospital admission with new neurocognitive or functional morbidities at discharge. Design, Setting, and Participants: This prospective cohort study from 46 centers in 10 countries included patients younger than 18 years who were hospitalized for acute SARS-CoV-2 or MIS-C between January 2, 2020, and July 31, 2021. Exposure: Severe neurological manifestations, which included acute encephalopathy, seizures or status epilepticus, meningitis or encephalitis, sympathetic storming or dysautonomia, cardiac arrest, coma, delirium, and stroke. Main Outcomes and Measures: The primary outcome was new neurocognitive (based on the Pediatric Cerebral Performance Category scale) and/or functional (based on the Functional Status Scale) morbidity at hospital discharge. Multivariable logistic regression analyses were performed to examine the association of severe neurological manifestations with new morbidity in each SARS-CoV-2-related condition. Results: Overall, 3568 patients younger than 18 years (median age, 8 years [IQR, 1-14 years]; 54.3% male) were included in this study. Most (2980 [83.5%]) had acute SARS-CoV-2; the remainder (588 [16.5%]) had MIS-C. Among the patients with acute SARS-CoV-2, 536 (18.0%) had a severe neurological manifestation during hospitalization, as did 146 patients with MIS-C (24.8%). Among survivors with acute SARS-CoV-2, those with severe neurological manifestations were more likely to have new neurocognitive or functional morbidity at hospital discharge compared with those without severe neurological manifestations (27.7% [n = 142] vs 14.6% [n = 356]; P < .001). For survivors with MIS-C, 28.0% (n = 39) with severe neurological manifestations had new neurocognitive and/or functional morbidity at hospital discharge compared with 15.5% (n = 68) of those without severe neurological manifestations (P = .002). When adjusting for risk factors in those with severe neurological manifestations, both patients with acute SARS-CoV-2 (odds ratio, 1.85 [95% CI, 1.27-2.70]; P = .001) and those with MIS-C (odds ratio, 2.18 [95% CI, 1.22-3.89]; P = .009) had higher odds of having new neurocognitive and/or functional morbidity at hospital discharge. Conclusions and Relevance: The results of this study suggest that children and adolescents with acute SARS-CoV-2 or MIS-C and severe neurological manifestations may be at high risk for long-term impairment and may benefit from screening and early intervention to assist recovery.


Subject(s)
COVID-19 , Hospitalization , Nervous System Diseases , SARS-CoV-2 , Systemic Inflammatory Response Syndrome , Humans , COVID-19/complications , COVID-19/epidemiology , Child , Female , Male , Child, Preschool , Hospitalization/statistics & numerical data , Adolescent , Prospective Studies , Systemic Inflammatory Response Syndrome/epidemiology , Nervous System Diseases/etiology , Nervous System Diseases/epidemiology , Infant , Severity of Illness Index
2.
Front Cardiovasc Med ; 10: 1309839, 2023.
Article in English | MEDLINE | ID: mdl-38155991

ABSTRACT

Kommerell's diverticulum in association with left or right aberrant subclavian arteries is a rare finding and is challenging to treat. Contemporary surgical and endovascular techniques provide a broad arsenal of possible treatments. Imaging techniques and modeling technology allow a more personalized strategy for each patient. In this case, we present a symptomatic patient with a Kommerell's diverticulum and a left aberrant subclavian artery complicated by proximal stenosis and poststenotic aneurysm. A hybrid technique using a single-branched thoracic stent-graft (Castor, MicroPort Medical, Shanghai, China) in combination with a surgical left subclavian-carotid bypass and endovascular occlusion of the poststenotic aneurysm using a vascular plug device (Amplatzer Vascular Plug, Abbott, Chicago, United States) was performed. This approach was planned and facilitated by the use of a 3D model. Alternative treatment options and the strengths of this approach are briefly reviewed and discussed.

