Molecular profiling of prostate cancer derived exosomes may reveal a predictive signature for response to docetaxel

Docetaxel is a cornerstone treatment for metastatic, castration resistant prostate cancer (CRPC) which remains a leading cause of cancer-related deaths, worldwide. The clinical usage of docetaxel has resulted in modest gains in survival, primarily due to the development of resistance. There are currently no clinical biomarkers available that predict whether a CRPC patient will respond or acquire resistance to this therapy. Comparative proteomics analysis of exosomes secreted from DU145 prostate cancer cells that are sensitive (DU145 Tax-Sen) or have acquired resistance (DU145 Tax-Res) to docetaxel, demonstrated significant differences in the amount of exosomes secreted and in their molecular composition. A panel of proteins was identified by proteomics to be differentially enriched in DU145 Tax-Res compared to DU145 Tax-Sen exosomes and was validated by western blotting. Importantly, we identified MDR-1, MDR-3, Endophilin-A2 and PABP4 that were enriched only in DU145 Tax-Res exosomes. We validated the presence of these proteins in the serum of a small cohort of patients. DU145 cells that have uptaken DU145 Tax-Res exosomes show properties of increased matrix degradation. In summary, exosomes derived from DU145 Tax-Res cells may be a valuable source of biomarkers for response to therapy.

Sorafenib-induced defective autophagy promotes cell death by necroptosis

Autophagy is one of the main cytoprotective mechanisms that cancer cells deploy to withstand the cytotoxic stress and survive the lethal damage induced by anti-cancer drugs. However, under specific conditions, autophagy may, directly or indirectly, induce cell death. In our study, treatment of the Atg5-deficient DU145 prostate cancer cells, with the multi-tyrosine kinase inhibitor, sorafenib, induces mitochondrial damage, autophagy and cell death. Molecular inhibition of autophagy by silencing ULK1 and Beclin1 rescues DU145 cells from cell death indicating that, in this setting, autophagy promotes cell death. Re-expression of Atg5 restores the lipidation of LC3 and rescues DU145 and MEF atg5-/- cells from sorafenib-induced cell death. Despite the lack of Atg5 expression and LC3 lipidation, DU145 cells form autophagosomes as demonstrated by transmission and immuno-electron microscopy, and the formation of LC3 positive foci. However, the lack of cellular content in the autophagosomes, the accumulation of long-lived proteins, the presence of GFP-RFP-LC3 positive foci and the accumulated p62 protein levels indicate that these autophagosomes may not be fully functional. DU145 cells treated with sorafenib undergo a caspase-independent cell death that is inhibited by the RIPK1 inhibitor, necrostatin-1. Furthermore, treatment with sorafenib induces the interaction of RIPK1 with p62, as demonstrated by immunoprecipitation and a proximity ligation assay. Silencing of p62 decreases the RIPK1 protein levels and renders necrostatin-1 ineffective in blocking sorafenib-induced cell death. In summary, the formation of Atg5-deficient autophagosomes in response to sorafenib promotes the interaction of p62 with RIPK leading to cell death by necroptosis.

sms: AnRPackage for the Construction of Microdata for Geographical Analysis

Changepoint analysis: a new approach for revealing animal movements and behaviors from satellite telemetry data

While telemetry is an invaluable tool for tracking animal movement patterns, the data generated by this technique is often challenging to interpret. Here, we addressed this issue by developing a novel method, based on changepoint analysis, which incorporated both the horizontal and vertical movement metrics and compared this output to that from a switching state‐space model (SSSM) that categorized behavior based on horizontal movement metrics. We deployed 20 satellite transmitters on postnesting loggerhead turtles at Rethymno, Crete, Greece between 2010 and 2011 to monitor their at‐sea behavior. We used both models to identify behavioral changes, such as the switches from migration to foraging, and from foraging to overwintering. The satellite‐tracked turtles exhibited three discrete migratory strategies, with 9 turtles migrating southwards to the coast of northern Africa, 6 turtles migrating northwards into the Aegean Sea, and 4 turtles remaining resident in the waters of Crete. The SSSM readily identified the switch from transiting to ARS behavior in most animals, but the CPA model was able to distinguish multiple modes and more subtle shifts in behavior corresponding with shifts from migration to foraging to overwintering behaviors. We have shown that by incorporating vertical movement metrics into the analysis of telemetry data, previously hidden shifts in behavior can be revealed. The resulting increase in ability to discern complex behavioral patterns of animals remotely will likely yield better management and conservation decisions for a wide array of organisms.

