Global methylome scores correlate with histological subtypes of colorectal carcinoma and show different associations with common clinical and molecular features

Background. The typical methylation patterns associated with cancer are hypermethylation at gene promoters and global genome hypomethylation. Aberrant CpG island hypermethylation at promoter regions and global genome hypomethylation have not been associated with histological colorectal carcinomas (CRC) subsets. Using Illumina’s 450 k Infinium Human Methylation beadchip, the methylome of 82 CRCs were analyzed, comprising different histological subtypes: 40 serrated adenocarcinomas (SAC), 32 conventional carcinomas (CC) and 10 CRCs showing histological and molecular features of microsatellite instability (hmMSI‐H), and, additionally, 35 normal adjacent mucosae. Scores reflecting the overall methylation at 250 bp, 1 kb and 2 kb from the transcription starting site (TSS) were studied. Results. SAC has an intermediate methylation pattern between CC and hmMSI‐H for the three genome locations. In addition, the shift from promoter hypermethylation to genomic hypomethylation occurs at a small sequence between 250 bp and 1 Kb from the gene TSS, and an asymmetric distribution of methylation was observed between both sides of the CpG islands (N vs. S shores). Conclusion. These findings show that different histological subtypes of CRC have a particular global methylation pattern depending on sequence distance to TSS and highlight the so far underestimated importance of CpGs aberrantly hypomethylated in the clinical phenotype of CRCs.This work was supported by two grants from Instituto de Salud Carlos III, Ministerio de Sanidad, Spain and FEDER funds (refs: PI12-1232, PI18-0144) and another from the European Union’s Horizon 2020 research and innovation program (ref. 848098

Uso de la analgesia acupuntural quirúrgica en la herniorrafía inguinal. The use of surgical acupunctural analysis in inguinal herniarhaphy

Por la importancia que ha alcanzado en nuestro país la aplicación de la medicina natural y tradicional y dentro de ésta la acupuntura, no sólo en el orden clínico sino con fines quirúrgicos, se realizó un estudio descriptivo y retrospectivo de 40 pacientes operados por hernia inguinal en el Hospital General Docente "Abel Santamaría Cuadrado" de Pinar del Río durante el período comprendido de enero a julio del año 2003, con el objetivo de evaluar la efectividad de la analgesia quirúrgica acupuntural en este tipo de cirugía. Se conformaron dos grupos (control y estudio). Al control se le aplicó anestesia espinal y al de estudio, analgesia quirúrgica acupuntural. Se comparó grado de analgesia transoperatoria y postoperatoria, así como las complicaciones. Se determinó el grado de satisfacción de los pacientes, para lo cual fue aplicada una escala analógica visual, siendo buena en un 90% de los pacientes, a los cuales se les aplicó la analgesia acupuntural. Este proceder es inocuo, de fácil aplicación, bien aceptado por el paciente, y representa un ahorro económico considerable, ya que disminuye los costos hospitalarios, por lo que recomendamos su empleo de forma sistemática. En todos los pacientes se aplicó la cirugía mayor ambulatoria. Palabras clave: ACUPUNTURA, ANALGESIA, HERNIA INGUINAL, MEDICINA TRADICIONAL. ABSTRACT By the importance the application of the traditional and natural medicine has gotten in our country, specially acupuncture, not only clinically but also with surgical purposes, a descriptive and retrospective study was performed with 40 patients operated on for inguinal hernia at "Abel Santamaría Cuadrado" Teaching University Hospital in Pinar del Río, from January to July 2003, with the purpose of assessing the effectiveness of the surgical acupunctural analgesia in this type of surgery. Two groups were formed (control and study). The control group was applied spinal anesthesia, and the study group was applied surgical acupunctural analgesia. The degree of transoperative and post-operative analgesia was compared, as well as the complications. The degree of the patient's satisfaction was registered, for which a visual analogical scale was applied, being good in 90% patients who underwent acupunctural analgesia. This procedure is harmless, easily applicable, well accepted by the patient, and represents a significant economical saving since it diminishes hospital costs. This is why its systematic use is recommended. All patients underwent major ambulatory surgery. Key words: ACUPUNCTURE, ANALGESIA, INGUINAL HERNIA, TRADITIONAL MEDICINE

miR-146a rs2431697 identifies myeloproliferative neoplasm patients with higher secondary myelofibrosis progression risk

