Cardiac Troponin T and Illness Severity in the Very-Low-Birth-Weight Infant

Introduction. Respiratory distress are very common in Very-low-birth-weight (VLBW) infants and Myocardial injury may play a role in the disease outcome. Cardiac troponin T (cTnT) is the most useful marker of injury in adult population, but has not been extensively studied in this population. Aim. To study the role of cTnT in VLBW infants and its association with clinical outcomes. Methods. All VLBW infants admitted to our NICU were included in the study. Echocardiography and blood samples for cTnT determination were collected at 24 and 48 hours of life, and values >0.1 ng/mL were considered CTnT-positive values. Results. A total of 116 neonates had their blood samples collected. The median cTnT concentration within 24 hours was 0.191 (0.1–0.79) ng/mL and within 48 hours was 0.293 (0.1–1.0) ng/mL. A logistic regression analysis showed that PDA, low GA, and use of dopamine were independently associated with positive cTnT and abnormal Dopplerfluxometry and diuretics use had protective effects and was independently associated with troponin values. Conclusion. We observed a high prevalence of positivecTnT values in VLBW infants associated with illness severity. Our findings suggest that cTnT may be a useful and early marker of myocardial injury in VLBW infants

Gestão da água e das águas residuais para uma viticultura e enologia sustentáveis no sul de Portugal - Revisão

Assessing sustainability of the wine industry requires improved characterization of its environmental impacts, namely in terms of water use. Therefore, quantification of water inputs and wastewater (WW) outputs is needed to highlight inefficiencies in wine production and related consequences for the environment. Water use and WW generation in irrigated viticulture and oenology remains insufficiently quantified for dry Mediterranean regions (e.g. South Portugal). This paper is focused on wine production under warm and dry climate conditions in the winegrowing region of Alentejo (South Portugal). This region experiences increasingly dry conditions, while the irrigated area keeps expanding, which puts exacerbates the pressure on existing local and regional water resources. Additionally, more erratic variation in climate conditions and the tendency for increasingly extreme climate events (e.g. heat waves) pose more challenges to Alentejo’s wine sector. We conclude that quantitative information on water use and management is not always easy to obtain or access, which hinders improved strategies and/or policies for water use at farm, winery and region-level. Up-to-date statistics and robust metrics can help to better characterize water use and WW flows for Alentejo’s wine region, while optimizing management in vineyards and wineries, in companies and region-wide. The paper is focused on a “Farm-Winery" scenario, which is the most common in South Portugal's wine sectorA avaliação da sustentabilidade da indústria vitivinícola requer uma caracterização detalhada do seu impacto ambiental, nomeadamente ao nível do factor água. A quantificação detalhada dos consumos de água e das águas residuais produzidas (WW) é crucial para identificação de ineficiências na indústria da vinha e do vinho. A utilização da água e a gestão dos efluentes em viticultura regada e na adega permanecem pouco quantificados nas regiões mediterrânicas. O presente trabalho centra-se na produção de vinho em condições de clima quente e seco, tomando como exemplo a região vitivinícola do Alentejo (Sul de Portugal). A região está sujeita a situações de seca mais frequentes e severas, enquanto a área regada continua em expansão, o que pressiona os recursos hídricos locais e regionais. Além disso, as condições climáticas altamente variáveis e a maior tendência para eventos climáticos extremos (e.g. ondas de calor) colocam desafios ao setor vitivinícola no Sul de Portugal. Concluímos que a informação quantitativa relativa ao uso e gestão de água não está sempre facilmente disponível, limitando a otimização de estratégias e/ou políticas para o uso da água ao nível da vinha, da adega e da região. Dados atualizados e indicadores robustos podem ajudar a caracterizar melhor o uso de água e a geração de água residual na região vitivinícola do Alentejo, otimizando a gestão na vinha e na adega, ao nível da empresa e da região. O artigo centra-se num cenário de produtor-engarrafador (“Farm-Winery”), que é o mais comum no setor vitivinícola no Sul de Portugalinfo:eu-repo/semantics/publishedVersio

