An arranged marriage for precision medicine: hypoxia and genomic assays in localized prostate cancer radiotherapy

Prostate cancer (CaP) is the most commonly diagnosed malignancy in males in the Western world with one in six males diagnosed in their lifetime. Current clinical prognostication groupings use pathologic Gleason score, pre-treatment prostatic-specific antigen and Union for International Cancer Control-TNM staging to place patients with localized CaP into low-, intermediate- and high-risk categories. These categories represent an increasing risk of biochemical failure and CaP-specific mortality rates, they also reflect the need for increasing treatment intensity and justification for increased side effects. In this article, we point out that 30-50% of patients will still fail image-guided radiotherapy or surgery despite the judicious use of clinical risk categories owing to interpatient heterogeneity in treatment response. To improve treatment individualization, better predictors of prognosis and radiotherapy treatment response are needed to triage patients to bespoke and intensified CaP treatment protocols. These should include the use of pre-treatment genomic tests based on DNA or RNA indices and/or assays that reflect cancer metabolism, such as hypoxia assays, to define patient-specific CaP progression and aggression. More importantly, it is argued that these novel prognostic assays could be even more useful if combined together to drive forward precision cancer medicine for localized CaP.

Experimental evidence for the immediate impact of fertilization and irrigation upon the plant and invertebrate communities of mountain grasslands

The response of montane and subalpine hay meadow plant and arthropod communities to the application of liquid manure and aerial irrigation – two novel, rapidly spreading management practices – remains poorly understood, which hampers the formulation of best practice management recommendations for both hay production and biodiversity preservation. In these nutrient-poor mountain grasslands, a moderate management regime could enhance overall conditions for biodiversity. This study experimentally assessed, at the site scale, among low-input montane and subalpine meadows, the short-term effects (1 year) of a moderate intensification (slurry fertilization: 26.7–53.3 kg N·ha−1·year−1; irrigation with sprinklers: 20 mm·week−1; singly or combined together) on plant species richness, vegetation structure, hay production, and arthropod abundance and biomass in the inner European Alps (Valais, SW Switzerland). Results show that (1) montane and subalpine hay meadow ecological communities respond very rapidly to an intensification of management practices; (2) on a short-term basis, a moderate intensification of very low-input hay meadows has positive effects on plant species richness, vegetation structure, hay production, and arthropod abundance and biomass; (3) vegetation structure is likely to be the key factor limiting arthropod abundance and biomass. Our ongoing experiments will in the longer term identify which level of management intensity achieves an optimal balance between biodiversity and hay production.

Irrigation development in Eritrea: potentials and constraints: Proceedings of the workshop of AEAS and SLM Programme Eritrea

Development of irrigation, which is of crucial importance in Eritrea, is perceived by many as the main technique for improving the precarious food security situation in this Sahelian country in the Horn of Africa. The present publication presents the outcome of a nationwide workshop held in 2003, which brought together administrators, scientists, and members of public development agencies and NGOs. These workshop participants presented experiences, lessons learnt, and ideas about how to move forward in relation to development of irrigation in Eritrea. Specifically, the publication deals with the following broad themes, lessons learnt, and experiences in Eritrea: · spate irrigation systems and measurement of performance, as well as experience with modernisation of spate irrigation systems in Eritrea · small-scale irrigation systems and their potentials and pitfalls, including development of low-cost micro irrigation · climate and irrigation, including rainfall forecasts · socio-economic aspects of irrigation, including gender questions, institutional requirements, and irrigation and livelihoods The publication contains an extensive summary in the Tigrinya language, in order to facilitate access to the key findings by local non-English-speaking stakeholders in irrigation development.

Healing of localized gingival recessions treated with coronally advanced flap alone or combined with either a resorbable collagen matrix or subepithelial connective tissue graft: A preclinical study.

