Development of NR0B2 as a therapeutic target for the re-education of tumor associated myeloid cells.

Immune checkpoint blockade (ICB) has had limited utility in several solid tumors such as breast cancer, a major cause of cancer-related mortality in women. Therefore, there is considerable interest in alternate strategies to promote an anti-cancer immune response. A paper co-published in this issue describes how NR0B2, a protein involved in cholesterol homeostasis, functions within myeloid immune cells to modulate the inflammasome and reduce the expansion of immune-suppressive regulatory T cells (Treg). Here, we develop NR0B2 as a potential therapeutic target. NR0B2 in tumors is associated with improved survival for several cancer types including breast. Importantly, NR0B2 expression is also prognostic of ICB success. Within breast tumors, NR0B2 expression is inversely associated with FOXP3, a marker of Tregs. While a described agonist (DSHN) had some efficacy, it required high doses and long treatment times. Therefore, we designed and screened several derivatives. A methyl ester derivative (DSHN-OMe) emerged as superior in terms of (1) cellular uptake, (2) ability to regulate expected expression of genes, (3) suppression of Treg expansion using in vitro co-culture systems, and (4) efficacy against the growth of primary and metastatic tumors. This work identifies NR0B2 as a target to re-educate myeloid immune cells and a novel ligand with significant anti-tumor efficacy in preclinical models.

NR0B2 re-educates myeloid immune cells to reduce regulatory T cell expansion and progression of breast and other solid tumors.

Although survival from breast cancer has dramatically increased, many will develop recurrent, metastatic disease. Unfortunately, survival for this stage of disease remains very low. Activating the immune system has incredible promise since it has the potential to be curative. However, immune checkpoint blockade (ICB) which works through T cells has been largely disappointing for metastatic breast cancer. One reason for this is a suppressive myeloid immune compartment that is unaffected by ICB. Cholesterol metabolism and proteins involved in cholesterol homeostasis play important regulatory roles in myeloid cells. Here, we demonstrate that NR0B2, a nuclear receptor involved in negative feedback of cholesterol metabolism, works in several myeloid cell types to impair subsequent expansion of regulatory T cells (Tregs); Tregs being a subset known to be highly immune suppressive and associated with poor therapeutic response. Within myeloid cells, NR0B2 serves to decrease many aspects of the inflammasome, ultimately resulting in decreased IL1ß; IL1ß driving Treg expansion. Importantly, mice lacking NR0B2 exhibit accelerated tumor growth. Thus, NR0B2 represents an important node in myeloid cells dictating ensuing Treg expansion and tumor growth, thereby representing a novel therapeutic target to re-educate these cells, having impact across different solid tumor types. Indeed, a paper co-published in this issue demonstrates the therapeutic utility of targeting NR0B2.

Re-education of myeloid immune cells to reduce regulatory T cell expansion and impede breast cancer progression.

Immune checkpoint blockade (ICB) has revolutionized cancer therapy but has had limited utility in several solid tumors such as breast cancer, a major cause of cancer-related mortality in women. Therefore, there is considerable interest in alternate strategies to promote an anti-cancer immune response. We demonstrate that NR0B2, a protein involved in cholesterol homeostasis, functions within myeloid immune cells to modulate the NLRP3 inflammasome and reduce the expansion of immune-suppressive regulatory T cells (Treg). Loss of NR0B2 increased mammary tumor growth and metastasis. Small molecule agonists, including one developed here, reduced Treg expansion, reduced metastatic growth and improved the efficacy of ICB. This work identifies NR0B2 as a target to re-educate myeloid immune cells providing proof-of-principle that this cholesterol-homeostasis axis may have utility in enhancing ICB.

Características clínicas del estado epiléptico en niños de un hospital de tercer nivel de Lima / Clinical characteristics of status epilepticus in children in a third level hospital of Lima