3.
Am J Occup Ther ; 77(6)2023 Nov 01.
Article in English | MEDLINE | ID: mdl-38015491

ABSTRACT

The global challenges humanity faces today, such as social and economic inequalities, occupational deprivation, racism, exclusion, displacement and migration crises, violence, wars, and political oppression, all contribute to health and participation inequities (Powell & Toppin, 2021). The depth and breadth of these inequities became strikingly evident and were exacerbated with the coronavirus 2019 pandemic (Khanijahani et al., 2021). More than ever before, we need to apply an occupational perspective to create caring communities that strengthen each person's sense of belonging (Beagan, 2015; Lavalley & Johnson, 2020; Mahoney & Kiraly-Alvarez, 2019). In this column, we argue that occupational therapy academic programs have a unique role in advancing justice, equity, diversity, and inclusion through the creation of caring communities.


Subject(s)
Diversity, Equity, Inclusion , Occupational Therapy , Humans , Social Justice , Violence
4.
Immunobiology ; 228(2): 152334, 2023 03.
Article in English | MEDLINE | ID: mdl-36641984

ABSTRACT

Helicobacter pylori is a gram-negative bacterium that is present in over half of the world's population. The colonization of the stomach́s gastric mucosa by H. pylori is related to the onset of chronic gastritis, peptic ulcer, and cancer. The estimated deaths from gastric cancer caused by this bacterial infection are in the 15,000-150,000 range. Current treatment for controlling the colonization of H. pylori includes the administration of two to four antibiotics and a gastric ATPase proton pump inhibitor. Nevertheless, the bacterium has shown increased resistance to antibiotics. Despite an extensive list of attempts to develop a vaccine, no approved vaccine against H. pylori is available. Recombinant viruses are a novel alternative for the control of primary pathogenic agents. In this work, we employed a baculovirus that carries a Thp1 transgene coding for nine H. pylori epitopes, some from the literature, and others were selected in silico from the sequence of H. pylori proteins (carbonic anhydrase, urease B subunit, gamma-glutamyl transpeptidase, Lpp20, Cag7, and CagL). We verified the expression of this hybrid multiepitopic protein in HeLa cells. Mice were inoculated with the recombinant baculovirus Bac-Thp1 using various administration routes: intranasal, intragastric, intramuscular, and a combination of intranasal and intragastric. We identified a strong adjuvant-independent IgG-antibody response in the serum of recombinant baculovirus-Thp1 inoculated mice, which was specific for a strain of H. pylori isolated from a human patient. The bacterium-specific IgG-antibodies were present in sera 125 days after the first vaccine administration. Also, H. pylori-specific IgA-antibodies were found in feces at 82 days after the first inoculation. A baculovirus-based vaccine for H. pylori is promising for controlling this pathogen in humans.


Subject(s)
Helicobacter Infections , Helicobacter pylori , Humans , Animals , Mice , Baculoviridae , HeLa Cells , Bacterial Vaccines , Immunoglobulin G , Antibodies, Bacterial
5.
Infect Ecol Epidemiol ; 13(1): 2277000, 2023.
Article in English | MEDLINE | ID: mdl-38187166

ABSTRACT

Introduction: The use of steroids has been proposed as a pharmacological approach to treat the SARS-CoV-2 infection to improve outcomes. However, there are doubts about safety against the development of superinfections and their worse outcomes. Objective: To establish the relative frequency of superinfection associated with using steroids in patients with SARS-CoV-2 infection. Materials and methods: We conducted a systematic literature review and meta-analysis using PRISMA standards in 5 databases (PubMed/Scopus/Cochrane/EMBASE/Google Scholar). The search was carried out between February 2020 and May 2023. The search terms were 'steroids' or 'superinfection' 'and' followed by 'SARS-CoV-2' or 'COVID-19'. Results: We found 77 studies, but only 10 with 3539 patients were included in the systematic review. All patients developed severe disease. The documented OR for superinfection through the meta-analysis was 1.437 (95% IC 0.869-2.378) with a p-value of 0.158 without showing a risk attributed to steroids and the development of superinfections. In the Funnel-plot analysis, no publication biases were found. Conclusion: No relationship was found between using steroids and superinfection in patients with SARS-CoV-2.

