Pancreatic cancer is expected to be the second deadliest malignancy in the USA by 2020. The survival rates for patients with other gastrointestinal malignancies have increased consistently during the ...past 30 years; unfortunately, however, the outcomes of patients with pancreatic cancer have not changed significantly. Although surgery remains the only curative treatment for pancreatic cancer, therapeutic strategies based on initial resection have not substantially improved the survival of patients with resectable disease over the past 25 years; presently, more than 80% of patients suffer disease relapse after resection. Preclinical evidence that pancreatic cancer is a systemic disease suggests a possible benefit for early administration of systemic therapy in these patients. In locally advanced disease, the role of chemoradiotherapy is increasingly being questioned, particularly considering the results of the LAP-07 trial. Novel biomarkers are clearly needed to identify subsets of patients likely to benefit from chemoradiotherapy. In the metastatic setting, FOLFIRINOX (folinic acid, 5-fluorouracil, irinotecan, and oxaliplatin), and nab-paclitaxel plus gemcitabine have yielded only modest improvements in survival. Thus, new treatments are urgently needed for patients with pancreatic cancer. Herein, we review the state-of-the-art of pancreatic cancer treatment, and the upcoming novel therapeutics that hold promise in this disease are also discussed.
Improvements in the outcomes of patients with pancreatic ductal adenocarcinoma (PDAC) have lagged behind advances made in the treatment of many other malignancies over the past few decades. For most ...patients with PDAC, cytotoxic chemotherapy remains the mainstay of treatment. For patients with resectable disease, modified 5-fluorouracil, leucovorin, irinotecan and oxaliplatin (mFOLFIRINOX) is the standard-of-care adjuvant therapy, although data from several randomized trials have shown improved outcomes with neoadjuvant treatment strategies. For patients with advanced-stage or metastatic disease, comprehensive genomic profiling has revealed several potentially actionable alterations in small subsets of patients and the feasibility of implementing such strategies is beginning to be confirmed. Novel therapies targeting certain aberrations, most notably BRCA1/2 mutations, mismatch repair (MMR) deficiencies or NTRK1-3 fusions, have shown considerable activity in clinical trials, and larotrectinib, entrectinib and pembrolizumab have received FDA approval for the treatment of patients with tumours harbouring NTRK fusions and MMR deficiencies, respectively, regardless of primary tumour histology. In this Review, we describe the available data on the activity of these and other agents in patients with PDAC. Our discussion is structured according to the acronym 'PRIME' to organize the various treatment strategies currently undergoing evaluation in clinical trials: Pathway inhibition, alteration of DNA Repair pathways, Immunotherapy, cancer Metabolism and targeting the Extracellular tumour microenvironment.
Patient-derived xenograft (PDX) models are now being widely used in cancer research and have the potential to greatly inform our understanding of cancer biology. However, many questions remain, ...especially regarding the ability of PDX models to affect clinical decision making. With these points in mind, we asked three scientists to give their opinions on the generation and uses of PDX models and the future of this field.
Paclitaxel has wide application in anticancer therapy but was never considered an efficacious agent in pancreatic cancer. A review of the experience with the Cremaphor formulation hinted at ...paclitaxel's activity in pancreatic cancer, but the early development was hampered by significant toxicities such as neutropenia and infection at clinically tolerable doses. However, such efficacy was confirmed in the recently completed phase III Metastatic Pancreatic Adenocarcinoma Clinical Trial (MPACT), in which the addition of nab-paclitaxel to gemcitabine significantly improved the survival of patients with metastatic pancreatic cancer. Several other Cremaphor-free formulations of paclitaxel had also been evaluated in pancreatic cancer, and the reasons for the success of the albumin nanoparticulate are examined here. In the era of biologic and molecularly targeted agents, the success of nab-paclitaxel in recalcitrant pancreatic cancer is a timely reminder of the importance and relevance of pharmacology and novel drug delivery technology in the development of anticancer drugs.
Developmental coordination disorder (DCD) is one of the most prevalent pediatric chronic conditions. Without proper intervention, significant delays in motor skill performance and learning may ...persist until adulthood. Moderate-to-vigorous physical exercise has been proven to improve motor learning (adaptation and consolidation) in children with or without disorders. However, the effect of a short bout of physical exercise on motor adaptation and consolidation in children with DCD has not been examined. Furthermore, the role of perceptual-motor integration and attention as mediators of learning has not been examined via neuroimaging in this population.
Therefore, the primary aims of this project will be to compare children with and without DCD to (a) examine the effect of acute exercise on motor learning (adaptation and consolidation) while performing a rotational visuo-motor adaptation task (rVMA), and (b) explore cortical activation in the dorsolateral- and ventrolateral-prefrontal cortex areas while learning the rVMA task under rest or post-exercise conditions.
