Natural products in modern life science

With a realistic threat against biodiversity in rain forests and in the sea, a sustainable use of natural products is becoming more and more important. Basic research directed against different organisms in Nature could reveal unexpected insights into fundamental biological mechanisms but also new pharmaceutical or biotechnological possibilities of more immediate use. Many different strategies have been used prospecting the biodiversity of Earth in the search for novel structure–activity relationships, which has resulted in important discoveries in drug development. However, we believe that the development of multidisciplinary incentives will be necessary for a future successful exploration of Nature. With this aim, one way would be a modernization and renewal of a venerable proven interdisciplinary science, Pharmacognosy, which represents an integrated way of studying biological systems. This has been demonstrated based on an explanatory model where the different parts of the model are explained by our ongoing research. Anti-inflammatory natural products have been discovered based on ethnopharmacological observations, marine sponges in cold water have resulted in substances with ecological impact, combinatory strategy of ecology and chemistry has revealed new insights into the biodiversity of fungi, in depth studies of cyclic peptides (cyclotides) has created new possibilities for engineering of bioactive peptides, development of new strategies using phylogeny and chemography has resulted in new possibilities for navigating chemical and biological space, and using bioinformatic tools for understanding of lateral gene transfer could provide potential drug targets. A multidisciplinary subject like Pharmacognosy, one of several scientific disciplines bridging biology and chemistry with medicine, has a strategic position for studies of complex scientific questions based on observations in Nature. Furthermore, natural product research based on intriguing scientific questions in Nature can be of value to increase the attraction for young students in modern life science

Resolving temporal links between the Högberget granite and the Wigström tungsten skarn deposit in Bergslagen (Sweden) using trace elements and U-Pb LA-ICPMS on complex zircons

Combined U-Pb and REE trace element LA-ICPMS analyses were performed on zircons, from the scheelite-bearing Wigström skarn, associated micro-granitic dykes and the highly evolved parental Högberget (sensu stricto) granite. Combined systematic of zircon typology and microtextures, trace elements and isotopic chemistry suggest the presence of several diverse zircon types, spanning from early- to late- magmatic stage into a hydrothermal stage. Early stage magmatic zircons (type M1 and M2-S) have high concentrations of U (3300–11500 ppm), Th (1500–7300 ppm), REEs (average ΣREEn: 11500) and Pb-C signatures and yield highly discordant data. Typological features are varying, but the majority consists of prismatic crystals with oscillatory zonations. In comparison, late stage magmatic zircons (type M2) have lower concentrations of U (200–3000 ppm), Th (100–1900 ppm), REEs (average ΣREEn: 7600) and Pb-C signatures (e.g. average 204Pb CPS: 300). Typological features include irregular, quasi-smooth forms which lack internal zonations. Geochronological analyses yield concordant data, after interpretation an 207Pb/206Pb weighted mean age of ~1.8 Ga is achieved. Hydrothermal zircon (skarn hosted, type H) associates with hydrothermal quartz, calcite, fluorite and scheelite within the skarn. Type H zircons shares similarities with type M2, yielding low concentrations of U (100–6200 ppm), Th (1–1500 ppm), and Pb-C signatures (e.g. average 204Pb CPS: 300), but slightly higher concentrations of REEs (average ΣREEn: 17800). Typological features display various forms, i.e. skeletal, irregular, oblong, and typically lacks prisms. Internal textures vary from zoned to homogenous, and spongy textures are common. Geochronological data are scattered, but display a concordant cluster around 1.8 Ga, calculated as 207Pb/206Pb weighted mean age of 1795±20 Ma (2.0 MSWD). The achieved ages further fortify a ~1.8 Ga for the tungsten metallogenesis in Bergslagen. Magmatic (early- and late types) and hydrothermal zircon can be distinguished via trace elemental discrimination diagram and in CI-chondrite normalized spidergrams. For discrimination diagram, Th versus Th/U, U versus Th, and ΣREEn versus Th diagrams clearly displays evolutionary transitional trend between the different zircon types. In spidergrams, Magmatic zircons have typical patterns for magmatic zircons (but shows LREE enrichments), whereas hydrothermal zircons display a convex pattern, which clearly distinguish the zircon populations apart.I Bergslagen, Sverige, finns Skandinaviens största tungstenstillgångar, och här har man i årtionden brutit denna värdefulla metall. Brytningen fick dock ett abrupt slut runt 80-talet, men i dagsläget finns planer från prospekterare att återuppta industrin. Bildningsmodellerna för tungstensmineraliseringarna har sedan länge varit omdebatterad, men brett accepterat är att värme från närliggande graniter genererade under sin bildning ett hydrotermalt system där metalliska element kunde utlösa, vilket vidare påverkade kringliggande bergarter och slutligen ansamlades malmen i en hydrotermal omvandlad bergart kallat skarn. I detta arbete har zirkoner används för att tidsmässigt knyta samman en tungstensmineralisering till en närliggande granit. Efter tolkning utav zirkon analyser kan en ålder runt 1.8 miljarder år för graniten och mineraliseringen härledas. Med de båda likvärdiga åldrarna stärks den nuvarande accepterade granitiska modellen för tungstensbildning i Bergslagen. För prospekterare medför detta att man bör fokusera och bedriva tungstensprospektering kring liknande graniter då dessa verkar ha en direkt koppling till höga malmkoncentrationer utav tungsten

