Antiangiogenesis beyond VEGF inhibition: A journey from antiangiogenic single-target to broad-spectrum agents

Although the inhibition of angiogenesis is an established modality of cancer treatment, concerns regarding toxicity and drug resistance still constitute barriers to be overcome. For almost a decade since the approval of bevacizumab in 2004, the efforts on antiangiogenic therapeutics have been mainly focused in inhibiting the VEGF pathway. The ongoing understanding of the complexity of the angiogenic process has broadened the spotlight to include concurrent and downstream players to the list of targeted inhibitors. In this review, we summarize the currently existing and the promising antiangiogenic treatments, envisioning an apparent evolutionary trend towards the development of angiogenesis inhibitors of three modalities: single-target, multi-target, and broad-spectrum agents. The clinical efficacy and some structural aspects of monoclonal antibodies, small molecules, endogenous and synthetic angiogenesis inhibitors and their molecular targets are discussed, and the targeting of endothelial cells with the use of cytotoxic drugs in a metronomic schedule is appraised. The reader is invited to revisit current expectations about antiangiogenic therapy in an attempt to set consistent clinical endpoints from which patients could gain real and lasting clinical benefits.     

Knowledge and Practices of Digestive Surgeons concerning Specialized Nutritional Support in Cancer Patients: A Survey Study

A survey study based on a 21-item questionnaire was conducted to assess knowledge and practices of digestive surgeons focused on nutritional support in gastrointestinal cancer patients. At least 5 staff digestive surgeons from 25 tertiary care hospitals throughout Spain were invited to participate and 116 accepted. Malnutrition was correctly defined by 81.9% of participants. In patients undergoing major abdominal surgery, 55.2% considered that preoperative nutritional support is indicated in all patients with malnutrition for a period of 7–14 days. For the diagnosis of malnutrition, only 18.1% of participants selected unintentional weight loss together with a fasting or semi-fasting period of more than one week. Regarding the advantages of enteral infusion, 93.7% of participants considered preservation of the integrity of the intestinal mucosa and barrier function, and in relation to peripheral parenteral nutrition, 86.2% selected the definition of nutrient infusion through a peripheral vein and 81.9% its indication for less than 7 days. Digestive surgeons had a limited knowledge of basic aspects of clinical nutrition in cancer patients, but there was some variability regarding clinical practice in individual cases. These findings indicate the need to develop standardized clinical protocols as well as a national consensus on nutrition support in cancer patients.     

The Antifungal Itraconazole Is a Potent Inhibitor of Chikungunya Virus Replication

Chikungunya virus (CHIKV) is the causative agent of chikungunya fever, a disabling disease that can cause long-term severe arthritis. Since the last large CHIKV outbreak in 2015, the reemergence of the virus represents a serious public health concern. The morbidity associated with viral infection emphasizes the need for the development of specific anti-CHIKV drugs. Herein, we describe the development and characterization of a CHIKV reporter replicon cell line and its use in replicon-based screenings. We tested 960 compounds from MMV/DNDi Open Box libraries and identified four candidates with interesting antiviral activities, which were confirmed in viral infection assays employing CHIKV-nanoluc and BHK-21 cells. The most noteworthy compound identified was itraconazole (ITZ), an orally available, safe, and cheap antifungal, that showed high selectivity indexes of >312 and >294 in both replicon-based and viral infection assays, respectively. The antiviral activity of this molecule has been described against positive-sense single stranded RNA viruses (+ssRNA) and was related to cholesterol metabolism that could affect the formation of the replication organelles. Although its precise mechanism of action against CHIKV still needs to be elucidated, our results demonstrate that ITZ is a potent inhibitor of the viral replication that could be repurposed as a broad-spectrum antiviral.     

Jejuketomycins A and B,polyketide glycosides with cancer cell migration inhibitory activity from Streptomyces sp. KCB15JA151

Two new polyketide glycosides jejuketomycins A (1) and B (2), were isolated from a culture of Streptomyces sp. KCB15JA151. Their chemical structures including the absolute configurations were determined by detailed analyses of the NMR and HRMS data and ECD calculations and spectral data. Compounds 1 and 2 possess an unusual 6/6/8 tricyclic ring system. Biological evaluation with the wound healing assay and time-lapse cell tracking analysis revealed that compounds 1 and 2 have significant inhibitory activities against cancer cell migration with low cytotoxicity.

Two new polyketide glycosides jejuketomycins A (1) and B (2), were isolated from a culture of Streptomyces sp. KCB15JA151.     

Changes in the fatty acid composition of plasma and red blood cell membrane during the first hours of life in human neonates

The objective of this work was to examine the changes in the fatty acid profiles of plasma lipid fractions and red blood cell membrane phospholipids in newborn infants during the first 6-8 h of life. Methyl esters of fatty acids from plasma free fatty acids and phospholipids and from membrane phosphatidylethanolamine, phosphatidylcholine and sphingomyelin for cord blood (n = 20) and venous blood (n = 19) were analyzed by GLC. Important changes were observed in plasma fatty acids. Palmitic and palmitoleic acid increased from birth to 6-8 h of age for both free fatty acids and phospholipids. Palmitic acid also increased in membrane phosphatidylcholine and phosphatidylethanolamine. In the former, stearic acid declined whereas oleic and docosatetraenoic acids increased. Phosphatidylethanolamine and sphingomyelin were less affected than phosphatidylcholine probably because the internal location of the two first fractions in erythrocyte membrane. Polyunsaturated fatty acids dropped slightly during the first hours of life in most lipid fractions. This may be a consequence of the interruption of placental fatty acid supply and the limited capacity of the newborn to desaturate their essential fatty acid tissue stores.     