Hybrid molecules of protoflavones and spirooxindole derivatives with selective cytotoxicity against triple-negative breast cancer cells

The combination of compounds with complementary bioactivities into hybrid molecules is an emerging concept in drug discovery. In this study, we aimed to synthesize new hybrid compounds based on p53-MDM2/X protein-protein interaction spiropyrazoline oxindole-based inhibitors and ataxia telangiectasia and Rad3-related (ATR) protoflavone-based inhibitors through copper(i) catalysed azide-alkyne cycloaddition. Five new hybrids were prepared along with three representative reference fragments. The compounds were tested against human breast cancer cell lines MCF-7 (hormone-dependent, wild-type p53) and MDA-MB-231 (triple-negative, mutant p53). Most of the new hybrids were more cytotoxic than their reference fragments and several showed 2-4 times selective toxicity against MDA-MB-231 cells. Relevant pharmacological benefit gained from the hybrid coupling was further confirmed by virtual combination index calculations using the Chou method. Compound 13 modulated doxorubicin-induced DNA damage response through inhibiting the ATR-dependent activation of Chk-1, while increasing the activation of Chk-2. Our results suggest that the new hybrids may serve as new leads against triple negative breast cancer

Enhancing anticancer activity of spiropyrazoline oxindoles by disrupting p53-MDMs PPIs

Cancer is a major public health problem worldwide with 18.1 million new cases of cancer and 9.6 million deaths worldwide in 20181. The protein p53 is involved in many biological processes that are important to maintain the normal function of the cells (e.g. apoptosis, cell arrest, and DNA repair). It is an attractive target in oncology because it can modulate several additional cellular processes that are relevant for the suppression of tumour development, such as opposing oncogenic metabolic reprogramming, activating autophagy, and restraining invasion and metastasis. In all types of human cancers, the p53 tumour suppressor function is inactivated by mutation or gene deletion or by negative regulators such as MDM2 and MDMX. In the last years, the most popular approach among medicinal chemists to activate the wild-type p53 was the inhibition of p53-MDM2 protein-protein interaction (PPI) using small molecules. However, it is currently known that the full reactivation of p53 is only achieved when the interactions of p53 with both negative regulators are inhibited. Due to the lack of dual p53-MDM2/X PPIs inhibitors in clinical trials, it is urgent to develop small molecules that inhibit p53-MDMs PPIs2. Our research team has been working on the development and optimization of spiropyrazoline oxindoles to obtain dual p53-MDM2/X PPIs inhibitors. Hence, we have already developed derivatives with good antiproliferative activities in HCT-116 p53(+/+) human colorectal carcinoma cell line, which induce apoptosis and cell cycle arrest at G0/G1 phase, upregulate p53 steady-state levels, and lead to a decrease of MDM2 levels3. In this communication, we report the structure-based computational optimization of this chemical family for the development of novel p53-MDM2/X interactions inhibitors. Our studies will shed light on the possible binding mode of spirooxindole derivatives to MDM2 and MDMX and will drive the hit-to-lead optimization strategy. Furthermore, we report our most recent optimization of the synthesis of these new spiropyrazoline oxindoles derivatives and the first preliminary biological results. Acknowledgements: This work was supported by National Funds (FCT/MEC, Fundacao para a Ciencia e Tecnologia and Ministerio da Educacao e Ciencia) through UID/DTP/04138/2019 (iMed.ULisboa), project PTDC/QUI-QOR/29664/2017, Principal Investigator grant CEECIND/01772/2017 (M. M. M. Santos) and PhD fellowships SFRH/BD/137544/2018 (E.A. Lopes) and SFRH/BD/117931/2016 (M. Espadinha). 1Ferlay, J., Colombet, M., Soerjomataram, I., Mathers, C., Parkin, D., Pineros, M., Znaor, A. and Bray, F., Int. J. Cancer, 2019, 144, 1941-1953. 2Espadinha M., Barcherini V., Lopes E. A., Santos M. M. M., Curr. Top. Med. Chem. 2018, 18, 647-660. 3a) Nunes R., Ribeiro C. J. A., Monteiro Â., Rodrigues C. M. P., Amaral J. D., Santos M. M. M., Eur. J. Med. Chem., 2017, 139, 168-179. b) Amaral J. D., Silva D., Rodrigues C. M. P., Sola S., Santos M. M. M., Front. Chem., 2019, 7, article

