The mitogen-activated protein kinase (MAPK) pathway has been implicated in the molecular pathogenesis of human cancers, including metastatic colorectal cancer (mCRC). This provides a rationale for ...the development of MAPK-targeted agents such as pimasertib.
Patients with KRAS mutant mCRC were treated in the second-line setting with FOLFIRI (5-fluorouracil/folinic acid/irinotecan) plus pimasertib. The primary objective of the safety run-in phase was to determine the maximum-tolerated dose (MTD) and the recommended phase II dose of pimasertib combined with FOLFIRI.
Sixteen patients were enrolled in the trial. Ten and six patients were treated daily with 45 and 60 mg of pimasertib plus FOLFIRI, respectively. The MTD was considered to be 45 mg per day. The most common treatment-emergent adverse events were diarrhoea, nausea, vomiting, asthenia and skin/rash event. Of the 15 patients in the efficacy analysis group, two patients had partial response, nine patients had stable disease, three patients had progressive disease as their best overall response and one patient could not be evaluated.
Dose escalation of pimasertib in combination with FOLFIRI was limited by toxicity. At the MTD of 45 mg per day, pimasertib was adequately tolerated in patients with mCRC and no unexpected or new safety signals or concerns were identified.
Cancer stem cells have been isolated from several solid tumors including prostate, colon, liver, breast, and ovarian cancer. Stem cells isolated from nervous system and prostate express CD133 ...antigen, which is widely used to isolate hematopoietic stem and progenitor cells. The aims of this study were to investigate the expression of the CD133-1 and CD133-2 epitopes in primary ovarian tumors and to biologically characterize CD133(+) ovarian cancer cells, also according to clinicopathologic parameters. Tissue specimens were obtained at primary surgery from 41 ovarian carcinomas; eight normal ovaries and five benign ovarian tumors were also collected. Flow cytometry with monoclonal antibodies against CD133-1 and CD133-2 epitopes was employed. FACS (fluorescence activated cell sorting) analysis enabled the selection of CD133(+) cells, whose epithelial origin was confirmed by immunofluorescence analysis with monoclonal anti-cytokeratin 7. CD133(+) cells gave rise to a 4.7 +/- 0.9-fold larger number of colonies than that documented in CD133(-) population (P < 0.001). Moreover, CD133(+) cells showed an enhanced proliferative potential compared to CD133(-) cells. The percentages of CD133-1- and CD133-2-expressing cells were significantly lower in normal ovaries/benign tumors with respect to those in ovarian carcinoma. Both the percentages of CD133-1- and CD133-2-expressing cells were significantly lower in omental metastases than in primary ovarian cancer (P = 0.009 and 0.007 for CD133-1- and CD133-2-expressing cells, respectively). There seems not to be any difference in the distribution of the percentage of CD133-1- and CD133-2-expressing cells according to clinicopathologic parameters and response to primary chemotherapy. CD133-1 and CD133-2 may be useful in order to select and enrich the population of CD133(+) ovarian tumor cells, which are characterized by a higher clonogenic efficiency and proliferative potential.
Cell-cell interactions are an observable manifestation of underlying complex biological processes occurring in response to diversified biochemical stimuli. Recent experiments with microfluidic ...devices and live cell imaging show that it is possible to characterize cell kinematics via computerized algorithms and unravel the effects of targeted therapies. We study the influence of spatial and temporal resolutions of time-lapse videos on motility and interaction descriptors with computational models that mimic the interaction dynamics among cells. We show that the experimental set-up of time-lapse microscopy has a direct impact on the cell tracking algorithm and on the derived numerical descriptors. We also show that, when comparing kinematic descriptors in two diverse experimental conditions, too low resolutions may alter the descriptors' discriminative power, and so the statistical significance of the difference between the two compared distributions. The conclusions derived from the computational models were experimentally confirmed by a series of video-microscopy acquisitions of co-cultures of unlabelled human cancer and immune cells embedded in 3D collagen gels within microfluidic devices. We argue that the experimental protocol of acquisition should be adapted to the specific kind of analysis involved and to the chosen descriptors in order to derive reliable conclusions and avoid biasing the interpretation of results.