Gene expression changes induced by ochratoxin A in renal and hepatic tissues of male F344 rat after oral repeated administration

Ochratoxin A (OTA), a naturally occurring mycotoxin, is nephrotoxic in all animal species tested and is considered a potent renal carcinogen, particularly in male rats. Its mechanism of toxicity is still unknown, although oxidative stress appears to be a plausible mechanism. Therefore, the objective of this study was to identify the biological pathways that are modulated in vivo by OTA in male F344 rats in order to gain further insight into its mechanism of renal toxicity. Rats were gavaged daily with OTA (500 microg/kg bw) and gene expression profiles in target and non-target organs were analyzed after 7 and 21 days administration. As was expected, a time-dependent increase of OTA concentrations was found in plasma, kidney and liver, with the concentrations found in both tissues being quite similar. However, histopathological examinations only revealed changes in kidney; signs of nephrotoxicity involving single cell necrosis and karyomegalic nuclei were observed in the treated rats. The number of differentially expressed genes in kidney was much higher than in liver (541 versus 11 at both time points). Several similarities were observed with other in vivo gene expression data. However, great differences were found with previous in vitro gene expression data, with the exception of DNA damage response which was not observed at mRNA level in any of our study conditions. Down-regulation was the predominant effect. Oxidative stress response pathway and genes involved in metabolism and transport were inhibited at both time points. RGN (regucalcin) - a gene implicated in calcium homeostasis - was strongly inhibited at both time points and genes implicated in cell survival and proliferation were up-regulated at day 21. Moreover, translation factors and annexin genes were up-regulated at both time points. Apart from oxidative stress, alterations of the calcium homeostasis and cytoskeleton structure may be present at the first events of OTA toxicity.     

A scoring system for AML patients aged 70 years or older,eligible for intensive chemotherapy: a study based on a large European data set using the DATAML,SAL, and PETHEMA registries

In a context of therapeutic revolution in older adults with AML, it is becoming increasingly important to select patients for the various treatment options by taking account of short-term efficacy and toxicity as well as long-term survival. Here, the data from three European registries for 1,199 AML patients aged 70 years or older treated with intensive chemotherapy were used to develop a prognostic scoring system. The median follow-up was 50.8 months. In the training set of 636 patients, age, performance status, secondary AML, leukocytosis, and cytogenetics, as well as NPM1 mutations (without FLT3-ITD), were all significantly associated with overall survival, albeit not to the same degree. These factors were used to develop a score that predicts long-term overall survival. Three risk-groups were identified: a lower, intermediate and higher-risk score with predicted 5-year overall survival (OS) probabilities of ≥12% (n = 283, 51%; median OS = 18 months), 3–12% (n = 226, 41%; median OS = 9 months) and <3% (n = 47, 8%; median OS = 3 months), respectively. This scoring system was also significantly associated with complete remission, early death and relapse-free survival; performed similarly in the external validation cohort (n = 563) and showed a lower false-positive rate than previously published scores. The European Scoring System ≥70, easy for routine calculation, predicts long-term survival in older AML patients considered for intensive chemotherapy.Subject terms: Acute myeloid leukaemia, Risk factors     

One Health surveillance of West Nile and Usutu viruses: a repeated cross-sectional study exploring seroprevalence and endemicity in Southern France, 2016 to 2020

BackgroundWest Nile virus (WNV) and Usutu virus (USUV), two closely related flaviviruses, mainly follow an enzootic cycle involving mosquitoes and birds, but also infect humans and other mammals. Since 2010, their epidemiological situation may have shifted from irregular epidemics to endemicity in several European regions; this requires confirmation, as it could have implications for risk assessment and surveillance strategies.AimTo explore the seroprevalence in animals and humans and potential endemicity of WNV and USUV in Southern France, given a long history of WNV outbreaks and the only severe human USUV case in France in this region.MethodsWe evaluated the prevalence of WNV and USUV in a repeated cross-sectional study by serological and molecular analyses of human, dog, horse, bird and mosquito samples in the Camargue area, including the city of Montpellier, between 2016 and 2020.ResultsWe observed the active transmission of both viruses and higher USUV prevalence in humans, dogs, birds and mosquitoes, while WNV prevalence was higher in horses. In 500 human samples, 15 were positive for USUV and 6 for WNV. Genetic data showed that the same lineages, WNV lineage 1a and USUV lineage Africa 3, were found in mosquitoes in 2015, 2018 and 2020.ConclusionThese findings support existing literature suggesting endemisation in the study region and contribute to a better understanding of USUV and WNV circulation in Southern France. Our study underlines the importance of a One Health approach for the surveillance of these viruses.