6.
Exp Hematol ; 110: 34-38, 2022 06.
Article in English | MEDLINE | ID: mdl-35306048

ABSTRACT

Children with Down syndrome (DS) are 10-fold more likely to develop B-cell acute lymphoblastic leukemia (B-ALL), with a higher frequency of rearrangements resulting in overexpression of cytokine receptor-like factor 2 (CRLF2). Here, we investigated the impact of CRLF2 overexpression on B-cell progenitor proliferation, immunophenotype, and gene expression profile in the Dp(16)1Yey (Dp16) mouse model of DS compared with wild-type (WT) mice. CRLF2 overexpression enhanced immature B-lymphoid colony development and increased the proportion of less differentiated pre-pro-B cells, with a greater effect in Dp16 versus WT. In CRLF2-rearranged (CRLF2-R) B-ALL patient samples, cells with higher CRLF2 expression exhibited a less differentiated B-cell immunophenotype. CRLF2 overexpression resulted in a gene expression signature associated with E2F signaling both in Dp16 B-progenitors and in DS-ALL patient samples, and PI3K/mTOR and pan-CDK inhibitors, which reduce E2F-mediated signaling, exhibited cytotoxicity in CRLF2-R B-ALL cell lines and patient samples. CRLF2 overexpression alone in Dp16 stem and progenitor cells did not result in leukemic transformation in recipient mice. Thus, CRLF2 overexpression results in reduced B-cell differentiation and enhanced E2F signaling in Dp16 B-progenitor cells and DS-ALL patient samples. These findings suggest a functional basis for the high frequency of CRLF2-R in DS-ALL as well as a potential therapeutically targetable pathway.


Subject(s)
Down Syndrome , Precursor Cell Lymphoblastic Leukemia-Lymphoma , Animals , Cell Differentiation/genetics , Disease Models, Animal , Down Syndrome/complications , Down Syndrome/genetics , Humans , Mice , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , Receptors, Cytokine/genetics , Signal Transduction
7.
Pediatr Neurol ; 128: 33-44, 2022 03.
Article in English | MEDLINE | ID: mdl-35066369

ABSTRACT

BACKGROUND: Our objective was to characterize the frequency, early impact, and risk factors for neurological manifestations in hospitalized children with acute severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection or multisystem inflammatory syndrome in children (MIS-C). METHODS: Multicenter, cross-sectional study of neurological manifestations in children aged <18 years hospitalized with positive SARS-CoV-2 test or clinical diagnosis of a SARS-CoV-2-related condition between January 2020 and April 2021. Multivariable logistic regression to identify risk factors for neurological manifestations was performed. RESULTS: Of 1493 children, 1278 (86%) were diagnosed with acute SARS-CoV-2 and 215 (14%) with MIS-C. Overall, 44% of the cohort (40% acute SARS-CoV-2 and 66% MIS-C) had at least one neurological manifestation. The most common neurological findings in children with acute SARS-CoV-2 and MIS-C diagnosis were headache (16% and 47%) and acute encephalopathy (15% and 22%), both P < 0.05. Children with neurological manifestations were more likely to require intensive care unit (ICU) care (51% vs 22%), P < 0.001. In multivariable logistic regression, children with neurological manifestations were older (odds ratio [OR] 1.1 and 95% confidence interval [CI] 1.07 to 1.13) and more likely to have MIS-C versus acute SARS-CoV-2 (OR 2.16, 95% CI 1.45 to 3.24), pre-existing neurological and metabolic conditions (OR 3.48, 95% CI 2.37 to 5.15; and OR 1.65, 95% CI 1.04 to 2.66, respectively), and pharyngeal (OR 1.74, 95% CI 1.16 to 2.64) or abdominal pain (OR 1.43, 95% CI 1.03 to 2.00); all P < 0.05. CONCLUSIONS: In this multicenter study, 44% of children hospitalized with SARS-CoV-2-related conditions experienced neurological manifestations, which were associated with ICU admission and pre-existing neurological condition. Posthospital assessment for, and support of, functional impairment and neuroprotective strategies are vitally needed.