OBJECTIVES To histologically evaluate the effectiveness of a porcine derived collagen matrix (CM) and a subepithelial connective tissue graft (CTG) for coverage of localized gingival recessions. MATERIALS AND METHODS Chronic single Miller Class I-like recessions were created at the buccal at the canines and at the third and fourth premolars in the upper and lower jaws of six beagle dogs. The defects were randomly treated with (1) coronally advanced flap surgery (CAF) + CM, (2) CAF + CTG, or (3) CAF alone. At 12 weeks, histometric measurements were made, e.g., between a reference point (N) - and the gingival margin (GM) - and the outer contour of the adjacent soft tissue (gingival thickness [GT]). RESULTS The postoperative healing was uneventful in all animals. No complications such as allergic reactions, abscesses or infections were noted throughout the entire study period. All three treatments resulted in coverage of localized gingival recessions. The histological analysis failed to identify any residues of CM or CTG. The histometric measurements revealed comparable outcomes for N-GM and GT values for all three groups (CAF + CM: 1.04 ± 0.69 mm/0.68 ± 0.33 mm; CAF + CTG: 1.15 ± 1.12 mm/0.76 ± 0.37 mm; CAF: 1.43 ± 0.45 mm/0.79 ± 0.24 mm). CONCLUSIONS In the used defect model, the application of CTG or CM in conjunction with CAF did not have an advantage over the use of CAF alone. CLINICAL RELEVANCE The use of CAF alone is a valuable option for the treatment localized Miller Class I recessions.

Measuring localized viscoelasticity of the vitreous body using intraocular microprobes.

Vitrectomy is a standard ophthalmic procedure to remove the vitreous body from the eye. The biomechanics of the vitreous affects its duration (by changing the removal rate) and the mechanical forces transmitted via the vitreous on the surrounding tissues during the procedure. Biomechanical characterization of the vitreous is essential for optimizing the design and control of instruments that operate within the vitreous for improved precision, safety, and efficacy. The measurements are carried out using a magnetic microprobe inserted into the vitreous, a method known as magnetic microrheology. The location of the probe is tracked by a microscope/camera while magnetic forces are exerted wirelessly by applied magnetic fields. In this work, in vitro artificial vitreous, ex vivo human vitreous and ex vivo porcine vitreous were characterized. In addition, in vivo rabbit measurements were performed using a suturelessly injected probe. Measurements indicate that viscoelasticity parameters of the ex vivo human vitreous are an order of magnitude different from those of the ex vivo porcine vitreous. The in vivo intra-operative measurements show typical viscoelastic behavior of the vitreous with a lower compliance than the ex vivo measurements. The results of the magnetic microrheology measurements were validated with those obtained by a standard atomic force microscopy (AFM) method and in vitro artificial vitreous. This method allows minimally-invasive characterization of localized mechanical properties of the vitreous in vitro, ex vivo, and in vivo. A better understanding of the characteristics of the vitreous can lead to improvements in treatments concerning vitreal manipulation such as vitrectomy.

The Chloroplast-Localized Phospholipases D a4 and a5 Regulate Herbivore-Induced Direct and Indirect Defenses in Rice

The oxylipin pathway is of central importance for plant defensive responses. Yet, the first step of the pathway, the liberation of linolenic acid following induction, is poorly understood. Phospholipases D (PLDs) have been hypothesized to mediate this process, but data from Arabidopsis (Arabidopsis thaliana) regarding the role of PLDs in plant resistance have remained controversial. Here, we cloned two chloroplast-localized PLD genes from rice (Oryza sativa), OsPLDα4 and OsPLDα5, both of which were up-regulated in response to feeding by the rice striped stem borer (SSB) Chilo suppressalis, mechanical wounding, and treatment with jasmonic acid (JA). Antisense expression of OsPLDα4 and -α5 (as-pld), which resulted in a 50% reduction of the expression of the two genes, reduced elicited levels of linolenic acid, JA, green leaf volatiles, and ethylene and attenuated the SSB-induced expression of a mitogen-activated protein kinase (OsMPK3), a lipoxygenase (OsHI-LOX), a hydroperoxide lyase (OsHPL3), as well as a 1-aminocyclopropane-1-carboxylic acid synthase (OsACS2). The impaired oxylipin and ethylene signaling in as-pld plants decreased the levels of herbivore-induced trypsin protease inhibitors and volatiles, improved the performance of SSB and the rice brown planthopper Nilaparvata lugens, and reduced the attractiveness of plants to a larval parasitoid of SSB, Apanteles chilonis. The production of trypsin protease inhibitors in as-pld plants could be partially restored by JA, while the resistance to rice brown planthopper and SSB was restored by green leaf volatile application. Our results show that phospholipases function as important components of herbivore-induced direct and indirect defenses in rice.