Myelofibrosis (MF) occurs as part of the natural history of polycythemia vera (PV) and essential thrombocythemia (ET), and remarkably shortens survival. Although JAK2V617F and CALR allele burden are the main transformation risk factors, inflammation plays a critical role by driving clonal expansion toward end-stage disease. NF-κB is a key mediator of inflammation-induced carcinogenesis. Here, we explored the involvement of miR-146a, a brake in NF-κB signaling, in MPN susceptibility and progression. rs2910164 and rs2431697, that affect miR-146a expression, were analyzed in 967 MPN (320 PV/333 ET/314 MF) patients and 600 controls. We found that rs2431697 TT genotype was associated with MF, particularly with post-PV/ET MF (HR = 1.5; p < 0.05). Among 232 PV/ET patients (follow-up time=8.5 years), 18 (7.8%) progressed to MF, being MF-free-survival shorter for rs2431697 TT than CC + CT patients (p = 0.01). Multivariate analysis identified TT genotype as independent predictor of MF progression. In addition, TT (vs. CC + CT) patients showed increased plasma inflammatory cytokines. Finally, miR-146a−/− mice showed significantly higher Stat3 activity with aging, parallel to the development of the MF-like phenotype. In conclusion, we demonstrated that rs2431697 TT genotype is an early predictor of MF progression independent of the JAK2V617F allele burden. Low levels of miR-146a contribute to the MF phenotype by increasing Stat3 signaling

Sarilumab in patients admitted to hospital with severe or critical COVID-19: a randomised, double-blind, placebo-controlled, phase 3 trial

Background: Elevated proinflammatory cytokines are associated with greater COVID-19 severity. We aimed to assess safety and efficacy of sarilumab, an interleukin-6 receptor inhibitor, in patients with severe (requiring supplemental oxygen by nasal cannula or face mask) or critical (requiring greater supplemental oxygen, mechanical ventilation, or extracorporeal support) COVID-19. Methods: We did a 60-day, randomised, double-blind, placebo-controlled, multinational phase 3 trial at 45 hospitals in Argentina, Brazil, Canada, Chile, France, Germany, Israel, Italy, Japan, Russia, and Spain. We included adults (≥18 years) admitted to hospital with laboratory-confirmed SARS-CoV-2 infection and pneumonia, who required oxygen supplementation or intensive care. Patients were randomly assigned (2:2:1 with permuted blocks of five) to receive intravenous sarilumab 400 mg, sarilumab 200 mg, or placebo. Patients, care providers, outcome assessors, and investigators remained masked to assigned intervention throughout the course of the study. The primary endpoint was time to clinical improvement of two or more points (seven point scale ranging from 1 [death] to 7 [discharged from hospital]) in the modified intention-to-treat population. The key secondary endpoint was proportion of patients alive at day 29. Safety outcomes included adverse events and laboratory assessments. This study is registered with ClinicalTrials.gov, NCT04327388; EudraCT, 2020-001162-12; and WHO, U1111-1249-6021. Findings: Between March 28 and July 3, 2020, of 431 patients who were screened, 420 patients were randomly assigned and 416 received placebo (n=84 [20%]), sarilumab 200 mg (n=159 [38%]), or sarilumab 400 mg (n=173 [42%]). At day 29, no significant differences were seen in median time to an improvement of two or more points between placebo (12·0 days [95% CI 9·0 to 15·0]) and sarilumab 200 mg (10·0 days [9·0 to 12·0]; hazard ratio [HR] 1·03 [95% CI 0·75 to 1·40]; log-rank p=0·96) or sarilumab 400 mg (10·0 days [9·0 to 13·0]; HR 1·14 [95% CI 0·84 to 1·54]; log-rank p=0·34), or in proportions of patients alive (77 [92%] of 84 patients in the placebo group; 143 [90%] of 159 patients in the sarilumab 200 mg group; difference −1·7 [−9·3 to 5·8]; p=0·63 vs placebo; and 159 [92%] of 173 patients in the sarilumab 400 mg group; difference 0·2 [−6·9 to 7·4]; p=0·85 vs placebo). At day 29, there were numerical, non-significant survival differences between sarilumab 400 mg (88%) and placebo (79%; difference +8·9% [95% CI −7·7 to 25·5]; p=0·25) for patients who had critical disease. No unexpected safety signals were seen. The rates of treatment-emergent adverse events were 65% (55 of 84) in the placebo group, 65% (103 of 159) in the sarilumab 200 mg group, and 70% (121 of 173) in the sarilumab 400 mg group, and of those leading to death 11% (nine of 84) were in the placebo group, 11% (17 of 159) were in the sarilumab 200 mg group, and 10% (18 of 173) were in the sarilumab 400 mg group. Interpretation: This trial did not show efficacy of sarilumab in patients admitted to hospital with COVID-19 and receiving supplemental oxygen. Adequately powered trials of targeted immunomodulatory therapies assessing survival as a primary endpoint are suggested in patients with critical COVID-19. Funding: Sanofi and Regeneron Pharmaceuticals

Performance of broiler chickens supplemented with Mexican oregano oil (Lippia berlandieri Schauer)