RESUMEN El estado epiléptico (EE) en niños exhibe altos niveles de morbi-mortalidad y ha sido poco estudiado en el Perú. Objetivo: Describir la frecuencia y características clínicas de niños con estado epiléptico, atendidos en el Hospital Cayetano Heredia de Lima. Material y métodos: Estudio retrospectivo y observacional, tipo serie de casos de niños menores de 14 años con diagnóstico de estado epiléptico, atendidos entre enero y diciembre de 2021. Resultados: Se registró EE en un 28,8% de todos los niños atendidos por crisis epilépticas durante el año 2021. Se incluyeron 23 niños que presentaron 46 EE, varones (73,9%), con una mediana de la edad de 2 años, diagnóstico subyacente de epilepsia o malformación cerebral (21,7%), atendidos en emergencia pediátrica (91%). El tipo semiológico predominante fue el EE motor generalizado (52,2%), con etiología sintomática remota (87%) y EEG registrado en un 63% de los casos, predominantemente de tipo normal (75,9%). La mediana de duración fue de 22 minutos, de resolución total, 7 minutos y resolución parcial, 2 minutos. Se empleó midazolam (78%) como primera línea de tratamiento y fenitoína (85%), como segunda línea. Conclusiones: El EE en niños fue una emergencia prevalente durante el año 2021. La mayoría fueron varones, cuya etiología predominante fue sintomática remota y el tipo semiológico más común fue el motor generalizado. Los niños fueron atendidos de acuerdo con las guías internacionales de manejo. Se insiste en la necesidad de un sistemático afronte de vigilancia epidemiológica.

SUMMARY Status Epilepticus (SE) in children exhibits high levels of morbidity and mortality and has been poorly studied in Perú. Objective: To describe the frequency and clinical characteristics of children with Status Epilepticus treated at Cayetano Heredia Hospital in Lima. Material and Methods: Retrospective and observational study, case series type, in children under 14 years of age, with Status Epilepticus treated between January and December of 2021. Results: SE was recorded in 28.8% of children with epileptic seizures seen during 2021. Twenty-three children presenting 46 SEs were included. The median age was 2 years, the majority (73,9%) being males, with diagnosis of epilepsy or brain malformation (21.7%) and treated in the pediatric emergency (91%). The predominant semiological pattern was of generalized motor type (52.2%), with remote symptomatic etiology (73.9%), and EEG recorded in a 63% of all cases, mainly reported as normal (75,9%). The median duration was 22 minutes of total resolution, 7 minutes, and of partial resolution, 2 minutes. Midazolam was used as the first line of treatment (78%), and phenytoin as the second line (85%). Conclusions: SE was a frequent condition observed in children throughout the year 2021. Most affected children were male, the predominant etiology was remote symptomatic, and the most common semiological type was the generalized motor. The children were treated according to international management guidelines. Asystematic epidemiological surveillance approach is highly encouraged.

Effect of within-litter birth weight variation after cross-fostering on piglet preweaning growth and mortality.

Cross-fostering is commonly used in commercial swine production to equalize litter sizes and/or adjust piglet birth weights within litters. However, there is limited published information on optimum cross-fostering procedures. This study evaluated the effects of within-litter birth weight variation after cross-fostering (using litters of 14 piglets) on piglet preweaning mortality (PWM) and weaning weight (WW). An RCBD was used (blocking factors were day of farrowing and sow parity, body condition score, and functional teat number) with an incomplete factorial arrangement of the following two treatments: 1) birth weight category (BWC): light (<1.0 kg), medium (1.0 to 1.5 kg), or heavy (1.5 to 2.0 kg); 2) litter composition: uniform, all piglets in the litter of the same BWC [uniform light (14 light piglets); uniform medium (14 medium piglets); uniform heavy (14 heavy piglets)]; mixed, piglets in the litter of two or more BWC [L+M (seven light and seven medium piglets); M+H (seven medium and seven heavy piglets); L+M+H (three light, six medium, and five heavy piglets)]. Piglets were weighed at 24 h after birth and randomly allotted to litter composition treatment from within BWC; all piglets were cross-fostered. There were 47 blocks of six litters (total 282 litters and 3,948 piglets). Weaning weights were collected at 18.7 ± 0.64 d of age; all PWM was recorded. Individual piglet WW and PWM data were analyzed using PROC MIXED and PROC GLIMMIX of SAS, respectively; models included fixed effects of BWC, litter composition, and the interaction, and random effects of sow within the block. There was litter composition by BWC interactions (P ≤ 0.05) for WW and PWM. Within each BWC, WW generally increased and PWM generally decreased as littermate weight decreased. For example, WW was greatest (P ≤ 0.05) for light piglets in uniform light litters, for medium piglets in L+M litters, and for heavy piglets in L+M+H litters. Preweaning mortality was lowest (P ≤ 0.05) for medium piglets in L+M litters, and for heavy piglets in L+M+H litters; however, litter composition had no effect (P > 0.05) on PWM of light piglets. In conclusion, increasing the average birth weight of littermates after cross-fostering generally decreased WW and increased PWM for piglets of all birth weight categories. This implies that the optimum approach to cross-fostering that maximizes piglet preweaning growth and survival is likely to vary depending on the birth weight distribution of the population.

Electrical Power Diversification: An Approach Based on the Method of Maximum Entropy in the Mean.