Subject(s)
COVID-19/complications , Nervous System Diseases/epidemiology , SARS-CoV-2 , Systemic Inflammatory Response Syndrome/epidemiology , Acute Disease , Adolescent , Brain Diseases/epidemiology , Brain Diseases/etiology , COVID-19/epidemiology , Child , Child, Preschool , Cross-Sectional Studies , Female , Headache/epidemiology , Headache/etiology , Humans , Infant , Intensive Care Units, Pediatric/statistics & numerical data , Logistic Models , Male , Nervous System Diseases/etiology , Prevalence , Risk Factors , South America/epidemiology , United States/epidemiology
8.
Eur J Ophthalmol ; 32(6): NP24-NP27, 2022 Nov.
Article in English | MEDLINE | ID: mdl-34015953

ABSTRACT

INTRODUCTION: Moraxella nonliquefaciens (M. nonliquefaciens) is a low pathogenicity microorganism, which rarely causes ocular infections, unless there is a predisposing factor. The main clinical manifestation of M. nonliquefaciens ocular infections is endophthalmitis and only five cases of corneal infection have been reported. This work shows an update in M. nonliquefaciens corneal infections, and the first reported case of keratitis due to M. nonliquefaciens superinfecting herpes simplex infection. CASE REPORT: A 84-year old woman with worsening of her herpes simplex keratitis, diagnosed, and treated 2 days before. The slit lamp showed deep paracentral infiltrate and hypopyon. A corneal sample was collected for culture prior to initiation of empiric antibiotic therapy with vancomycin and ceftazidime fortified, oral acyclovir, and cyclopentolate. The strain was identified as M. nonliquefaciens and topical antibiotic therapy was adjusted to ciprofloxacin and ceftazidime. After 2 weeks, the epithelial defect and the infiltrate were resolved and prednisolone was added to the regimen. As the corneal oedema and neovascularization decreased, acyclovir, and prednisolone were slowly tapered. About 4 months later, the visual outcome was 20/50 and the ophthalmic examination showed a clear cornea with a paracentral leucoma. CONCLUSION: Keratitis due to M. nonliquefaciens is rare and should be suspected in patients with local predisposing factors such as corneal damage or previous corneal infection. Prompt and appropriate combined treatment for the predisposing lesions and the keratitis may improve the prognosis and avoid a more aggressive approach.


Subject(s)
Ceftazidime , Keratitis, Herpetic , Acyclovir/therapeutic use , Aged, 80 and over , Anti-Bacterial Agents/therapeutic use , Ceftazidime/therapeutic use , Ciprofloxacin/therapeutic use , Cyclopentolate/therapeutic use , Female , Humans , Keratitis, Herpetic/diagnosis , Keratitis, Herpetic/drug therapy , Moraxella , Prednisolone/therapeutic use , Vancomycin/therapeutic use
9.
Medwave ; 21(3): e8176, 2021 Apr 23.
Article in Spanish, English | MEDLINE | ID: mdl-34081683

ABSTRACT

INTRODUCTION: The association of COVID-19 with diabetes mellitus is bidirectional. In one direction, diabetes mellitus is associated with an increased risk of severe COVID-19. In the opposite direction, in patients with COVID-19 new-onset diabetes mellitus, severe diabetic ketoacidosis and severe metabolic complications have been described. CLINICAL CASE: This report describes two patients with diabetes mellitus who came to our hospital with ketoacidosis resulting from new-onset diabetes mellitus. We describe the clinical course and the management approach during the COVID-19 pandemic. CONCLUSION: COVID-19 is associated with metabolic complications such as severe diabetic ketoacidosis.


INTRODUCCIÓN: La relación entre la enfermedad por el coronavirus de 2019 (COVID-19) secundaria a SARS-CoV-2 y la diabetes mellitus es bidireccional. Por un lado, la diabetes mellitus se asocia con un mayor riesgo de COVID-19 grave. Por otro lado, en pacientes con COVID-19 se han observado diabetes mellitus de nueva aparición con presentaciones de cetoacidosis diabética y complicaciones metabólicas graves de dicha presentación. CASOS CLÍNICOS: En este informe, describimos a dos pacientes pediátricos con diabetes mellitus que acudieron a nuestro hospital con cetoacidosis diabética, de debut inicial. Describimos la evolución y el manejo clínico y terapéutico durante la pandemia de COVID-19. CONCLUSIÓN: La infección por COVID-19 puede precipitar complicaciones como cetoacidosis diabética severa.


