An Incidental Finding of a Cardiac Sarcoma

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Integrin αvβ6-specific therapy for pancreatic cancer developed from foot-and-mouth-disease virus

GOALS OF INVESTIGATION: The 5-year survival rate for pancreatic ductal adenocarcinoma (PDAC) has remained at <5% for decades because no effective therapies have been identified. Integrin αvβ6 is overexpressed in most PDAC and represents a promising therapeutic target. Thus, we attempted to develop an αvβ6-specific peptide-drug conjugate (PDC) for therapy of PDAC. METHODOLOGY: We conjugated the DNA-binding pyrrolobenzodiazepine (PBD)-based payload SG3249 (tesirine) to an αvβ6-specific 20mer peptide from the VP1 coat protein of foot-and-mouth-disease virus (FMDV) (forming conjugate SG3299) or to a non-targeting peptide (forming conjugate SG3511). PDCs were tested for specificity and toxicity on αvβ6-negative versus-positive PDAC cells, patient-derived cell lines from tumor xenografts, and on two different in vivo models of PDAC. Immunohistochemical analyses were performed to establish therapeutic mechanism. RESULTS: The αvβ6-targeted PDC SG3299 was significantly more toxic (up to 78-fold) for αvβ6-expressing versus αvβ6-negative PDAC cell lines in vitro, and achieved significantly higher toxicity at equal dose than the non-targeted PDC SG3511 (up to 15-fold better). Moreover, SG3299 eliminated established (100mm3) Capan-1 PDAC human xenografts, extending the lifespan of mice significantly (P=0.005). Immunohistochemistry revealed SG3299 induced DNA damage and apoptosis (increased γH2AX and cleaved caspase 3, respectively) associated with significant reductions in proliferation (Ki67), β6 expression and PDAC tumour growth. CONCLUSION: The FMDV-peptide drug conjugate SG3299 showed αvβ6-selectivity in vitro and in vivo and can specifically eliminate αvβ6-positive cancers, providing a promising new molecular- specific therapy for pancreatic cancer

Bioengineered 3D models of human pancreatic cancer recapitulate in vivo tumour biology

Patient-derived in vivo models of human cancer have become a reality, yet their turnaround time is inadequate for clinical applications. Therefore, tailored ex vivo models that faithfully recapitulate in vivo tumour biology are urgently needed. These may especially benefit the management of pancreatic ductal adenocarcinoma (PDAC), where therapy failure has been ascribed to its high cancer stem cell (CSC) content and high density of stromal cells and extracellular matrix (ECM). To date, these features are only partially reproduced ex vivo using organoid and sphere cultures. We have now developed a more comprehensive and highly tuneable ex vivo model of PDAC based on the 3D co-assembly of peptide amphiphiles (PAs) with custom ECM components (PA-ECM). These cultures maintain patient-specific transcriptional profiles and exhibit CSC functionality, including strong in vivo tumourigenicity. User-defined modification of the system enables control over niche-dependent phenotypes such as epithelial-to-mesenchymal transition and matrix deposition. Indeed, proteomic analysis of these cultures reveals improved matrisome recapitulation compared to organoids. Most importantly, patient-specific in vivo drug responses are better reproduced in self-assembled cultures than in other models. These findings support the use of tuneable self-assembling platforms in cancer research and pave the way for future precision medicine approaches

Non-Atherosclerotic Coronary and Vascular Disease Case Report: Searching for a Rare Clinical Entity

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Multimodal Treatment Eliminates Cancer Stem Cells and Leads to Long-Term Survival in Primary Human Pancreatic Cancer Tissue Xenografts.

Copyright: 2013 Hermann et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.PURPOSE: In spite of intense research efforts, pancreatic ductal adenocarcinoma remains one of the most deadly malignancies in the world. We and others have previously identified a subpopulation of pancreatic cancer stem cells within the tumor as a critical therapeutic target and additionally shown that the tumor stroma represents not only a restrictive barrier for successful drug delivery, but also serves as a paracrine niche for cancer stem cells. Therefore, we embarked on a large-scale investigation on the effects of combining chemotherapy, hedgehog pathway inhibition, and mTOR inhibition in a preclinical mouse model of pancreatic cancer. EXPERIMENTAL DESIGN: Prospective and randomized testing in a set of almost 200 subcutaneous and orthotopic implanted whole-tissue primary human tumor xenografts. RESULTS: The combined targeting of highly chemoresistant cancer stem cells as well as their more differentiated progenies, together with abrogation of the tumor microenvironment by targeting the stroma and enhancing tissue penetration of the chemotherapeutic agent translated into significantly prolonged survival in preclinical models of human pancreatic cancer. Most pronounced therapeutic effects were observed in gemcitabine-resistant patient-derived tumors. Intriguingly, the proposed triple therapy approach could be further enhanced by using a PEGylated formulation of gemcitabine, which significantly increased its bioavailability and tissue penetration, resulting in a further improved overall outcome. CONCLUSIONS: This multimodal therapeutic strategy should be further explored in the clinical setting as its success may eventually improve the poor prognosis of patients with pancreatic ductal adenocarcinoma

Consensus Document on Transthoracic Echocardiography in Portugal

Echocardiography is the most widely used imaging technique in modern cardiological clinical practice, since it is readily available, portable and safe, and provides a comprehensive morphological and functional assessment at low cost compared to other imaging modalities. Recent technological advances have introduced new echocardiographic techniques and widened the clinical applications of echocardiography. However, these developments have also led to an increase in information, rendering interpretation of the data provided by the exam more complex; this may result in assessment errors by less experienced operators. Standardization of procedures and training in echocardiography is therefore essential to ensure quality and safety for patients. The present document aims to contribute to this end, recommending quality requirements for operators and echocardiography laboratories in Portugal.info:eu-repo/semantics/publishedVersio

ER stress protein AGR2 precedes and is involved in the regulation of pancreatic cancer initiation

The work was supported by a grant A12008 from CR-UK (L. Dumartin, N.R. Lemoine and T. Crnogorac-Jurcevic)

Elderberry Concentrate Juice Industrial By-Products Characterization and Valorisation

The elderberry juice industry generates by-products that can be valorised as a source of valuable compounds, namely anthocyanins and carbohydrates recovered from pomace and retentate. This work aims to valorise the anthocyanins and carbohydrates present in pomace and retentate, focused on the analysis and characterization of the polysaccharides present and their use for the stability of pink beverages. The present work shows that pomace contains 50% of carbohydrates, in which glucose and xylose are the major constituents, probably arising from cellulose and xyloglucans of cell walls polysaccharides and from the moiety of main anthocyanins present in berry skin. The concentrated juice is rich mainly in free sugars (55%), glucose and fructose, containing also pectic polysaccharides. However, a large amount of compounds are retained in the ultrafiltration membranes of 100 kDa, constituting the retentate, comprising 52% of water insoluble material. The remaining 48% constitutes the water-soluble fraction, composed of 47% of free sugars, mainly fructose (80%), and 14% of polymeric material constituted by 38% of pectic polysaccharides and 44% of anthocyanins. The use of the colourant in the form of a complex pectic polysaccharides-anthocyanins allowed to achieve a higher colour stability than the isolated anthocyanins, over more than 22 days. This property allowed to use the retentate water soluble fraction as a natural colourant ingredient to develop a stable pink tonic water