A genetic perspective on cetacean evolution

Studies of cetacean evolution using genetics and other biomolecules have come a long way—from the use of allozymes and short sequences of mitochondrial or nuclear DNA to the assembly of full nuclear genomes and characterization of proteins and lipids. Cetacean research has also advanced from using only contemporary samples to analyzing samples dating back thousands of years, and to retrieving data from indirect environmental sources, including water or sediments. Combined, these studies have profoundly deepened our understanding of the origin of cetaceans; their adaptation and speciation processes; and of the past population change, migration, and admixture events that gave rise to the diversity of cetaceans found today

Discovery of spirooxadiazoline oxindoles with dual-stage antimalarial activity

© 2022 Published by Elsevier Masson SAS.Malaria remains a prevalent infectious disease in developing countries. The first-line therapeutic options are based on combinations of fast-acting artemisinin derivatives and longer-acting synthetic drugs. However, the emergence of resistance to these first-line treatments represents a serious risk, and the discovery of new effective drugs is urgently required. For this reason, new antimalarial chemotypes with new mechanisms of action, and ideally with activity against multiple parasite stages, are needed. We report a new scaffold with dual-stage (blood and liver) antiplasmodial activity. Twenty-six spirooxadiazoline oxindoles were synthesized and screened against the erythrocytic stage of the human malaria parasite P. falciparum. The most active compounds were also tested against the liver-stage of the murine parasite P. berghei. Seven compounds emerged as dual-stage antimalarials, with IC50 values in the low micromolar range. Due to structural similarity with cipargamin, which is thought to inhibit blood-stage P. falciparum growth via inhibition of the Na + efflux pump PfATP4, we tested one of the most active compounds for anti-PfATP4 activity. Our results suggest that this target is not the primary target of spirooxadiazoline oxindoles and further studies are ongoing to identify the main mechanism of action of this scaffold.This work was supported by FCT (Fundação para a Ciência e a Tecnologia, I.P.) through iMed.ULisboa (UID/DTP/04138/2019), project PTDC/QUI-QOR/29664/2017, and PhD fellowship SFRH/BD/137544/2018 (E. Lopes). The NMR spectrometers are part of the National NMR Network (PTNMR) and are partially supported by Infrastructure Project Nº 022161 (co-financed by FEDER through COMPETE 2020, POCI and PORL and FCT through PIDDAC). Financial support from FCT and Portugal 2020 to the Portuguese Mass Spectrometry Network (Rede Nacional de Espectrometria de Massa – RNEM; LISBOA-01-0145-FEDER-402-022125) is also acknowledged.info:eu-repo/semantics/publishedVersio

Discovery of MDM2-p53 and MDM4-p53 protein-protein interactions small molecule dual inhibitors