Subject(s)
COVID-19/complications , Diabetic Ketoacidosis/etiology , Brain Edema/etiology , Child , Female , Humans , Hypoxia, Brain/etiology , Male
10.
EMBO J ; 40(13): e103311, 2021 07 01.
Article in English | MEDLINE | ID: mdl-33978236

ABSTRACT

Due to their capability to transport chemicals or proteins into target cells, cell-penetrating peptides (CPPs) are being developed as therapy delivery tools. However, and despite their interesting properties, arginine-rich CPPs often show toxicity for reasons that remain poorly understood. Using a (PR)n dipeptide repeat that has been linked to amyotrophic lateral sclerosis (ALS) as a model of an arginine-rich CPP, we here show that the presence of (PR)n leads to a generalized displacement of RNA- and DNA-binding proteins from chromatin and mRNA. Accordingly, any reaction involving nucleic acids, such as RNA transcription, translation, splicing and degradation, or DNA replication and repair, is impaired by the presence of the CPPs. Interestingly, the effects of (PR)n are fully mimicked by protamine, a small arginine-rich protein that displaces histones from chromatin during spermatogenesis. We propose that widespread coating of nucleic acids and consequent displacement of RNA- and DNA-binding factors from chromatin and mRNA accounts for the toxicity of arginine-rich CPPs, including those that have been recently associated with the onset of ALS.


Subject(s)
Arginine/genetics , Cell-Penetrating Peptides/genetics , DNA-Binding Proteins/genetics , RNA-Binding Proteins/genetics , Amyotrophic Lateral Sclerosis/genetics , Cell Line, Tumor , Chromatin/genetics , DNA/genetics , HeLa Cells , Histones/genetics , Humans , Nucleic Acids/genetics , RNA/genetics , RNA Splicing/genetics , RNA, Messenger/genetics , Spermatogenesis/genetics
11.
Thromb Update ; 3: 100047, 2021 May.
Article in English | MEDLINE | ID: mdl-38620776

ABSTRACT

Sickle cell trait (SCT) is the carrier state for sickle cell disease (SCD) and is usually perceived as a mild condition; however, previous studies have shown that hypoxemia may trigger sickle-cell related complications in these patients, including splenic infarction. Hypoxemia is a common finding in patients with COVID-19 pneumonia. We present the case of a 19-year-old male with a history of epilepsy who presented to the emergency room due to abdominal pain in the left flank that appeared after presenting generalized tonic-clonic seizures and fever. SARS-CoV-2 RT-PCR testing in nasopharyngeal swab was positive and an abdominal computerized tomography (CT) revealed a massive splenic infarction. Hemoglobinopathy study using high-efficiency liquid chromatography demonstrated the presence of 39.7% HbS, thus confirming the diagnosis of SCT. Hypoxemia, endothelial dysfunction and hypercoagulability caused by SARS-CoV-2 infection could lead to complement activation and microangiopathy, triggering the vaso-occlusive crisis that led to splenic infarction.

12.
BMC Med ; 18(1): 359, 2020 11 16.
Article in English | MEDLINE | ID: mdl-33190637

ABSTRACT

BACKGROUND: Limited evidence exists on the role of glucose-lowering drugs in patients with COVID-19. Our main objective was to examine the association between in-hospital death and each routine at-home glucose-lowering drug both individually and in combination with metformin in patients with type 2 diabetes mellitus admitted for COVID-19. We also evaluated their association with the composite outcome of the need for ICU admission, invasive and non-invasive mechanical ventilation, or in-hospital death as well as on the development of in-hospital complications and a long-time hospital stay. METHODS: We selected all patients with type 2 diabetes mellitus in the Spanish Society of Internal Medicine's registry of COVID-19 patients (SEMI-COVID-19 Registry). It is an ongoing, observational, multicenter, nationwide cohort of patients admitted for COVID-19 in Spain from March 1, 2020. Each glucose-lowering drug user was matched with a user of other glucose-lowering drugs in a 1:1 manner by propensity scores. In order to assess the adequacy of propensity score matching, we used the standardized mean difference found in patient characteristics after matching. There was considered to be a significant imbalance in the group if a standardized mean difference > 10% was found. To evaluate the association between treatment and study outcomes, both conditional logit and mixed effect logistic regressions were used when the sample size was ≥ 100. RESULTS: A total of 2666 patients were found in the SEMI-COVID-19 Registry, 1297 on glucose-lowering drugs in monotherapy and 465 in combination with metformin. After propensity matching, 249 patients on metformin, 105 on dipeptidyl peptidase-4 inhibitors, 129 on insulin, 127 on metformin/dipeptidyl peptidase-4 inhibitors, 34 on metformin/sodium-glucose cotransporter 2 inhibitor, and 67 on metformin/insulin were selected. No at-home glucose-lowering drugs showed a significant association with in-hospital death; the composite outcome of the need of intensive care unit admission, mechanical ventilation, or in-hospital death; in-hospital complications; or long-time hospital stays. CONCLUSIONS: In patients with type 2 diabetes mellitus admitted for COVID-19, at-home glucose-lowering drugs showed no significant association with mortality and adverse outcomes. Given the close relationship between diabetes and COVID-19 and the limited evidence on the role of glucose-lowering drugs, prospective studies are needed.