Markradar- och resistivitetsmätningar : undersökningar utav korrosionsförhöjande markegenskaper kring fjärrvärmeledningar i Ängelholm

District heating pipes at two localities in Ängelholm have been investigated with two geophysical methods; ground penetrating radar (GPR) and resistivity measurements (ERT, Electrical Resistivity Tomography). District heating pipes are constantly exposed to the influence of external- and internal forces. As a result the pipes degrade over time, and leakage can eventually occur. Management owners have expressed a wish that techniques should be developed for easier management of the grid (DH- and sewerage pipes). A three-year Vinnova project was therefore launched in late 2015, with the aim to implement and evaluate five different methods. In this study one of these methods is evaluated, which is to correlate the two geophysical survey methods; ground penetrating radar and resistivity measurements. The rationale of this study has been to mainly examine soil conditions in areas around the pipes and to detect soil transitions zones since these constitute potential differences in the ground, which can lead to corrosion. These conditions may pose an increased risk of damage to the pipes. Ground penetrating radar is a method which provides information whether or not objects in the ground can act as a reflector. If the electromagnetic pulse is suppressed, the area can for example contain clay rich soils. Correlated with resistivity measurements these areas should obtain lower resistivity, since clay rich soils exhibit low resistance. The results of the geophysical surveys have been correlated. From the interpretation, it is clear that the soil transitions are housed in the two premises, where a soil transition in each locality could be detected. The conclusion is that this method has good potential to detect soil transitions in relative large scale. Excavations of the premises will be made at a later stage in the Vinnova project, which will provide a kind of "hindsight" of the pipes condition.Fjärrvärmeledningar vid två lokaler i Ängelholm har undersökts med två geofysiska metoder, markradar och resistivitetsundersökningar. Fjärrvärmeledningar är ständigt utsatta för påverkan av yttre faktor som t.ex. skjuvspänningar, och inre faktorer t.ex. termal expansion. Som följd av dessa faktorer förslits ledningar i varierad takt och läckage kan slutligen uppstå. Ledningsägare önskar att tekniker utvecklas för att enklare förvalta ledningsnätet (FV- och VA-ledningar). Ett tre-årigt Vinnovaprojekt startades i slutet av 2015 vars mål är att bl.a. validera och utvärdera fem olika metoder. I detta examensarbete utvärderas en av dessa metoder, vilket går ut på att korrelera två geofysiska undersökningsmetoder, markradar (GPR, Ground Penetrating Radar) och resistivitetsundersökningar (ERT, Electrical Resistivity Tomography). Det som har undersöks i denna studie är främst markförhållander kring ledningsrör, förhållanden som kan utgöra förhöjd skaderisk för ledningarna. Här söks främst områden där jordartsövergångar påvisas. Dessa kan utgör potentialskillnader i marken vilket kan leda initiera korrosionsprocesser. Markradar är en metod vilket ger utslag om objekt i marken innehar en god eller dålig reflektoryta. Om den elektromagnetiska pulsen dämpas, utgörs området sannolikt utav lerrika jordar. Korrelerat med resistivitetsundersökningar borde dessa zoner erhålla låg resistivitet då lerrika jordar är lågresistiva. Resultaten från de geofysiska undersökningarna har korrelerats. Utav tolkningen framgår det att jordartsövergångar inryms vid båda lokalerna, där man kunde påvisa en jordartsövergång vid vardera lokal. Detta ger en indikation att metoden fungerar för att lokalisera jordartsövergångar i relativ stor skala. Utgrävningar av lokalerna kommer att göras under ett senare skede i projektet, varvid man då erhåller ett slags ”facit” över ledningarnas tillstånd