RPL is a very debated condition, in which many issues concerning definition, etiological factors to investigate or therapies to apply are still controversial. ML could help clinicians to reach an ...objectiveness in RPL classification and access to care. Our aim was to stratify RPL patients in different risk classes by applying an ML algorithm, through a diagnostic work-up to validate it for the appropriate prognosis and potential therapeutic approach. 734 patients were enrolled and divided into 4 risk classes, according to the numbers of miscarriages. ML method, called Support Vector Machine (SVM), was used to analyze data. Using the whole set of 43 features and the set of the most informative 18 features we obtained comparable results: respectively 81.86 ± 0.35% and 81.71 ± 0.37% Unbalanced Accuracy. Applying the same method, introducing the only features recommended by ESHRE, a correct classification was obtained only in 58.52 ± 0.58%. ML approach could provide a Support Decision System tool to stratify RPL patients and address them objectively to the proper clinical management.
Triggering mechanisms and causative processes of deep-seated gravitational slope deformations (DSGSD) in Alpine and high mountain areas include, among others, post-glacial de-buttressing, ...earthquake-induced ground shaking, or co-seismic surface faulting. Distinguishing between climatic or tectonically driven factors is challenging since faults and fracture systems can play both an active and/or passive role in the process initiation. We applied an integrated approach, including morpho-structural analysis, geologic field survey, a paleoseismological approach applied to trenching, radiocarbon dating and detailed sedimentological analysis, to a DSGSD located in the Cavargna Valley (N Italy), an area that was never occupied by extensive ice tongues in the Upper Pleistocene and Holocene. We were able to document at least two phases of movement from the Middle Holocene onwards and related triggering factors. Thanks to the comparison with dated lacustrine turbidites in the Alpine Lakes, we argue a seismic triggering for the landslide onset, with a possible source located in southern Switzerland, close to the Insubric Line. The later evolution of the landslide was instead driven by climatic predisposing conditions (humid and cold), instead, corresponding to a phase of enhanced slope instability.
Purpose
After injection in the bloodstream, a lipid nanoparticle (LDE) resembling low-density lipoprotein (LDL) concentrates in atherosclerotic lesions of cholesterol-fed rabbits. Here, rabbits with ...atherosclerosis were treated with carmustine, an antiproliferative agent used in cancer chemotherapy, associated to LDE to investigate the effects on the lesions.
Methods
Twenty-seven male New Zealand rabbits were fed a 1 % cholesterol diet for 8 weeks. After 4 weeks nine animals were treated with intravenous saline solution, nine with intravenous LDE alone, and nine with intravenous LDE-carmustine (4 mg/kg, weekly for 4 weeks).
Results
LDE-carmustine reduced lesion size by 90 % compared to the controls. LDE-carmustine reduced the presence of macrophages, vascular smooth muscle cells, and regulatory T cells in the arterial intima, as well as the presence of matrix metallopeptidase-9, interleukin-1β and TNF-α and lipoprotein receptors, namely LDL-receptor, LDL-related protein-1, scavenger receptor class B member 1. When injected alone, without association to carmustine, LDE was not different from injected saline solution.
Conclusions
LDE-carmustine treatment resulted in marked reduction of lesion area, of the invasion of the arterial intima by macrophages and vascular smooth muscle cells and pro-inflammatory factors. Therefore, this new formulation shows great potential for therapy of atherosclerotic cardiovascular disease.
Paracalanid copepods, common in tropical zooplankton communities, are known hosts for a variety of parasites. Nevertheless, relatively little is known about the prevalence and consequences of ...parasitism in these copepods. In this study, we analyzed the relationship between two paracalanid copepods, Parvocalanus crassirostris and Paracalanus spp., with a common parasite, the alveolate protist Ellobiopsis chattoni, in a subtropical environment on the south-east Brazilian coast. We assessed the frequency and abundance of parasites in juveniles and adult male and female copepods. We observed that 22 out of 4014 Paracalanus spp. (0.55%) and 98 out of 3920 P. crassirostris were infected (2.5%). E. chattoni were rarely found in other taxa (about 0.05% for Oithona spp. and Acartia lilljeborgii). The parasites were most frequently attached to cephalosome appendages (73.6%), with up to four cells per copepod. The parasites were more prevalent in adults than juveniles, and adult females were more frequently infected than males. E. chattoni had a likely negative impact on copepod growth because the infected females were smaller than the non-infected females (p < 0.001). Females are usually bigger and live longer than males, which could account for their high frequency of infection.
PDF