Subject(s)
Coronavirus Infections/mortality , Diabetes Mellitus, Type 2/drug therapy , Dipeptidyl-Peptidase IV Inhibitors/therapeutic use , Hypoglycemic Agents/standards , Insulin/therapeutic use , Metformin/therapeutic use , Pneumonia, Viral/mortality , Respiration, Artificial/statistics & numerical data , Sodium-Glucose Transporter 2 Inhibitors/therapeutic use , Aged , Aged, 80 and over , Betacoronavirus , COVID-19 , Cohort Studies , Coronavirus Infections/complications , Coronavirus Infections/therapy , Diabetes Mellitus, Type 2/complications , Drug Therapy, Combination , Female , Hospital Mortality , Hospitalization , Humans , Hypoglycemic Agents/therapeutic use , Intensive Care Units , Length of Stay/statistics & numerical data , Logistic Models , Male , Noninvasive Ventilation/statistics & numerical data , Pandemics , Pneumonia, Viral/complications , Pneumonia, Viral/therapy , Prospective Studies , SARS-CoV-2 , Spain
14.
EMBO J ; 39(16): e104324, 2020 08 17.
Article in English | MEDLINE | ID: mdl-32614092

ABSTRACT

Full differentiation potential along with self-renewal capacity is a major property of pluripotent stem cells (PSCs). However, the differentiation capacity frequently decreases during expansion of PSCs in vitro. We show here that transient exposure to a single microRNA, expressed at early stages during normal development, improves the differentiation capacity of already-established murine and human PSCs. Short exposure to miR-203 in PSCs (miPSCs) induces a transient expression of 2C markers that later results in expanded differentiation potency to multiple lineages, as well as improved efficiency in tetraploid complementation and human-mouse interspecies chimerism assays. Mechanistically, these effects are at least partially mediated by direct repression of de novo DNA methyltransferases Dnmt3a and Dnmt3b, leading to transient and reversible erasure of DNA methylation. These data support the use of transient exposure to miR-203 as a versatile method to reset the epigenetic memory in PSCs, and improve their effectiveness in regenerative medicine.


Subject(s)
Cell Differentiation , DNA Methylation , Epigenesis, Genetic , Induced Pluripotent Stem Cells/metabolism , MicroRNAs/metabolism , Animals , Cell Line , DNA (Cytosine-5-)-Methyltransferases/genetics , DNA (Cytosine-5-)-Methyltransferases/metabolism , DNA Methyltransferase 3A , Humans , Induced Pluripotent Stem Cells/cytology , Mice , MicroRNAs/genetics , DNA Methyltransferase 3B
15.
Org Biomol Chem ; 18(17): 3288-3296, 2020 05 06.
Article in English | MEDLINE | ID: mdl-32286579

ABSTRACT

Recurrence and drug resistance are major challenges in the treatment of acute myeloid leukemia (AML) that spur efforts to identify new clinical targets and active agents. STAT3 has emerged as a potential target in resistant AML, but inhibiting STAT3 function has proven challenging. This paper describes synthetic studies and biological assays for a naphthalene sulfonamide inhibitor class of molecules that inhibit G-CSF-induced STAT3 phosphorylation in cellulo and induce apoptosis in AML cells. We describe two different approaches to inhibitor design: first, variation of substituents on the naphthalene sulfonamide core allows improvements in anti-STAT activity and creates a more thorough understanding of anti-STAT SAR. Second, a novel approach involving hybrid sulfonamide-rhodium(ii) conjugates tests our ability to use cooperative organic-inorganic binding for drug development, and to use SAR studies to inform metal conjugate design. Both approaches have produced compounds with improved binding potency. In vivo and in cellulo experiments further demonstrate that these approaches can also lead to improved activity in living cells, and that compound 3aa slows disease progression in a xenograft model of AML.


