The Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR and Jak/STAT pathways are frequently activated in leukemia and other hematopoietic disorders by upstream mutations in cytokine receptors, aberrant chromosomal ...translocations as well as other genetic mechanisms. The Jak2 kinase is frequently mutated in many myeloproliferative disorders. Effective targeting of these pathways may result in suppression of cell growth and death of leukemic cells. Furthermore it may be possible to combine various chemotherapeutic and antibody-based therapies with low molecular weight, cell membrane-permeable inhibitors which target the Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR and Jak/STAT pathways to ultimately suppress the survival pathways, induce apoptosis and inhibit leukemic growth. In this review, we summarize how suppression of these pathways may inhibit key survival networks important in leukemogenesis and leukemia therapy as well as the treatment of other hematopoietic disorders. Targeting of these and additional cascades may also improve the therapy of chronic myelogenous leukemia, which are resistant to BCR-ABL inhibitors. Furthermore, we discuss how targeting of the leukemia microenvironment and the leukemia stem cell are emerging fields and challenges in targeted therapies.
Vandetanib did not demonstrate any superiority alone or in combination with gemcitabine in the progression-free survival of patients affected by advanced biliary tract cancer compared with ...gemcitabine alone. The safety profile of vandetanib given (alone or in combination with gemcitabine) does not show any additional adverse events (AEs) or worsening of already known AEs.
The management of biliary tract cancers (BTCs) is complex due to limited data on the optimal therapeutic approach. This phase II multicenter study evaluated the efficacy and tolerability of vandetanib monotherapy compared with vandetanib plus gemcitabine or gemcitabine plus placebo in patients with advanced BTC.
Patients were randomized in a 1 : 1 : 1 ratio to three treatment groups: vandetanib 300 mg monotherapy (V), vandetanib 100 mg plus gemcitabine (V/G), gemcitabine plus placebo (G/P). Vandetanib (300 mg or 100 mg) or placebo was given in single oral daily doses. Gemcitabine 1000 mg/m2 was i.v. infused on day 1 and day 8 of each 21-day cycle. The primary end point was progression-free survival (PFS). Secondary end points were: objective response rate (ORR), disease control rate, overall survival, duration of response, performance status and safety outcomes.
A total of 173 patients (mean age 63.6 years) were recruited at 19 centers across Italy. Median (95% confidence intervals) PFS (days) were 105 (72–155), 114 (91–193) and 148 (71–225), respectively, for the V, V/G and G/P treatment groups, with no statistical difference among them (P = 0.18). No statistical difference between treatments was observed for secondary end points, except ORR, which slightly favored the V/G combination over other treatments. The proportion of patients reporting adverse events (AEs) was similar for the three groups (96.6% in V arm, 91.4% in the V/G arm and 89.3% in the G/P arm).
Vandetanib treatment did not improve PFS in patients with advanced BTC. The safety profile of vandetanib did not show any additional AEs or worsening of already known AEs.
NCT00753675.
Recently, strategies for acute myeloid leukemia (AML) therapy have been developed that target anti-apoptotic BCL2 family members using BH3-mimetic drugs such as ABT-737. Though effective against BCL2 ...and BCL-X(L), ABT-737 poorly inhibits MCL-1. Here we report that, unexpectedly, ABT-737 induces activation of the extracellular receptor activated kinase and induction of MCL-1 in AML cells. MEK inhibitors such as PD0325901 and CI-1040 have been used successfully to suppress MCL-1. We report that PD0325901 blocked ABT-737-induced MCL-1 expression, and when combined with ABT-737 resulted in potent synergistic killing of AML-derived cell lines, primary AML blast and CD34+38-123+ progenitor/stem cells. Finally, we tested the combination of ABT-737 and CI-1040 in a murine xenograft model using MOLM-13 human leukemia cells.Whereas control mice and CI-1040-treated mice exhibited progressive leukemia growth, ABT-737, and to a significantly greater extent, ABT-737+CI-1040 exerted major anti-leukemia activity. Collectively, results demonstrated unexpected anti-apoptotic interaction between the BCL2 family-targeted BH3-mimetic ABT-737 and mitogen-activated protein kinase signaling in AML cells: the BH3 mimetic is not only restrained in its activity by MCL-1, but also induces its expression. However, concomitant inhibition by BH3 mimetics and MEK inhibitors could abrogate this effect and may be developed into a novel and effective therapeutic strategy for patients with AML.
