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1.
Ann Rheum Dis ; 82(12): 1594-1605, 2023 12.
Article in English | MEDLINE | ID: mdl-37666646

ABSTRACT

BACKGROUND: The vacuoles, E1-enzyme, X linked, autoinflammatory and somatic (VEXAS) syndrome is an adult-onset autoinflammatory disease (AID) due to postzygotic UBA1 variants. OBJECTIVES: To investigate the presence of VEXAS syndrome among patients with adult-onset undiagnosed AID. Additional studies evaluated the mosaicism distribution and the circulating cytokines. METHODS: Gene analyses were performed by both Sanger and amplicon-based deep sequencing. Patients' data were collected from their medical charts. Cytokines were quantified by Luminex. RESULTS: Genetic analyses of enrolled patients (n=42) identified 30 patients carrying UBA1 pathogenic variants, with frequencies compatible for postzygotic variants. All patients were male individuals who presented with a late-onset disease (mean 67.5 years; median 67.0 years) characterised by cutaneous lesions (90%), fever (66.7%), pulmonary manifestations (66.7%) and arthritis (53.3%). Macrocytic anaemia and increased erythrocyte sedimentation rate and ferritin were the most relevant analytical abnormalities. Glucocorticoids ameliorated the inflammatory manifestations, but most patients became glucocorticoid-dependent. Positive responses were obtained when targeting the haematopoietic component of the disease with either decitabine or allogeneic haematopoietic stem cell transplantation. Additional analyses detected the UBA1 variants in both haematopoietic and non-haematopoietic tissues. Finally, analysis of circulating cytokines did not identify inflammatory mediators of the disease. CONCLUSION: Thirty patients with adult-onset AID were definitively diagnosed with VEXAS syndrome through genetic analyses. Despite minor interindividual differences, their main characteristics were in concordance with previous reports. We detected for the first time the UBA1 mosaicism in non-haematopoietic tissue, which questions the previous concept of myeloid-restricted mosaicism and may have conceptual consequences for the disease mechanisms.


Subject(s)
Arthritis , Mosaicism , Adult , Humans , Male , Female , Cytokines/genetics , Ferritins , Glucocorticoids , Mutation
3.
Nat Chem Biol ; 12(4): 218-25, 2016 Apr.
Article in English | MEDLINE | ID: mdl-26829472

ABSTRACT

A hallmark of targeted cancer therapies is selective toxicity among cancer cell lines. We evaluated results from a viability screen of over 200,000 small molecules to identify two chemical series, oxalamides and benzothiazoles, that were selectively toxic at low nanomolar concentrations to the same 4 of 12 human lung cancer cell lines. Sensitive cell lines expressed cytochrome P450 (CYP) 4F11, which metabolized the compounds into irreversible inhibitors of stearoyl CoA desaturase (SCD). SCD is recognized as a promising biological target in cancer and metabolic disease. However, SCD is essential to sebocytes, and accordingly SCD inhibitors cause skin toxicity. Mouse sebocytes did not activate the benzothiazoles or oxalamides into SCD inhibitors, providing a therapeutic window for inhibiting SCD in vivo. We thus offer a strategy to target SCD in cancer by taking advantage of high CYP expression in a subset of tumors.


Subject(s)
Antineoplastic Agents/pharmacology , Benzothiazoles/pharmacology , Drug Discovery/methods , Lung Neoplasms/enzymology , Oxamic Acid/analogs & derivatives , Stearoyl-CoA Desaturase/antagonists & inhibitors , Animals , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/therapeutic use , Antineoplastic Agents/toxicity , Benzothiazoles/pharmacokinetics , Benzothiazoles/therapeutic use , Benzothiazoles/toxicity , Cell Line, Tumor , Cytochrome P-450 Enzyme System/metabolism , Cytochrome P450 Family 4 , Female , Humans , Lung Neoplasms/pathology , Male , Mice , Mice, SCID , Molecular Structure , Molecular Targeted Therapy , Oxamic Acid/pharmacokinetics , Oxamic Acid/pharmacology , Oxamic Acid/therapeutic use , Oxamic Acid/toxicity , Protein Binding , Sebaceous Glands/drug effects , Sebaceous Glands/enzymology , Sebaceous Glands/pathology , Xenograft Model Antitumor Assays
4.
Nano Lett ; 14(5): 2941-5, 2014 May 14.
Article in English | MEDLINE | ID: mdl-24745894