Subject(s)
Antineoplastic Agents/chemistry , Leukemia, Myeloid, Acute/drug therapy , Naphthalenes/chemistry , Protein Kinase Inhibitors/chemistry , STAT3 Transcription Factor/antagonists & inhibitors , Sulfonamides/chemistry , Animals , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Cell Line, Tumor , Drug Screening Assays, Antitumor , Humans , Mice , Models, Molecular , Molecular Targeted Therapy , Neoplasms, Experimental , Oxidation-Reduction , Protein Binding , Protein Kinase Inhibitors/pharmacology , STAT3 Transcription Factor/genetics , Structure-Activity Relationship
16.
Blood Adv ; 3(24): 4215-4227, 2019 12 23.
Article in English | MEDLINE | ID: mdl-31856268

ABSTRACT

Atovaquone, a US Food and Drug Administration-approved antiparasitic drug previously shown to reduce interleukin-6/STAT3 signaling in myeloma cells, is well tolerated, and plasma concentrations of 40 to 80 µM have been achieved with pediatric and adult dosing. We conducted preclinical testing of atovaquone with acute myeloid leukemia (AML) cell lines and pediatric patient samples. Atovaquone induced apoptosis with an EC50 <30 µM for most AML lines and primary pediatric AML specimens. In NSG mice xenografted with luciferase-expressing THP-1 cells and in those receiving a patient-derived xenograft, atovaquone-treated mice demonstrated decreased disease burden and prolonged survival. To gain a better understanding of the mechanism of atovaquone, we performed an integrated analysis of gene expression changes occurring in cancer cell lines after atovaquone exposure. Atovaquone promoted phosphorylation of eIF2α, a key component of the integrated stress response and master regulator of protein translation. Increased levels of phosphorylated eIF2α led to greater abundance of the transcription factor ATF4 and its target genes, including proapoptotic CHOP and CHAC1. Furthermore, atovaquone upregulated REDD1, an ATF4 target gene and negative regulator of the mechanistic target of rapamycin (mTOR), and caused REDD1-mediated inhibition of mTOR activity with similar efficacy as rapamycin. Additionally, atovaquone suppressed the oxygen consumption rate of AML cells, which has specific implications for chemotherapy-resistant AML blasts that rely on oxidative phosphorylation for survival. Our results provide insight into the complex biological effects of atovaquone, highlighting its potential as an anticancer therapy with novel and diverse mechanisms of action, and support further clinical evaluation of atovaquone for pediatric and adult AML.


Subject(s)
Atovaquone/pharmacology , Leukemia, Myeloid, Acute/metabolism , Oxidative Phosphorylation/drug effects , Signal Transduction/drug effects , Activating Transcription Factor 4/metabolism , Adolescent , Animals , Apoptosis/drug effects , Cell Line, Tumor , Cell Survival/drug effects , Child , Child, Preschool , Disease Models, Animal , Female , Humans , Infant , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/mortality , Leukemia, Myeloid, Acute/pathology , Male , Mice , Mice, Knockout , Xenograft Model Antitumor Assays
17.
rev. udca actual. divulg. cient ; 22(1): e1177, Ene-Jun. 2019. graf
Article in English | LILACS-Express | LILACS | ID: biblio-1094777