MDM2 and MDM4 are key negative regulators of p53, an important protein involved in several cell processes (e. g. cell cycle and apoptosis). Not surprisingly, the p53 tumor suppressor function is inactivated in tumors over -expressing these two proteins. Therefore, both MDM2 and MDM4 are considered important therapeutic targets for an effective reactivation of the p53 function. Herein, we present our studies on the development of spi-ropyrazoline oxindole small molecules able to inhibit MDM2/4-p53 protein-protein interactions (PPIs). Twenty-seven potential spiropyrazoline oxindole dual inhibitors were prepared based on in silico structural optimization studies of a hit compound with MDM2 and MDM4 proteins. The antiproliferative activity of the target com-pounds was evaluated in cancer cell lines harboring wild-type p53 and overexpressing MDM2 and/or MDM4. The most active compounds in SJSA-1 cells, 2q and 3b, induce cell death via apoptosis and control cell growth by targeting the G0/G1 cell cycle checkpoint in a concentration-dependent manner. The ability of the five most active spiropyrazoline oxindoles in dissociating p53 from MDM2 and MDM4 was analyzed by an immu-noenzymatic assay. Three compounds inhibited MDM2/4-p53 PPIs with IC50 values in the nM range, while one compound inhibited more selectively the MDM2-p53 PPI over the MDM4-p53 PPI. Collectively, these results show: i) 3b may serve as a valuable lead for obtaining selective MDM2-p53 PPI inhibitors and more efficient anti-osteosarcoma agents; ii) 2a, 2q and 3f may serve as valuable leads for obtaining dual MDM2/4 inhibitors and more effective p53 activators

Recurrent bacteremia after injection of N-butyl-2-cyanoacrylate for treatment of bleeding gastric varices: a case report and review of the literature

Abstract\ud \ud Background\ud Bleeding from gastric varices has high mortality rate, and obliteration using N-butyl-2-cyanoacrylate is the treatment of choice. Recurrent bacteremia is rarely reported following the procedure. We aimed to report a case of recurrent bacteremia after N-butyl-2-cyanoacrylate treatment and to review published cases.\ud \ud \ud Case presentation and review\ud In May 2014, a 43-year-old Brazilian male presented with lower gastrointestinal bleeding. Endoscopy showed active bleeding from gastric varix. Injection of N-butyl-2-cyanoacrylate was performed and the patient was discharged. Over the next 4 months he presented with three episodes of bacteremia with severe sepsis and no identifiable focus of infection. Oral prophylaxis was initiated in September 2014 and he has remained free of bacteremia. Six other cases of recurrent bacteremia following sclerosis with N-butyl-2-cyanoacrylate were reported in the literature. All patients had portal hypertension and bleeding from gastric varices. Average age of patients was 55.7 years and the median time from endoscopic procedure to the first episode of bacteremia was 105 days (range 14–365). The mean number of episodes of bacteremia per patient was 2.5.\ud \ud \ud Conclusion\ud Recurrent bacteremia associated with endoscopic treatment with N-2-butyl-cyanoacrylate is rare, but should be suspected in patients in which investigation shows no other focus of infection. Secondary prophylaxis should be considered after the first episode

Cytokines induced during chronic hepatitis B virus infection promote a pathway for NK cell–mediated liver damage

Hepatitis B virus (HBV) causes chronic infection in more than 350 million people worldwide. It replicates in hepatocytes but is non-cytopathic; liver damage is thought to be immune mediated. Here, we investigated the role of innate immune responses in mediating liver damage in patients with chronic HBV infection. Longitudinal analysis revealed a temporal correlation between flares of liver inflammation and fluctuations in interleukin (IL)-8, interferon (IFN)-α, and natural killer (NK) cell expression of tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) directly ex vivo. A cross-sectional study confirmed these findings in patients with HBV-related liver inflammation compared with healthy carriers. Activated, TRAIL-expressing NK cells were further enriched in the liver of patients with chronic HBV infection, while their hepatocytes expressed increased levels of a TRAIL death–inducing receptor. IFN-α concentrations found in patients were capable of activating NK cells to induce TRAIL-mediated hepatocyte apoptosis in vitro. The pathogenic potential of this pathway could be further enhanced by the ability of the IFN-α/IL-8 combination to dysregulate the balance of death-inducing and regulatory TRAIL receptors expressed on hepatocytes. We conclude that NK cells may contribute to liver inflammation by TRAIL-mediated death of hepatocytes and demonstrate that this non-antigen–specific mechanism can be switched on by cytokines produced during active HBV infection