ABSTRACT

We have designed and synthesized five azulene derivatives containing gold-binding groups at different points of connectivity within the azulene core to probe the effects of quantum interference through single-molecule conductance measurements. We compare conducting paths through the 5-membered ring, 7-membered ring, and across the long axis of azulene. We find that changing the points of connectivity in the azulene impacts the optical properties (as determined from UV-vis absorption spectra) and the conductivity. Importantly, we show here that simple models cannot be used to predict quantum interference characteristics of nonalternant hydrocarbons. As an exemplary case, we show that azulene derivatives that are predicted to exhibit destructive interference based on widely accepted atom-counting models show a significant conductance at low biases. Although simple models to predict the low-bias conductance do not hold with all azulene derivatives, we demonstrate that the measured conductance trend for all molecules studied actually agrees with predictions based on the more complete GW calculations for model systems.


Subject(s)
Azulenes/chemistry , Hydrocarbons/chemistry , Azulenes/chemical synthesis , Gold/chemistry , Hydrocarbons/chemical synthesis , Molecular Structure , Quantum Theory
5.
Med. UIS ; 24(2): 195-199, mayo.-ago. 2011. tab
Article in Spanish | LILACS | ID: lil-668949

ABSTRACT

Objetivo: analizar los resultados en cirugía de control de daño en una institución con alta incidencia de trauma en México. Materiales y métodos: estudio prospectivo descriptivo, realizado en el Hospital General de ciudad Juárez. Se incluyeron 66 pacientes con lesiones severas en abdomen ocasionadas por proyectil de arma de fuego o por arma punzo-cortante, sometidos a cirugía de control de daño durante el periodo de abril del 2008 a diciembre del 2010. El análisis estadístico se realizó con porcentajes como medidas de resumen de variables. Resultados: el promedio de edad fue de 29,6 años, con 59 pacientes heridos por arma de fuego y 7 por arma blanca. El tiempo quirúrgico promedio fue de 97 minutos. La víscera hueca más lesionada fue el intestino delgado con 35 casos y el órgano sólido fue el hígado con 30. Se encontró un hemoperitoneo en promedio de 3350 ml. Además, 64 pacientes presentaron choque hipovolémico grado IV y dos pacientes grado III. La principal complicación fue la presencia de infección de sitio quirúrgico y la principal causa de muerte postquirúrgica la falla orgánica múltiple secundaria a la presencia de la triada mortal la cual consiste en la presencia de hipotermia, acidosis metabólica y coagulopatía. Conclusiones: Los pacientes en edad productiva son los más afectados. El principal mecanismo de acción son las heridas por proyectil de arma de fuego. Se presenta una alta morbimortalidad relacionada en este tipo de pacientes, como son la presencia de sepsis y fistulas; asociándose la mortalidad principalmente a la falla orgánica múltiple y a la presencia de choque hipovolémico...


Objective: to analyze the results of damage control surgery in an institution with high incidence of trauma in México. Materials and methods: prospective and descriptive study, realized in the Hospital General of Ciudad Juarez. It was included 66 patients with several abdominal injuries made by missile of fi rearms or sharp-edged objects underwent to damage control surgery between April 2008 and December 2010. The statistical analysis was with percentages as summary measures of variables. Results: the average age was 29.6 years old, with 59 patients with fi rearm’s injuries and 7 patients with incised wounds. The average surgical time was 97 minutes. The most injured hollow viscus was small intestine with 35 cases and the solid organ was the liver with 30 patients injured. It was found an average hemoperitoneum of 3350 ml. Besides, 64 patients showed IV degree hypovolemic shock and 2 with III degree shock. The main complication was surgical site infection and the main cause of postsurgical death was multiple organ failure secondary to the presence of the deadly triad which is hypothermia, metabolic acidosis and coagulopathy. Conclusions: the patients in the productive age are most affected. The principal mechanism of action is injuries by a fi rearm projectile. It has a high morbimortality related to these patients, such as sepsis and fistulas, associating mainly the mortality to the multiple organ failure and the presence of hypovolemic shock...


Subject(s)
Acidosis , Hypothermia , Wounds and Injuries
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