ABSTRACT

ABSTRACT Frogskin is the most limiting disease of cassava crops in Colombia, causing losses in production up to 90%. Since this disease was associatated with 16SrIII phytoplasma presence, a study was carried out to isolate this phytoplasma using liquid and solid culture media. Root, petiol, stem, leaf and cutting tissues of cassava affected by frogsking were employed as source materials. Molecular and microscopy techniques were applied to verify the phytoplasma growth and to discard other microorganism´s presence. The results showed that the media consistently allow phytoplasma growth, and colonies in solid medium were obtained. PCR, qPCR and sequencing tests confirmed the presence of 16SrIII group phytoplasmas in both liquid and solid culture media. Additionally, the isolation of a pigeon pea witches' broom phytoplasma strain (group 16SrIX) was obtained from stems, petioles and flowers of symptomatic Catharanthus roseus confirming the effectiveness of the medium in the phytoplasma isolation and culture. This is the first isolation of field-collected phytoplasma strains in groups 16SrIII and 16SrIX in America that confirm and corroborate the previous results in phytoplasma cultivation achieved on micropropagated and field-collected phytoplasma infected samples.


RESUMEN En Colombia, el ''cuero de sapo'' es la enfermedad más limitante del cultivo de yuca, que ocasiona pérdidas en producción de raíces hasta del 90%. La presente investigación tuvo como objetivo, el aislamiento in vitro del fitoplasma asociado a cuero de sapo. Para ello, se emplearon medios de cultivo líquido y sólido, usando tejidos de raíces, peciolos, tallos, hojas y semillas de yuca, afectada por la enfermedad. Pruebas de PCR, qPCR, secuenciación, microscopia de luz y microscopia electrónica de transmisión fueron aplicadas, para verificar el crecimiento de fitoplasmas y descartar la presencia de otros microrganismos. Los resultados muestran que los medios permiten, consistentemente, el crecimiento de fitoplasmas, obteniendo colonias en medio sólido a partir de medio líquido. Las pruebas de PCR, qPCR y secuenciación confirmaron presencia de Cassava frogskin phytoplasma del grupo 16SrIII, en los dos medios de cultivo. Además, a partir de las colonias, se lograron fotografías de células con morfología y tamaño similares a las fitoplasmáticas. Es la primera vez, en el mundo, que se consolida información suficiente del aislamiento de fitoplasmas en medio artificial. Adicionalmente, se logró el aislamiento de Pigeon pea witches´ broom phytoplasma del grupo IX, a partir de tallos, peciolos y flores de vinca (Catharanthus roseus), con síntomas asociados a fitoplasmas. Este proceso permitió corroborar la efectividad del medio y la morfología de las células fitoplasmáticas, bajo microscopia electrónica.

18.
Intractable Rare Dis Res ; 8(1): 29-35, 2019 Feb.
Article in English | MEDLINE | ID: mdl-30881855

ABSTRACT

Retroperitoneal fibrosis (RPF) is a rare disease characterized by chronic inflammation and periaortic fibrosis that affects retroperitoneal structures and often entraps the ureters. The idiopathic form has an incidence of 0.1-1.3/100,000 person-years. A substantial percentage of patients with idiopathic retroperitoneal fibrosis (IRF), as well as patients with orbital pseudotumor, is associated with IgG4-related disease (IgG4-RD). It is not clear what percentage of IRF is related to the spectrum of the IgG4-RD or if both represent different stages of the same disease (especially in those cases with extra-retroperitoneal involvement). Histopathological features such as storiform fibrosis, obliterative phlebitis and tissue infiltration of IgG4-positive plasma cells (ratio IgG4+/IgG higher than 0.4) are essential to identify this association. Extra-retroperitoneal manifestations are often presented among patients with IgG4-related RPF. About 90% of cases of IRF have a good prognosis, with adequate response to treatment. We report a case of a 59-year-old woman with history of past occupational asbestos exposure and smoking habit. She was diagnosed with RPF, periaortitis and orbital pseudotumor, without histopathologic or serologic features of IgG4- related disease. This could be related to the fact that the biopsy was done in a place with scarce inflammatory activity but high fibrosis. We want to emphasize the usual need to perform several biopsies or to be guided by positron emission tomography (PET-CT) in order to achieve a histopathological confirmation. Our case differs from the main IgG4 international cohorts in the involvement of the retroperitoneum, aorta and eye, whereas the usual involvement includes liver, pancreas, lymph nodes and salivary glands. Our patient had lower IgG4 serum levels than those described in the international cohorts. However, they were similar to those of the Spanish population.

SELECTION OF CITATIONS
SEARCH DETAIL
...