Colorectal cancer incidences in Lynch syndrome: a comparison of results from the prospective lynch syndrome database and the international mismatch repair consortium

Objective To compare colorectal cancer (CRC) incidences in carriers of pathogenic variants of the MMR genes in the PLSD and IMRC cohorts, of which only the former included mandatory colonoscopy surveillance for all participants. Methods CRC incidences were calculated in an intervention group comprising a cohort of confirmed carriers of pathogenic or likely pathogenic variants in mismatch repair genes (path_MMR) followed prospectively by the Prospective Lynch Syndrome Database (PLSD). All had colonoscopy surveillance, with polypectomy when polyps were identified. Comparison was made with a retrospective cohort reported by the International Mismatch Repair Consortium (IMRC). This comprised confirmed and inferred path_MMR carriers who were first- or second-degree relatives of Lynch syndrome probands. Results In the PLSD, 8,153 subjects had follow-up colonoscopy surveillance for a total of 67,604 years and 578 carriers had CRC diagnosed. Average cumulative incidences of CRC in path_MLH1 carriers at 70 years of age were 52% in males and 41% in females; for path_MSH2 50% and 39%; for path_MSH6 13% and 17% and for path_PMS2 11% and 8%. In contrast, in the IMRC cohort, corresponding cumulative incidences were 40% and 27%; 34% and 23%; 16% and 8% and 7% and 6%. Comparing just the European carriers in the two series gave similar findings. Numbers in the PLSD series did not allow comparisons of carriers from other continents separately. Cumulative incidences at 25 years were < 1% in all retrospective groups. Conclusions Prospectively observed CRC incidences (PLSD) in path_MLH1 and path_MSH2 carriers undergoing colonoscopy surveillance and polypectomy were higher than in the retrospective (IMRC) series, and were not reduced in path_MSH6 carriers. These findings were the opposite to those expected. CRC point incidence before 50 years of age was reduced in path_PMS2 carriers subjected to colonoscopy, but not significantly so

Impact of Adiponectin Overexpression on Allergic Airways Responses in Mice

Obesity is an important risk factor for asthma. Obese individuals have decreased circulating adiponectin, an adipose-derived hormone with anti-inflammatory properties. We hypothesized that transgenic overexpression of adiponectin would attenuate allergic airways inflammation and mucous hyperplasia in mice. To test this hypothesis, we used mice overexpressing adiponectin (Adipo Tg). Adipo Tg mice had marked increases in both serum adiponectin and bronchoalveolar lavage (BAL) fluid adiponectin. Both acute and chronic ovalbumin (OVA) sensitization and challenge protocols were used. In both protocols, OVA-induced increases in total BAL cells were attenuated in Adipo Tg versus WT mice. In the acute protocol, OVA-induced increases in several IL-13 dependent genes were attenuated in Adipo Tg versus WT mice, even though IL-13 per se was not affected. With chronic exposure, though OVA-induced increases in goblet cells numbers per millimeter of basement membrane were greater in Adipo Tg versus WT mice, mRNA abundance of mucous genes in lungs was not different. Also, adiponectin overexpression did not induce M2 polarization in alveolar macrophages. Our results indicate that adiponectin protects against allergen-induced inflammatory cell recruitment to the airspaces, but not development of goblet cell hyperplasia

Freqüência cardíaca máxima em esteira ergométrica em diferentes horários Frecuencia cardíaca máxima en cinta ergométrica a diferentes horarios Maximal heart rate on treadmill at different times