Species relationships in the bottlenose dolphin (genus Tursiops Gervais, 1855) are controversial. We carried out a comprehensive osteological study of 264 skulls, including type specimens, and 90 ...postcranial skeletons of Tursiops spp. to address taxonomic uncertainties in Australia using two-dimensional (2D) measurements, and three-dimensional geometric morphometrics (3DGM), tooth and vertebral counts, and categorical data. Analyses provided support for the presence of two forms, aligned to the Indo-Pacific bottlenose dolphin (Tursiops aduncus (Ehrenberg, 1832)) and the common bottlenose dolphin (Tursiops truncatus (Montagu, 1821)), including type specimens. The Burrunan dolphin (Tursiops australis Charlton-Robb, Gershwin, Thompson, Austin, Owen and McKechnie, 2011) fell well within T. truncatus for both 2D and 3DGM methods. Thirteen Tursiops spp. specimens, no T. australis specimens, were of intermediate size (2D) and could not be assigned to either species. For 3DGM data, there was a strong allometric influence and few non-allometric differences between species. Length and width of the cranium and rostrum were important discriminating variables. Tursiops aduncus was smaller, had more teeth, fewer vertebrae, and more erosion on the pterygoids and frontals than T. truncatus. Overall cranium shape was round in T. aduncus and angular in T. truncatus. Skull length of T. aduncus was smaller in low than in high latitudes. This study highlights the importance of large sample size, multiple analytical methods, and extensive geographical coverage when undertaking taxonomic studies.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The coastal area extending east of the city of Martigues, between the bays of Bonnieu and that of Chariot, is characterized by an alternation of gently sloping rocky coast and 5 m high cliffs ...composed of Miocene limestone. The foot of the cliff is marked by a well developed notch and a discontinuous wave-cut platform; at its base, the sea bottom reaches a maximum depth of about 4.5–6 m. The emerged area shows boulders placed up to 10 m inland of the coastline at around 2 m above s.l. and, weighing as much as 35 tonnes. A geomorphological survey was conducted by means of a Terrestrial Laser Scanner to estimate boulder sizes. The particular focus of the proposed study was to estimate the minimum wave height required to detach and transport two boulders, originally joined together as one bigger one and weighing approximately 25 tonnes, from the wave-cut platform onto the surf bench. Hydrodynamic models developed by various authors were used to calculate the minimum wave height necessary to move them. The data obtained from the resulting hydrodynamic equations were compared to wave-climate data collected over the last 15 years by the buoy off the coast of Marseille, in the Gulf of Lion. The present study seems to confirm that it would not have been necessary to have a tsunami impact (among other things, never recorded in the last 20 years) to move a 25 tonnes boulder. Indeed, hydrodynamic equations suggest that the boulder might have been broken and only subsequently moved due to the impact of waves generated by an extreme storm which would have occurred prior to December 2003. This hypothesis seems to be in agreement with the morphology of the sea bottom, hydrodynamic features of the area as well as eyewitnesses.
To evaluate the safety and feasibility of stereotactic body radiation therapy (SBRT) with simultaneous integrated boost (SIB) and simultaneous integrated protection (SIP) in borderline resectable and ...locally advanced pancreatic ductal adenocarcinoma.
Patients receiving SBRT following induction chemotherapy from January 2017 to December 2018 were included in this observational analysis. SBRT was delivered in five consecutive daily fractions by administering 30 Gy to the planning target volume while simultaneously delivering a 50 Gy SIB to the tumour–vessel interface. SIP was created by lowering the dose to 25 Gy on the overlap area between the planning target volume and the planning organ at risk volume. The primary end point was acute and late gastrointestinal grade ≥3 toxicity. Secondary end points were freedom from local progression, overall survival and progression-free survival (PFS).
Fifty-nine consecutive patients (27 borderline resectable and 32 locally advanced) were included. Fifty-eight patients (98.3%) completed the SBRT planned treatment and 35 patients (59.4%) received surgical resection following SBRT. No acute or late grade ≥3 SBRT-related adverse events were observed. The median follow-up time was 15.1 months in the overall cohort and 18.1 months in censored patients. One- and 2-year freedom from local progression rates were 85% and 80% versus 79.7% and 60.6% in resected and unresected patients, respectively (P = 0.33). The median overall survival and PFS were 30.2 months and 19 months from diagnosis and 19.1 months and 10.7 months from SBRT in the entire cohort. Resected patients had improved 2-year overall survival rates (72.5% versus 49%, P = 0.012) and median PFS (13 months versus 5 months; P < 0.001) relative to unresected patients. There was no survival difference between borderline resectable and locally advanced patients.
SBRT with SIB/SIP had an excellent toxicity profile and could be administered safely on pancreatic ductal adenocarcinoma patients, even in a total neoadjuvant setting.
•The SBRT with SIB/SIP may help the safe delivery of ablative doses to the tumour.•No acute or late grade ≥ 3 SBRT-related adverse events were observed with SIB/SIP.•Borderline resectable pancreatic cancer patients are more likely to benefit from SBRT with SIB/SIP.
PDF