One hundred twenty children will be recruited (60 DCD, 60 controls) and within-cohort randomly assigned to either exercise (13-minute shuttle run task) or rest prior to performing the rVMA task. Adaptation and consolidation will be evaluated via two error variables and three retention tests (1h, 24h and 7 days post adaptation). Cortical activation will be registered via functional near-infrared spectroscopy (fNIRS) during the baseline, adaptation, and consolidation.
We expect to find exercise benefits on motor learning and attention so that children with DCD profiles will be closer to those of children with typical development. The results of this project will provide further evidence to: (a) better characterize children with DCD for the design of educational materials, and (b) establish acute exercise as a potential intervention to improve motor learning and attention.
Objective: To assess the Gaussianity of the human alpha rhythm using the envelope signal and the coefficient of variation of the envelope (CVE). Methods: Envelope analysis relies on the fact that the ...CVE for Gaussian noise is <inline-formula><tex-math notation="LaTeX">\sqrt{(4-\pi)/\pi }\approx 0.523</tex-math></inline-formula>. CVE can thus be used as a hallmark to detect Gaussianity, and any significant deviation from Gaussianity can be linked to synchronous neural dynamics. We applied envelope analysis to EEG and iEEG public databases. Results: The human alpha rhythm can be characterized either as a synchronous or as a Gaussian signal based on the value of its CVE. Furthermore, Fourier analysis showed the canonical spectral peak at <inline-formula><tex-math notation="LaTeX">\approx</tex-math></inline-formula>10Hz is present in both the synchronous and Gaussian cases, thus demonstrating this same peak can be produced by different underlying neural dynamics. Conclusion: Human EEG can be classified using envelope parameters. This study confirms the original interpretation of Adrian regarding the origin of the alpha rhythm but also opens the door for the study of Gaussianity in brain dynamics. Significance: Envelope analysis constitutes a novel complement to Fourier-based methods for neural signal analysis relating amplitude modulations (CVE) to signal energy. These results suggest a broader interpretation for event-related synchronization/desynchronization (ERS/ERD) may be needed.
Recently, there has been an increasing interest in the development and characterization of patient-derived tumor xenograft (PDX) models for cancer research. PDX models mostly retain the principal ...histologic and genetic characteristics of their donor tumor and remain stable across passages. These models have been shown to be predictive of clinical outcomes and are being used for preclinical drug evaluation, biomarker identification, biologic studies, and personalized medicine strategies. This article summarizes the current state of the art in this field, including methodologic issues, available collections, practical applications, challenges and shortcomings, and future directions, and introduces a European consortium of PDX models.
PDX models are increasingly used in translational cancer research. These models are useful for drug screening, biomarker development, and the preclinical evaluation of personalized medicine strategies. This review provides a timely overview of the key characteristics of PDX models and a detailed discussion of future directions in the field.
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•An improved FMMOCS (i-FMMOCS) filter for salt and pepper noise in images is presented.•A comparison on 46 images with 20 different noise densities (5–98%) is performed.•i-FMMOCS ...outperforms other state of the art filters both visually and quantitatively.•Wilcoxon's test ensures a significant superiority from a statistical point of view.•It removes the noise without compromising fine details regardless of the noise density.
Noise reduction is a paramount preliminary step in many computer vision applications in which the presence of undesired noise can distort the results. Lately, the removal of high density salt and pepper noise, as a particular case of impulse noise, has experimented a peak of interest. In this paper, a novel filter, called the improved fuzzy mathematical morphology open-close filter (i-FMMOCS), is presented. This filter considerably improves the results obtained by the so-called fuzzy mathematical morphology open-close filter, through the use of some fuzzy mathematical operators, especially designed to avoid the use of the noisy pixels into the computations. A statistical analysis using some objective restoration measures and the visual comparison of the experimental results show that the proposed filter outperforms significantly several state-of-the-art filters for images corrupted from 5% up to 98% of salt and pepper noise.
A quarter of all solid tumors harbor KRAS oncogenes. Yet, no selective drugs have been approved to treat these malignancies. Genetic interrogation of the MAPK pathway revealed that systemic ablation ...of MEK or ERK kinases in adult mice prevent tumor development but are unacceptably toxic. Here, we demonstrate that ablation of c-RAF expression in advanced tumors driven by KrasG12V/Trp53 mutations leads to significant tumor regression with no detectable appearance of resistance mechanisms. Tumor regression results from massive apoptosis. Importantly, systemic abrogation of c-RAF expression does not inhibit canonical MAPK signaling, hence, resulting in limited toxicities. These results are of significant relevance for the design of therapeutic strategies to treat K-RAS mutant cancers.
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•Ablation of c-RAF expression induces regression of Kras/Trp53 mutant lung tumors•Loss of c-RAF expression does not affect MAPK signaling•Systemic ablation of c-RAF expression in adult mice has limited toxic effects
Sanclemente et al. generate oncogenic Kras mice that allow inducible deletion of Raf1, encoding c-RAF, and/or Braf in established KrasG12V or KrasG12V;Trp53−/− lung tumors. They show that systemic c-RAF ablation has limited toxicity and leads to significant tumor regression without having an impact on MAPK activity.
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