Pancreatic neuroendocrine tumor progression and resistance to everolimus: the crucial role of NF-kB and STAT3 interplay.

PURPOSE: The finding of mTOR overactivation in patients affected by pancreatic neuroendocrine tumors (Pa-NETs) led to their treatment with the mTOR inhibitor everolimus. Unfortunately, the efficacy of everolimus is restricted by the occurrence of resistance. The mechanisms leading to Pa-NETs' progression and resistance are not well understood. Notably, chronic inflammation is implicated in NET development. NF-kB is involved in inflammation and drug resistance mechanisms through the activation of several mediators, including STAT3. In this respect, NF-κB and STAT3 interaction is implicated in the crosstalk between inflammatory and tumor cells. METHODS: We investigated the expression of NF-kB in different Pa-NETs by RT-qPCR and immunohistochemistry. Then, we studied the role of NF-κB and STAT3 interplay in QGP-1 cells. Subsequently, we assessed the impact of NF-κB and STAT3 inhibitors in QGP-1 cell proliferation and spheroids growth. Finally, we evaluated the implication of the NF-kB pathway in everolimus-resistant Pa-NET cells. RESULTS: We found that the increased NF-kB expression correlates  with a higher grade in Pa-NETs. The activation of the STAT3 pathway induced by TNFα is mediated by NF-kB p65. NF-kB p65 and STAT3 inhibitors decrease QGP-1 viability, spheroids growth, and Pa-NETs cell proliferation. These effects are maintained in everolimus-resistant QGP-1R cells. Interestingly, we found that NF-kB, STAT3, IL-8, and SOCS3 are overexpressed in QGP-1R compared to QGP-1. CONCLUSION: Since the NF-kB pathway is implicated in Pa-NETs' progression and resistance to everolimus, these data could explain the potential use of NF-kB as a novel therapeutic target in Pa-NET patients.

Antibodies against Actinobacillus pleuropneumoniae, Mycoplasma hyopneumoniae and influenza virus and their relationships with risk factors, clinical signs and lung lesions in pig farms with one-site production systems in Brazil.

A study was conducted on 21 pig herds using one-site production system in the southeast region of Brazil to assess the relationships among serological results for primary pathogens involved in respiratory diseases (Actinobacillus pleuropneumoniae, App; Mycoplasma hyopneumoniae, Mhyo; and swine influenza virus, SIV), cough index, pneumonia index, pleuritis and herd characteristics. The prevalence of antibodies against Mhyo and SIV increased throughout the raising phases, with the highest prevalence in slaughtered pigs (> 40%), while pigs in 65% (14/21) of nurseries demonstrated marked seroprevalence of App that decreased until the day of slaughter. Pleuritis and pulmonary consolidations were recorded in 9.0 and 72.4%, respectively, of the 908 evaluated lungs. Histopathological analysis of the lung lesions revealed suppurative bronchopneumonia in almost half of the lungs (48.9%). Regression analyses were conducted to identify risk factors associated with the cough index; pleuritis; pulmonary consolidation; and App, Mhyo and SIV serological results. All-in-all-out management in nursery buildings reduced the seroprevalence of Mhyo in herds. App seroprevalence was associated with pleuritis, and the presence of cough episodes in growing pigs was associated with SIV seropositivity in nursery pigs.

Efeito da ordem de parto e da perda de peso durante a lactação no desempenho reprodutivo subsequente de matrizes suínas / The effect of parity order and lactation weight loss on subsequent reproductive performance of sows