Periodontal Soft Tissue Root Coverage Procedures: Practical Applications From the AAP Regeneration Workshop

Focused Clinical Question: How should gingival recession (GR) defects be managed based on current evidence? Summary: The purpose of this practical application is to illustrate the management of GR defects with a primary outcome goal of complete root coverage. The consensus in dental literature and among expert clinicians is that root coverage may be attained through the application of different procedures and that outcomes are generally measured by reduced defect depth, gain in clinical attachment, and an increase in keratinized tissue (KT). These procedures may include the use of: 1) subepithelial connective tissue graft (SCTG); 2) coronally advanced flap; 3) free gingival graft; and 4) soft tissue graft substitutes (acellular dermal matrix and xenogeneic collagen matrix materials) and biologics (recombinant human platelet‐derived growth factor and enamel matrix derivative). The variability in these techniques revolves around the inclusion or avoidance of a palatal donor graft. The decision as to how to approach a specific clinical GR‐type defect should be a combination of considerations relative to the clinician's surgical goals and the patient's understanding of the anticipated outcome. The associated systematic review (Chambrone and Tatakis, J Periodontol 2015;86(Suppl.):S8‐S51) provides clear evidence that SCTG‐based procedures provide the best outcome for mean and complete root coverage, as well as an increase in KT. Patient‐reported outcomes, a topic that needs additional research, should be considered in the decision‐making process. Conclusion: Based on the available evidence and the illustrated cases included in this practical application, root coverage can be predictably achieved and a successful clinical outcome can be maintained long term.

Periodontal Soft Tissue Root Coverage Procedures: A Systematic Review From the AAP Regeneration Workshop

Background: This paper aims to create a “bridge” between research and practice by developing a practical, extensive, and clinically relevant study that translates evidence‐based findings on soft tissue root coverage (RC) of recession‐type defects to daily clinical practice. Methods: This review is prepared in accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta‐Analyses) statement based on the proposed focused questions. A literature search with no restrictions regarding status or the language of publication was performed for MEDLINE and EMBASE databases up to and including June 2013. Systematic reviews (SRs), randomized clinical trials, controlled clinical trials, case series, and case reports evaluating recession areas that were treated by means of RC procedures were considered eligible for inclusion through the three parts of the study (part I, an overview of the base of SRs; part II, an alternative random‐effects meta‐analyses on mean percentage of RC and sites exhibiting complete RC; and part III, an SR of non‐randomized trials exploring other conditions not extensively evaluated by previous SRs). Data on Class I, II, III, and IV recessions, type of histologic attachment achieved with treatment, recipient‐ and donor‐site anatomic characteristics, smoking‐related outcomes, root surface conditions, tooth type and location, long‐term effectiveness outcomes, unusual conditions that may be reported during conventional daily practice, and patient‐centered outcomes were assessed as well. Results: Of the 2,456 potentially eligible trials, 234 were included. Data on Class I, II, III, and IV gingival recessions, histologic attachment achieved after treatment, recipient‐ and donor‐site anatomic characteristics, smoking‐related outcomes, root surface conditions/biomodification, tooth type and location, long‐term effectiveness outcomes and unusual conditions that may be reported during conventional daily practice, and patient‐centered outcomes (i.e., esthetic, visual analog scale, complications, hypersensitivity, patients perceptions) were assessed. Subepithelial connective tissue (CT)‐based procedures and coronally advanced flap plus acellular dermal matrix grafts, enamel matrix derivative, or collagen matrix led to the best improvements of recession depth, clinical attachment level (CAL) gain, and keratinized tissue (KT). Some conditions, such as smoking and use of magnification, may affect RC outcomes. Conclusions: All RC procedures can provide significant reduction in recession depth and CAL gain for Miller Class I and II recession‐type defects. Subepithelial CT graft‐based procedures provided the best outcomes for clinical practice because of their superior percentages of mean and complete RC, as well as significant increase of KT.

Periodontal Soft Tissue Root Coverage Procedures: A Consensus Report From the AAP Regeneration Workshop

Background: Management of gingival recession defects, a common periodontal condition, using root coverage procedures is an important aspect of periodontal regenerative therapy. The goal of the periodontal soft tissue root coverage procedures group was to develop a consensus report based on the accompanying systematic review of root coverage procedures, including priorities for future research and identification of the best evidence available to manage different clinical scenarios. Methods: The group reviewed and discussed the accompanying systematic review, which covered treatment of single‐tooth recession defects, multiple‐tooth recession defects, and additional focused questions on relevant clinical topics. The consensus group members submitted additional material for consideration by the group in advance and at the time of the meeting. The group also identified priorities for future research. Results: All reviewed root coverage procedures provide significant reduction in recession depth, especially for Miller Class I and II recession defects. Subepithelial connective tissue graft (SCTG) procedures provide the best root coverage outcomes. Acellular dermal matrix graft (ADMG) or enamel matrix derivative (EMD) in conjunction with a coronally advanced flap (CAF) can serve as alternatives to autogenous donor tissue. Additional research is needed to do the following: 1) assess the treatment outcomes for multiple‐tooth recession defects, oral sites other than maxillary canine and premolar teeth, and Miller Class III and IV defects; 2) assess the role of patient‐ and site‐specific factors on procedure outcomes; and 3) obtain evidence on patient‐reported outcomes. Conclusions: Predictable root coverage is possible for single‐tooth and multiple‐tooth recession defects, with SCTG procedures providing the best root coverage outcomes. Alternatives to SCTG are supported by evidence of varying strength. Additional research is needed on treatment outcomes for specific oral sites. Clinical Recommendation: For Miller Class I and II single‐tooth recession defects, SCTG procedures provide the best outcomes, whereas ADMG or EMD in conjunction with CAF may be used as an alternative.

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Efficiency, Inefficiency and the MENA Frontier