Beyond CD19: Opportunities for Future Development of Targeted Immunotherapy in Pediatric Relapsed-Refractory Acute Leukemia

Chimeric antigen receptor (CAR) T cell therapy has been used as a targeted approach in cancer therapy. Relapsed and refractory acute leukemia in pediatrics has been difficult to treat with conventional therapy due to dose limiting toxicities. With the recent success of CD 19 CAR in pediatric patients with B cell ALL, this mode of therapy has become a very attractive option for these patients with high risk disease. In this review, we will discuss current treatment paradigms of pediatric acute leukemia, and potential therapeutic targets for additional high risk populations, including T cell ALL, AML, and infant ALL

Cytotoxic drugs activate KSHV lytic cycle in latently infected PEL cells by inducing a moderate ROS increase controlled by HSF1, NRF2 and p62/SQSTM1

Previous studies have indicated that cytotoxic treatments may induce or not activate viral lytic cycle activation in cancer cells latently infected by Kaposi’s sarcoma-associated herpesvirus (KSHV). To investigate the molecular mechanisms responsible for such an effect, we compared two cytotoxic treatments able to induce the viral lytic cycle, named 12-O-tetradecanoylphorbol 13-acetate (TPA) (T) in combination with sodium butyrate (B) and bortezomib (BZ), with two cytotoxic treatments that did not activate this process, named metformin (MET) and quercetin (Q). Our results indicated that TB and bortezomib increased levels of oxygen reactive species (ROS) while metformin and quercetin reduced them. The finding that N-acetylcysteine (NAC), a reactive oxigen species (ROS) scavenger, counteracted K-bZIP expression induced by TB or bortezomib, confirmed that an ROS increase played a role in KSHV lytic cycle activation. Moreover, we found that TB and bortezomib up-regulated p62/Sequestosome1(p62/SQSTM1) protein, while metformin and quercetin down-regulated it. p62/SQSTM1 silencing or the inhibition of NF-E2-related factor 2 (NRF2) or Heat Shock Factor 1 (HSF1), that mediate p62/SQSTM1 transcription, also reduced KSHV lytic antigen expression induced by TB or bortezomib. Interestingly, such combination treatments further increased intracellular ROS and cytotoxicity induced by the single TB or bortezomib treatment, suggesting that NRF2, HSF1 and p62/SQSTM1 keep the ROS level under control, allowing primary effusion lymphoma (PEL) cells to continue to survive and KSHV to replicate

Aspirin-dependent effects on purinergic P2Y1 receptor express

Chronic treatment with aspirin in healthy volunteers (HVs) is associated with recovery of adenosine diphosphate (ADP)-induced platelet activation. The purinergic P2Y1 receptor exerts its effects via a Gq-protein, which is the same biochemical pathway activated by thromboxane-A2 receptor. We hypothesized that recovery of ADP-induced platelet activation could be attributed to increased P2Y1 expression induced by chronic aspirin exposure. We performed a multi-phase investigation which embraced both in vitro and in vivo experiments conducted in (1) human megakaryoblastic DAMI cells, (2) human megakaryocytic progenitor cell cultures, (3) platelets obtained from HVs treated with aspirin and (4) platelets obtained from aspirin-treated patients. DAMI cells treated with aspirin or WY14643 (PPARα agonist) had a significant up-regulation of P2Y1 mRNA, which was shown to be a PPARα-dependent process. In human megakaryocytic progenitors, in the presence of aspirin or WY14643, P2Y1 mRNA expression was higher than in mock culture. P2Y1 expression increased in platelets obtained from HVs treated with aspirin for 8 weeks. Platelets obtained from patients who were on aspirin for more than 2 months had increased P2Y1 expression and ADP-induced aggregation compared with patients on aspirin treatment for less than a month. Overall, our results suggest that aspirin induces genomic changes in megakaryocytes leading to P2Y1 up-regulation and that PPARα is the nuclear receptor involved in this regulation. Since P2Y1 is coupled to the same Gq-protein of thromboxane-A2 receptor, platelet adaptation in response to pharmacological inhibition seems not to be receptor specific, but may involve other receptors with the same biochemical pathway