Consensus and differences in primary radiotherapy for localized and locally advanced prostate cancer in Switzerland: A survey on patterns of practice

INTRODUCTION External beam radiotherapy (EBRT), with or without androgen deprivation therapy (ADT), is an established treatment option for nonmetastatic prostate cancer. Despite high-level evidence from several randomized trials, risk group stratification and treatment recommendations vary due to contradictory or inconclusive data, particularly with regard to EBRT dose prescription and ADT duration. Our aim was to investigate current patterns of practice in primary EBRT for prostate cancer in Switzerland. MATERIALS AND METHODS Treatment recommendations on EBRT and ADT for localized and locally advanced prostate cancer were collected from 23 Swiss radiation oncology centers. Written recommendations were converted into center-specific decision trees, and analyzed for consensus and differences using a dedicated software tool. Additionally, specific radiotherapy planning and delivery techniques from the participating centers were assessed. RESULTS The most commonly prescribed radiation dose was 78 Gy (range 70-80 Gy) across all risk groups. ADT was recommended for intermediate-risk patients for 6 months in over 80 % of the centers, and for high-risk patients for 2 or 3 years in over 90 % of centers. For recommendations on combined EBRT and ADT treatment, consensus levels did not exceed 39 % in any clinical scenario. Arc-based intensity-modulated radiotherapy (IMRT) is implemented for routine prostate cancer radiotherapy by 96 % of the centers. CONCLUSION Among Swiss radiation oncology centers, considerable ranges of radiotherapy dose and ADT duration are routinely offered for localized and locally advanced prostate cancer. In the vast majority of cases, doses and durations are within the range of those described in current evidence-based guidelines.

Spatial genomic heterogeneity within localized, multifocal prostate cancer

Herein we provide a detailed molecular analysis of the spatial heterogeneity of clinically localized, multifocal prostate cancer to delineate new oncogenes or tumor suppressors. We initially determined the copy number aberration (CNA) profiles of 74 patients with index tumors of Gleason score 7. Of these, 5 patients were subjected to whole-genome sequencing using DNA quantities achievable in diagnostic biopsies, with detailed spatial sampling of 23 distinct tumor regions to assess intraprostatic heterogeneity in focal genomics. Multifocal tumors are highly heterogeneous for single-nucleotide variants (SNVs), CNAs and genomic rearrangements. We identified and validated a new recurrent amplification of MYCL, which is associated with TP53 deletion and unique profiles of DNA damage and transcriptional dysregulation. Moreover, we demonstrate divergent tumor evolution in multifocal cancer and, in some cases, tumors of independent clonal origin. These data represent the first systematic relation of intraprostatic genomic heterogeneity to predicted clinical outcome and inform the development of novel biomarkers that reflect individual prognosis.

Incorporation of tissue-based genomic biomarkers into localized prostate cancer clinics.

Localized prostate cancer (PCa) is a clinically heterogeneous disease, which presents with variability in patient outcomes within the same risk stratification (low, intermediate or high) and even within the same Gleason scores. Genomic tools have been developed with the purpose of stratifying patients affected by this disease to help physicians personalize therapies and follow-up schemes. This review focuses on these tissue-based tools. At present, four genomic tools are commercially available: Decipher™, Oncotype DX®, Prolaris® and ProMark®. Decipher™ is a tool based on 22 genes and evaluates the risk of adverse outcomes (metastasis) after radical prostatectomy (RP). Oncotype DX® is based on 17 genes and focuses on the ability to predict outcomes (adverse pathology) in very low-low and low-intermediate PCa patients, while Prolaris® is built on a panel of 46 genes and is validated to evaluate outcomes for patients at low risk as well as patients who are affected by high risk PCa and post-RP. Finally, ProMark® is based on a multiplexed proteomics assay and predicts PCa aggressiveness in patients found with similar features to Oncotype DX®. These biomarkers can be helpful for post-biopsy decision-making in low risk patients and post-radical prostatectomy in selected risk groups. Further studies are needed to investigate the clinical benefit of these new technologies, the financial ramifications and how they should be utilized in clinics.