Como muitas medidas do desempenho humano apresentam variações circadianas que parecem acompanhar o ritmo da temperatura corporal, o objetivo deste estudo foi comparar a freqüência cardíaca máxima (FCmax) no teste de Bruce (Tbruce) em diferentes horários do dia. Foram estudados 11 indivíduos do gênero masculino, com 22,0 ± 1,6 anos, fisicamente ativos e do cronotipo intermediário. Observaram-se FC de repouso (FCrep), FC máxima (FCmax), percepção de esforço (PE) e tempo até a exaustão (TBruce). Para medir a FC, foi utilizado o cardiofreqüencímetro Polar Vantage NV. A PE foi obtida pela escala de Borg (6-20). Aplicou-se o protocolo de Bruce para esteira ergométrica, até a exaustão, em seis horários distintos: 9:00, 12:00, 15:00, 18:00, 21:00 e 24:00 horas. Os resultados foram submetidos à análise de variância para medidas repetidas, seguida do teste de Tukey (p < 0,05) e ao ajuste Cosinor para identificação de padrões rítmicos. Houve diferença significativa entre a FCrep das 15:00 e 24:00 horas (67,2 ± 6,9 e 60,4 ± 6,4bpm) e na FCmax das 12:00 e 24:00 horas (197,4 ± 7,9 e 191,3 ± 5,8bpm). Não foi observada diferença na PE e no TBruce. Foi encontrada ritmicidade em um indivíduo na FCrep, um na FCmax e dois no TBruce. Concluiu-se que, em condições não controladas, mantendo-se as atividades diárias, tanto a FCrep quanto a Fcmax apresentam valores mais baixos por volta das 24:00 horas, sem perda no desempenho aeróbio máximo e sem alteração da PE. Esses achados devem ser considerados na avaliação aeróbia e na prescrição de exercícios em horários mais tardios.<br>Debido a que muchas medidas de desempeño humano presentan variaciones circadianas que parecen acompañar el ritmo de la temperatura corporal, el objetivo de este estudio ha sido el de comparar la frecuencia cardíaca máxima (FCmax) en el test de Bruce (TBruce) en diferentes horarios del día. Fueron estudiados 11 individuos del género masculino, con 22,0 ± 1,6 años, físicamente activos y de cronotipo intermedio. Se observó la FC de reposo (FCrep), FC máxima (FCmax), percepción de esfuerzo (PE) y tiempo hasta la extenuación (TBruce). Para medir la FC se usó el cardiofrecuencímetro Polar Vantage NV. La PE se obtuvo por la escala de Borg (6-20). Se aplicó el protocolo de Bruce para cinta ergométrica, hasta la extenuación, en 6 horarios distintos: 9:00, 12:00, 15:00, 18:00, 21:00 y 24:00 horas. Los resultados fueron sometidos a análisis de varianza para medidas repetidas, seguida del test de Tukey (p < 0,05) y al ajuste Cosinor para identificación de los padrones rítmicos. Hubo diferencia significativa entre la FCrep de las 15:00 y 24:00 h (67,2 ± 6,9 y 60,4 ± 6,4 bpm) y en la FCmax de las 12:00 y 24:00 horas (197,4 ± 7,9 y 191,3 ± 5,8 bpm). No fue observada diferencia en la PE y en el TBruce. Se encontró ritmo en 1 individuo en la FCrep, 1 en la FCmax y 2 en el TBruce. A partir de esto se concluyó que, en condiciones no controladas, manteniéndose las actividades diarias, tanto la FCrep, como la Fcmax, presentan valores más bajos alrededor de las 24:00 horas, sin pérdida en el desempeño aeróbico máximo y sin alteración de PE. Estos resultados deben ser considerados en la evaluación aeróbica y en la prescripción de ejercicios en horarios más tardíos.<br>The aim of this study was to compare the maximal heart rate (HRmax) in the Bruce test (TBruce) at different times of the day, since several measurements of the human performance present circadian variations which seem to follow the body temperature rhythm. Eleven male individuals, with 22.0 ± 1.6 years, physically active and from the intermediate chronotype were studied. The resting HR (HRres), maximal HR (HRmax), perceived exertion (PE) and time until exhaustion (TBruce) were observed. The Polar Vantage NV cardiofrequencymeter was used in order to measure the HR. The PE was obtained through the Borg's scale (6-20). The protocol by Bruce for treadmill was applied until exhaustion, at 6 different times: 9:00; 12:00; 15:00; 18:00; 21:00 and 24:00 hours. The results were submitted to the variance analysis for repeated measurements, followed by Tukey test (p < 0.05) and the Cosinor adjustment for identification of rhythmic patterns. There was significant difference between the HRres of the 15:00 and 24:00 h (67.2 ± 6.9 and 60.4 bpm) and in the HR max of the 12:00 and 24:00 hours (197.4 ± 7.9 and 191.3 ± 5.8 bpm). No difference was identified in the PE and in the TBruce. Rhythmicity was found in 1 individual in the HRres, 1 in the HRmax and 2 in the TBruce. It was concluded that in uncontrolled conditions, whenever daily activities are kept, both HRres and HRmax present lower indices around 24:00 hours, with no loss in the maximal aerobic performance and no PE alteration. These findings should be considered in the aerobic evaluation and in the exercises prescription at later times

Genetic regulation of OAS1 nonsense-mediated decay underlies association with COVID-19 hospitalization in patients of European and African ancestries

The chr12q24.13 locus encoding OAS1-OAS3 antiviral proteins has been associated with coronavirus disease 2019 (COVID-19) susceptibility. Here, we report genetic, functional and clinical insights into this locus in relation to COVID-19 severity. In our analysis of patients of European (n = 2,249) and African (n = 835) ancestries with hospitalized versus nonhospitalized COVID-19, the risk of hospitalized disease was associated with a common OAS1 haplotype, which was also associated with reduced severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) clearance in a clinical trial with pegIFN-lambda 1. Bioinformatic analyses and in vitro studies reveal the functional contribution of two associated OAS1 exonic variants comprising the risk haplotype. Derived human-specific alleles rs10774671-A and rs1131454-A decrease OAS1 protein abundance through allele-specific regulation of splicing and nonsense-mediated decay (NMD). We conclude that decreased OAS1 expression due to a common haplotype contributes to COVID-19 severity. Our results provide insight into molecular mechanisms through which early treatment with interferons could accelerate SARS-CoV-2 clearance and mitigate against severe COVID-19.N

Additional file 1 of Colorectal cancer incidences in Lynch syndrome: a comparison of results from the prospective lynch syndrome database and the international mismatch repair consortium

Additional file 1