Heterogeneity of KRAS, NRAS, BRAF and PIK3CA mutations in metastatic colorectal cancer and potential effects on therapy in the CAPRI GOIM trial

Background: Evidence suggests that metastatic colorectal carcinoma (mCRC) has a high level of intratumor heterogeneity. We carried out a quantitative assessment of tumor heterogeneity for KRAS, NRAS, BRAF and PIK3CA mutations, in order to assess potential clinical implications. Patients and methods: Tumor samples (n = 182) from the CAPRI-GOIM trial of first-line cetuximab + FOLFIRI in KRAS exon-2 wild-type mCRC patients were assessed by next-generation sequencing that allows quantitative assessment of mutant genes. Mutant allelic frequency was normalized for the neoplastic cell content and, assuming that somatic mutations usually affect one allele, the Heterogeneity Score (HS) was calculated by multiplying by 2 the frequency of mutant alleles in neoplastic cells. Therefore, HS virtually corresponds to the fraction of neoplastic cells carrying a specific mutation. Results: The KRAS HS ranged between 12 and 260 with mean value of 87.1 and median value of 84.4, suggesting that in most CRC, the majority of neoplastic cells carry mutant KRAS. Similar findings were observed for NRAS (HS range 35.5-146.7; mean 102.8; median 117.1). In contrast, in BRAF (HS range 17.1-120; mean 54.8; median 54.3) and PIK3CA (HS range 14.3-120; mean 59.5; median 47.3) mutant cases, only a fraction of neoplastic cells seem to carry the mutant allele. The response rate was 70% in KRAS mutant patients with an HS <33 (low KRAS; n = 10) and 45.7% in KRAS HS >33 patients (high KRAS; n = 35); median progression-free survival were 7.97 and 8.37 months, respectively. Low-KRAS tumors had a higher frequency of additional mutations in PIK3CA when compared with high-KRAS (6/10 versus 8/35). Conclusions: KRAS and NRAS mutations are usually present in the majority of neoplastic cells, whereas BRAF and PIK3CA mutations often affect a limited fraction of transformed cells. Resistance to cetuximab in low-KRAS patients might be driven by the complex mutational profile rather than KRAS mutation load

Concentrações de hormônio na carcaça de tilápias-do-nilo e maturação precoce após reversão sexual Hormone concentration in carcass of Nile tilapia submitted to early maturation after sexual reversion

Um total de 1.500 larvas de tilápia-do-nilo foi distribuído em 15 aquários de 20 L (100 larvas cada um) para comparação de dois métodos de masculinização: via oral, com dieta com hormônio (60 mg do 17 &#945;-metiltestosterona.kg-1); e via banho de imersão (6 mg do 17 &#945;-metiltestosterona.L-1), cada um com cinco repetições. As larvas e os juvenis foram amostrados no dia 1 (início do experimento) e aos 30 (final do período de alimentação com hormônio), 40, 45, 60 e 90 dias. Uma amostra de 0,5 g de peixe foi coletada em cada repetição para análise da testosterona corporal. Os peixes alimentados com a dieta com hormônio receberam ração experimental por 30 dias e ração comercial até o final do experimento, e banho de imersão receberam ração comercial e foram submetidos a banhos de imersão (6 mg da 17 &#945;-metiltestosterona.L-1), de 36 horas, nos dias 6 e 10 após início do experimento. Nos peixes que receberam a ração sem hormônio (controle), os valores de testosterona corporal se mantiveram praticamente estáveis ao longo do experimento, aumentando moderadamente a partir de 60 dias. As concentrações de testosterona corporal nos peixes que receberam a dieta com hormônio ou o banho de imersão foram mais altas aos 30 dias. Nos peixes submetidos ao banho de imersão, os valores reduziram aos 40 dias e aumentaram novamente até os 60 dias de observação, enquanto naqueles submetidos à dieta com hormônio, as concentrações de testosterona aumentaram gradativamente até 60 dias. A utilização de 17 &#945;-metiltestosterona por via oral ou banho de imersão das larvas estimula a maturação sexual dos peixes a partir dos 45 dias, especialmente naqueles alimentados com ração contendo hormônio. As concentrações desse hormônio na carcaça são inferiores ao preconizado pelo Codex Alimentarius do Brasil como seguras para consumo humano.<br>A total of 1,500 larvae of Nile tilapia was distributed in 15 20-L aquaria (100 larvae in each one) to compare two methods of masculinization: via oral application, using a diet with hormone (60 mg 17&#945;-methyltestosterone.kg-1); and through immersion bath (6 mg 17&#945;-metyltestosterone.L-1), each one with five replicates. Larvae and juvenile were sampled on day 1 (beginning of the experiment) and on days 30 (end of hormone feeding period), 40, 45, 60 and 90. One sample with 0.5 g of fish was collected from each replication for analysis of body testosterone. Fish fed diet with hormone were given experimental ration for 30 days and commercial ration until the end of the experiment, and fish in immersion bath received commercial ration and they were submitted to immersion bath (6 mg 17 &#945;-metyltestosterone.L-1) for 36 hours on days 6 and 10 after the beginning of the experiment. For fish given ration without hormone (control), values of body testosterone were almost totally steady over the experiment, moderately increasing from day 60. Concentrations of body testosterone in fish fed diet with hormone or immersion bath were the highest on day 30. For fish submitted to immersion bath, the values were reduced on day 40 and they increased again until 60 days of observation, while for those submitted to diet with hormone, concentrations of testosterone gradually increased until 60 days. The use of 17 &#945;-methyltestosterone through oral administration or immersion bath of larvae promotes sexual maturation of fish from day 45, especially on those fed diet with hormone. Concentrations of hormone in the carcass are lower than the recommended by Codex Alimentarius from Brazil as safe for human consumption