Electrical energy is generated in different ways, each located at some specific geographical area, and with different impact on the environment. Different sectors require heterogeneous rates of energy delivery, due to economic requirements. An important problem to solve is to determine how much energy must be sent from each supplier to satisfy each demand. Besides, the energy distribution process may have to satisfy ecological, technological, or economic cost constraints.

Synthesis of exo-Imidazolidin-2-one Dienes, Their Isomerization, and Selectivity in Diels-Alder Cycloadditions.

An efficient and alternative synthesis of exo-imidazolidin-2-one dienes is described. A condensation reaction was carried out with bis-imino derivatives, diacetyl, and triphosgene, affording symmetrically N, N-disubstituted dienes. The use of alkyl methyl α-diketones led to the formation of nonsymmetrical dienes, which underwent isomerization to provide more stable inner-outer-ring dienes under Lewis acid conditions. Evaluation was made of the reactivity as well as regio- and stereoselectivity of these dienes in Diels-Alder reactions. They proved to be highly reactive and selective. DFT calculations of the transition states accounted for their behavior.

Condensation of Diacetyl with Alkyl Amines: Synthesis and Reactivity of p-Iminobenzoquinones and p-Diiminobenzoquinones.

Condensation reactions between diacetyl and α-branched primary alkylamines under mild and neutral conditions provided a mixture of 2,5-dimethylbenzoquinone(alkylimines), 2,5-dimethylbenzoquinone(bis-alkyldiimines), and N,N'-dialkyl-2,5-dimethylbenzene-1,4-diamines, which were efficiently separated as pure products by column chromatography. Both 2,5-dimethylbenzoquinone(alkylimines) and 2,5-dimethylbenzoquinone(bis-alkyldiimines) underwent an interchange of the alkylimino group when treated with anilines, followed by reductive aromatization, to provide diarylamines and 1,4-dianilinobenzenes, respectively. Evaluation was also made of the reactivity and selectivity of these compounds in the presence of anilines, thiophenols and alkylhalides.

Regioselective synthesis of 1,2-dihydroquinolines by a solvent-free MgBr2-catalyzed multicomponent reaction.

A highly efficient and regioselective synthesis of 1,2-dihydroquinolines via a multicomponent reaction between an aniline and two ketones is described. This reaction was catalyzed by magnesium bromide and carried out under solvent-free conditions. When the reaction was performed by using 3-substituted anilines and nonsymmetrically substituted ketones, principally a single product was found among the four expected regioisomers. A variety of anilines and ketones, including cyclic ketones, were evaluated providing a series of 1,2-dihydroquinolines with diverse substitution patterns. A study of the mechanism is discussed. There is evidence of the in situ formation of the imine as a result of the reaction between the aniline and one of the ketones, before annulation to the heterocyclic ring.

Palladium-catalyzed synthesis of natural and unnatural 2-, 5-, and 7-oxygenated carbazole alkaloids from N-arylcyclohexane enaminones.

A palladium-catalyzed synthesis of the carbazole framework is described, including the preparation of 2-, 5-, and 7-oxygenated natural and unnatural carbazole alkaloids. A series of N-arylcyclohexane enaminones, generated by condensation of cyclohexane-1,3-dione with diverse anilines, were aromatized by a Pd(0)-catalyzed thermal treatment to afford the corresponding diarylamines. The latter were submitted to a Pd(II)-catalyzed cyclization and methylation processes to provide the desired carbazoles, including clausine V. Following an inverse strategy, a new and short total synthesis of glycoborine is also reported.

A concise total synthesis of the natural carbazole clauraila A.

A short and efficient total synthesis of naturally occurring carbazole clauraila A (1) is described. The approach is designed on the basis of the key regioselective Diels-Alder reaction of the properly substituted exo-2-oxazolidinone diene 3 with acrolein (4) to give the corresponding adduct 2. The latter is converted to functionalised diarylamine 8, which is cyclised to the desired carbazole 1 through a Pd-promoted or -catalysed double C-H bond activation process in a fairly good overall yield.

Synthesis and Diels-Alder cycloadditions of exo-imidazolidin-2-one dienes.

An efficient and versatile synthesis of novel exo-imidazolidin-2-one dienes is described. This involves the base-assisted condensation/cyclization cascade reaction of the monoimino derivatives of diacetyl with a series of isocyanates. This methodology enables preparation of symmetrical dienes, as long as the substrates have the same N substituent. Moreover, use of different N-substituted starting materials leads to formation of nonsymmetrical dienes. The reactivity of these dienes was evaluated in Diels-Alder reactions, showing a high reactivity.