Investigou-se o efeito da ordem de parto (OP) e da perda de peso durante a lactação no desempenho reprodutivo de 666 matrizes suínas. Foram formadas três classes de OP (OP1, OP2 e OP3-5) e duas classes de percentual de perda de peso (≤1% e >1%) durante a lactação. Foram avaliados: taxa de parto, intervalo desmame-estro (IDE) e tamanho da leitegada subsequente. Houve interação de OP versus perda de peso na taxa de parto das fêmeas (P<0,05). As fêmeas OP1 e OP2 tiveram maior chance (P<0,05) de não parir na classe >1% de perda de peso. A maior perda de peso não foi um fator de risco para não parir na condição OP3-5 (P>0,05). Não houve interação de OP versus perda de peso (P>0,05) para IDE e total de leitões nascidos. Fêmeas OP1 apresentaram IDE mais longo e menor tamanho da leitegada no parto subsequente (P<0,05) do que fêmeas OP2 e OP3-5. As perdas corporais na lactação não influenciaram o IDE (P>0,05), mas reduziram o tamanho da leitegada subsequente (P<0,05). Conclui-se que maior perda de peso na lactação resulta em aumento de falhas reprodutivas nas fêmeas mais jovens e reduz o tamanho da leitegada subsequente em todas as OP.

The effect of parity (PO) and weight loss during lactation on the subsequent reproductive performance of 666 sows was investigated. Sows were allocated into three PO classes (PO1, PO2 and PO3-5) and into two classes of weight loss percentage (≤1% and >1%) during lactation. Farrowing rate, weaning to estrus interval (WEI) and total born at next farrow were evaluated. There was an interaction effect between PO and weight loss on the farrowing rate (P<0.05). PO1 and PO2 females had more chance (P<0.05) of failure to farrow when weight loss was higher than 1%. However, the higher weight loss was not a risk factor to low farrowing rate in PO3-5 females (P>0.05). There was no interaction between PO and weight loss (P>0.05) on WEI and subsequent total born. PO1 females showed longer WEI and lower litter size on subsequent farrowing compared to PO2 and PO3-5 females. Weight loss did not affect WEI (P>0.05), but it decreased subsequent litter size (P<0.05). High weight loss during lactation results an increase in reproductive failures in young females and decreases subsequent litter size in all parity orders.

Newborn piglet traits associated with survival and growth performance until weaning.

Pre-weaning piglet mortality represents significant economic losses, and approximately half of this mortality occurs within the first 3 days after birth. Factors involved in postnatal mortality can also be associated with a poor growth performance until weaning. The aim of this study was to evaluate the effect of some variables measured right after birth on piglet survival during the first week of life and growth performance until weaning. Piglets included in the analysis (n=612) were born from 3 to 5 parity sows. Piglets were monitored for blood oxygen saturation (SatO2), heart rate (HR), blood glucose concentration, rectal temperature at birth (RT0 h) and at 24h after birth (RT24 h). Genetic line, birth following or not an obstetric intervention, birth order, sex, skin color, integrity of the umbilical cord, and time elapsed from birth until first attempts to stand were also recorded. Piglets were weighed at birth (BW), and at 7, 14 and 21 days after birth in order to evaluate their postnatal development. Cumulative mortality rates were 3.3%, 5.4% and 8.7% at 3, 7 and 21 days after birth, respectively. Body temperature at birth (RT0 h) did not affect (P>0.05) the survival nor the piglet growth performance. Piglets with cyanotic skin and those that took more than 5 min to stand showed higher chance of mortality (P<0.05) compared to normal skin piglets and to piglets which stood before 1 min, respectively. Piglets with broken umbilical cord had higher odds (P<0.05) of mortality up to 3 days after birth, respectively. Higher odds (P<0.05) of mortality up to 3 or 7 days were associated with later birth order (>9), low BW (<1275g), low (24-30 mg/dl) and high (45-162 mg/dl) blood glucose concentrations, or low RT24 h (<38.1°C). Piglets with BW<1545 g, low RT24 h (<38.6°C) and female piglets had higher odds of a low weight at weaning (P<0.05). Among the factors studied, cyanotic skin, delay for standing, broken umbilical cord, high birth order, low BW, low RT24 h, and both low and high blood glucose concentrations are indicators of a lower ability of piglets to survive during the first week after birth. The growth performance until weaning is compromised in piglets with a lower BW, a lower RT24 h and if they are female pigs.