The objective of this research was to evaluate the inclusion of two qualities of Mexican oregano oil (MOO) in broiler diets on broiler weight, feed intake, feed efficiency, average daily gain, and water intake. The qualities were MOO1 (4% thymol, 60% carvacrol) and MOO2 (40% thymol, 20% carvacrol). Nine treatments were prepared by the combinations of MOO1 + MOO2 (0, 400, and 800 mg kg&#8722;1; added per kg of feed) respectively: 0+0, 0+400, 0+800, 400+0, 400+400, 400+800, 800+0, 800+400, and 800+800. Eighteen chicks per treatment were divided in a completely randomized design into nine cages. Broiler weights were altered by the treatments at 21 d, when 400+400 had the highest weight, and on day 39, when the greatest weight was seen in broilers on treatments 800+0 and 800+400. Feed intake was affected by treatment on day 39, with broilers on 800+0 exhibiting the highest values. Water intake was influenced by the treatments on days 14, 21, 35, and 39, when 0+0 represented the lowest. Feed efficiency was altered by the treatments on days 14, 28, 35, and 39, whereas average daily gain was affected from days 14 to 39. Supplementation of Mexican oregano oil has beneficial effects on broiler weight, feed efficiency, average daily gain, and feed and water intakes. Combinations of thymol and carvacrol levels have varying effects on these parameters. The higher relative body weights of groups 400+0, 800+0, and 800+400 suggest positive market value effects of these combinations of Mexican oregano oil

Pre-Germinative Treatments and Morphophysiological Traits in Enterolobium cyclocarpum and Piscidia piscipula (Fabaceae) from the Yucatan Peninsula, Mexico

Enterolobium cyclocarpum and Piscidia piscipula are two important tree Fabaceae species distributed from the Yucatan Peninsula, Mexico. Our aims were focused on the E. cyclocarpum and P. piscipula seeds for: (1) to examine the seed permeability and imbibition rate, (2) to evaluate the effect of seed pre-germinative treatments, and (3) to characterize the structures involved on the presence of physical dormancy (PY). We used fresh seeds to determine seed permeability and imbibition rate, seed viability by means of tetrazolium test, furthermore, we applied mechanical scarification and boiler shocks for 5 s, 10 s and 15 s treatments. Morphological characterization of the seed coat was by Scanning Electron Microscope (SEM). Seed viability in E. cyclocarpum and P. piscipula were 100% and 96%, respectively. Seed permeability and imbibition rate in E. cyclocarpum were low. The highest germination in E. cyclocarpum was in the mechanical scarification (92%), while in P. piscipula, this parameter was in the 10 s boiling water treatment (76.0%). The presence of PY was confirmed in both species because they showed low seed permeability, and imbibition rate; furthermore, exhibited macrosclereids cells. The present research seeks to promote the sustainable use of E. cyclocarpum and P. piscipula

Functional complexity emerging from anatomical constraints in the brain: the significance of network modularity and rich-clubs

The large-scale structural ingredients of the brain and neural connectomes have been identified in recent years. These are, similar to the features found in many other real networks: the arrangement of brain regions into modules and the presence of highly connected regions (hubs) forming rich-clubs. Here, we examine how modules and hubs shape the collective dynamics on networks and we find that both ingredients lead to the emergence of complex dynamics. Comparing the connectomes of C. elegans, cats, macaques and humans to surrogate networks in which either modules or hubs are destroyed, we find that functional complexity always decreases in the perturbed networks. A comparison between simulated and empirically obtained resting-state functional connectivity indicates that the human brain, at rest, lies in a dynamical state that reflects the largest complexity its anatomical connectome can host. Last, we generalise the topology of neural connectomes into a new hierarchical network model that successfully combines modular organisation with rich-club forming hubs. This is achieved by centralising the cross-modular connections through a preferential attachment rule. Our network model hosts more complex dynamics than other hierarchical models widely used as benchmarks.This work has been supported by (G.Z.L.) the European Union Seventh Framework Programme FP7/2007–2013 under grant agreement number PIEF-GA-2012-331800, the German Federal Ministry of Education and Research (Bernstein Center II, grant no. 01GQ1001A), and the European Union’s Horizon 2020 research and innovation programme under grant agreement No. 720270 (HBP SGA1). Y.C. and C.S.Z. were supported by the Hong Kong Baptist University (HKBU) Strategic Development Fund, the Hong Kong Research Grant Council (GRF12302914), HKBU FRG2/14-15/025 and the National Natural Science Foundation of China (No. 11275027). G.D. is supported by the European Research Council Advanced Grant: DYSTRUCTURE (295129) and by the Spanish Research Project PSI2013-42091-P; and M.L.K. by the European Research Council Consolidator Grant: CAREGIVING (615539)