Den Weizen von der Spreu trennen – Altersbezogene Personalpolitik und Innovationen auf der Betriebsebene

Adopting a dynamic perspective, this paper investigates age-related staffing patterns in German establishments and their effect on innovative performance. First, we investigate how establishments achieve the necessary workforce rejuvenation - from the inflow of younger or from outflows of older workers. In addition, we explore whether certain staffing patterns are more likely to appear under different economic regimes. In a second step, we analyse whether an establishment's innovative performance is related to the staffing patterns it experiences. The analysis of linked-employer-employee data shows that most of the 585 German establishments covered rejuvenate by inflows of younger workers. Half of the establishments also use the outflow of older workers. Furthermore, workforces are more likely to become more age-heterogeneous in growing establishments. Finally, we do not find evidence that a youth-centred human resource strategy (always) fosters innovation.@Dieser Beitrag untersucht die altersbezogene Personalpolitik deutscher Betriebe und deren Einfluss auf die Innovationsfähigkeit. Zuerst wird dargestellt, wie Betriebe verhindern, dass ihre Belegschaften altern. Beispielsweise werden bevorzugt jüngere Beschäftigte eingestellt und ältere Beschäftigte verlassen den Betrieb. Anschließend wird geprüft, ob bestimmte Einstellungs- und Entlassungsstrategien stärker in bestimmten wirtschaftlichen Umständen erfolgen. In einem zweiten Schritt wird analysiert, ob die Innovationsleistung von Betrieben mit deren Personalpolitik zusammenhängt. Die Analyse von verknüpften Beschäftigten-Betriebsdaten zeigt, dass die Mehrheit der untersuchten Betriebe sich durch das Einstellen jüngerer Beschäftigte verjüngt. Die Hälfte dieser Betriebe entlassen zudem Beschäftigte, die älter als der Durchschnitt der Belegschaft sind. Wir finden zudem, dass sich die Altersheterogenität in wachsenden Betrieben erhöht. Schließlich finden wir keine Evidenz dafür, dass eine jugendzentrierte Personalpolitik die Innovationsfähigkeit der Betriebe verbessert.Dieser Beitrag untersucht die altersbezogene Personalpolitik deutscher Betriebe und deren Einfluss auf die Innovationsfähigkeit. Zuerst wird dargestellt, wie Betriebe verhindern, dass ihre Belegschaften altern. Beispielsweise werden bevorzugt jüngere Beschäftigte eingestellt und ältere Beschäftigte verlassen den Betrieb. Anschließend wird geprüft, ob bestimmte Einstellungs- und Entlassungsstrategien stärker in bestimmten wirtschaftlichen Umständen erfolgen. In einem zweiten Schritt wird analysiert, ob die Innovationsleistung von Betrieben mit deren Personalpolitik zusammenhängt. Die Analyse von verknüpften Beschäftigten-Betriebsdaten zeigt, dass die Mehrheit der untersuchten Betriebe sich durch das Einstellen jüngerer Beschäftigte verjüngt. Die Hälfte dieser Betriebe entlassen zudem Beschäftigte, die älter als der Durchschnitt der Belegschaft sind. Wir finden zudem, dass sich die Altersheterogenität in wachsenden Betrieben erhöht. Schließlich finden wir keine Evidenz dafür, dass eine jugendzentrierte Personalpolitik die Innovationsfähigkeit der Betriebe verbessert