Current concepts on coronary revascularization in diabetic patients

Diabetic mellitus (DM) patients with coronary artery disease (CAD) are at higher risk of cardiovascular events compared with non-DM individuals. While aggressive cardiovascular prevention and adequate blood glucose control remain cornerstones of therapy, the decision when and how to proceed to coronary revascularization in an individual DM patient should be based on the extent of CAD, ischaemic burden, ventricular function, as well as comorbidities. While in patients with stable symptoms, moderate CAD on coronary angiography and preserved left ventricular function a conservative strategy may be a valuable initial strategy, in patients with acute coronary syndromes (ACS) an early invasive approach should be favoured. The revascularization strategy for DM patients with complex multivessel CAD should be discussed within a heart team consisting of cardiologists, cardiac surgeons, and anaesthesiologists. In general, the threshold for coronary artery bypass surgery (CABG) should be lower for DM than for non-DM individuals. In patients undergoing percutaneous coronary intervention, the use of drug-eluting stents (DES) and—in the setting of ACS—of potent platelet inhibitors, such as prasugrel or ticagrelor, should be favoured. In the near future, multiple strategies may further favourably impact the prognosis of DM patients undergoing coronary revascularization. These include alternative antiplatelet agents such as thromboxane receptor inhibitors, the broad use of second generation DES, and possibly the implantation of bioresorbable stents. Coronary artery bypass surgery outcomes may also further improve by wide implementation of arterial revascularization, reduction in perioperative stroke by avoiding clamping of the aorta, reduction in wound infection by minimally invasive techniques, and optimization of post-operative medical managemen

Deep coral oases in the South Tyrrhenian Sea

A Mediterranean ‘‘roche du large’’ ecosystem, represented by four rocky shoals, located a few miles apart on a muddy bottom at 70–130 m depth in the gulf of St. Eufemia (Calabria, South Tyrrhenian Sea), was studied by means of Remotely Operated Vehicle (ROV) photo imaging. The shoals host highly diversified coral communities, mainly composed of arborescent colonies of gorgonians (Callogorgia verticillata, Paramuricea clavata, Paramuricea macrospina, Bebryce mollis, Villogorgia bebrycoides, Corallium rubrum, and Leptogorgia sarmentosa), and antipatharians (Antipathella subpinnata, Antipathes dichotoma and Parantipathes larix). The coral colonies reach high densities (up to ca. 17 colonies m22) and large sizes, such as the over 1.5 m wide antipatharian colonies. We hypothesized that the abundance and composition of the coral assemblages differed significantly among the rocky shoals and with respect to the surrounding soft bottoms. Various environmental variables were tested as possible explanatory factors of the observed differences. Moreover, due to their off- coast localization, we report here that these unique ecosystems are potentially subjected to a strong pressure from the local fishing activities, which were tentatively characterized. The recorded coral b-diversity among the shoals supports the hypothesis that these habitats behave like small oases of hard substrata interspersed in a muddy bottom. Because of their intrinsic beauty and rarity and their biological and ecological value, we stress the need of specific actions aimed at the urgent protection of these oases of biodiversity

Persistence of pristine deep-sea coral gardens in the Mediterranean Sea (SW Sardinia)

Leiopathes glaberrima is a tall arborescent black coral species structuring important facies of the deep-sea rocky bottoms of the Mediterranean Sea that are severely stifled by fishing activities. At present, however, no morphological in vivo description, ecological characterization, age dating and evaluation of the possible conservation actions have ever been made for any population of this species in the basin. A dense coral population was reported during two Remotely Operated Vehicle (ROV) surveys conducted on a rocky bank off the SW coasts of Sardinia (Western Mediterranean Sea). L. glaberrima forms up to 2 m-tall colonies with a maximal observed basal diameter of nearly 7 cm. The radiocarbon dating carried out on a colony from this site with a 4 cm basal diameter revealed an approximately age of 2000 years. Considering the size-frequency distribution of the colonies in the area it is possible to hypothesize the existence of other millennial specimens occupying a supposedly very stable ecosystem. The persistence of this ecosystem is likely guaranteed by the heterogeneous rocky substrate hosting the black coral population that represents a physical barrier against the mechanical impacts acted on the surrounding muddy areas, heavily exploited as trawling fishing grounds. This favorable condition, together with the existence of a nursery area for catsharks within the coral ramifications and the occurrence of a meadow of the now rare soft bottom alcyonacean Isidella elongata in small surviving muddy inclaves, indicates that this ecosystem have to be considered a pristine Mediterranean deep-sea coral sanctuary that would deserve special protection

Efecto del Locus CSN3 sobre la composición de la leche de cabra de raza murciano-granadina

CICYT AGL2002-04304-C03-01-02- 03 GA