Bounded integer model‐based analysis of psoriasis area and severity index in patients with moderate‐to‐severe plaque psoriasis receiving BI 730357

Abstract BI 730357 is investigated as an oral treatment of plaque psoriasis. We analyzed the impact of three dosage regimens on the Psoriasis Area and Severity Index (PASI) response with modeling based on phase I and II data from 109 healthy subjects and 274 patients with moderate‐to‐severe plaque psoriasis. The pharmacokinetics (PK) was characterized by a two‐compartment model with dual absorption paths and a first‐order elimination. Higher baseline C‐reactive protein was associated with lower clearance and patients generally had lower clearance compared with healthy subjects. A bounded integer PK/pharmacodynamic model characterized the effect on the observed PASI. The maximum drug effect was largest for patients with no prior biologic use, smaller for patients with prior use of non‐interleukin‐17 inhibitors, and smallest for patients with prior interleukin‐17 inhibitor use. The models allowed robust simulation of large patient populations, predicting a plateau in PASI outcomes for BI 730357 exposure above 2000 nmol/L

Exceptional preservation of reidite in the Rochechouart impact structure, France: New insights into shock deformation and phase transition of zircon

Reidite, the high-pressure zircon (ZrSiO4) polymorph, is a diagnostic indicator of impact events. Natural records of reidite are, however, scarce, occurring mainly as micrometer-sized lamellae, granules, and dendrites. Here, we present a unique sequence of shocked zircon grains found within a clast from the Chassenon suevitic breccia (shock stageIII) from the ~200 Ma, 20–50 km wide Rochechouart impact structure in France. Our study comprises detailed characterization with scanning electron microscopy coupled with electron backscatter diffraction with the goal of investigating the stability and response of ZrSiO4 under extreme P–T conditions. The shocked zircon grains have preserved various amounts of reidite ranging from 4% up to complete conversion. The grains contain various variants of reidite, including the common habits: lamellae and granular reidite. In addition, three novel variants have been identified: blade, wedge, and massive domains. Several of these crosscut and offset each other, revealing that reidite can form at multiple stages during an impact event. Our data provide evidence that reidite can be preserved in impactites to a much greater extent than previously documented. We have further characterized reversion products of reidite in the form of fully recrystallized granular zircon grains and minute domains of granular zircon in reidite-bearing grains that occur in close relationship to reidite. Neoblasts in these grains have a distinct crystallography that is the result of systematic inheritance of reidite. We interpret that the fully granular grains have formed from prolonged exposure of temperatures in excess of 1200 °C. Reidite-bearing grains with granular domains might signify swift quenching from temperatures close to 1200 °C. Grains subjected to these specific conditions therefore underwent partial zircon-to-reidite reversion, instead of full grain recrystallization. Based on our ZrSiO4 microstructural constraints, we decipher the grains evolution at specific P–T conditions related to different impact stages, offering further understanding of the behavior of ZrSiO4 during shock

Personalised biopsy schedules based on risk of Gleason upgrading for patients with low-risk prostate cancer on active surveillance.

ObjectiveTo develop a model and methodology for predicting the risk of Gleason upgrading in patients with prostate cancer on active surveillance (AS) and using the predicted risks to create risk-based personalised biopsy schedules as an alternative to one-size-fits-all schedules (e.g. annually). Furthermore, to assist patients and doctors in making shared decisions on biopsy schedules, by providing them quantitative estimates of the burden and benefit of opting for personalised vs any other schedule in AS. Lastly, to externally validate our model and implement it along with personalised schedules in a ready to use web-application.Patients and methodsRepeat prostate-specific antigen (PSA) measurements, timing and results of previous biopsies, and age at baseline from the world's largest AS study, Prostate Cancer Research International Active Surveillance (PRIAS; 7813 patients, 1134 experienced upgrading). We fitted a Bayesian joint model for time-to-event and longitudinal data to this dataset. We then validated our model externally in the largest six AS cohorts of the Movember Foundation's third Global Action Plan (GAP3) database (>20 000 patients, 27 centres worldwide). Using the model predicted upgrading risks; we scheduled biopsies whenever a patient's upgrading risk was above a certain threshold. To assist patients/doctors in the choice of this threshold, and to compare the resulting personalised schedule with currently practiced schedules, along with the timing and the total number of biopsies (burden) planned, for each schedule we provided them with the time delay expected in detecting upgrading (shorter is better).ResultsThe cause-specific cumulative upgrading risk at the 5-year follow-up was 35% in PRIAS, and at most 50% in the GAP3 cohorts. In the PRIAS-based model, PSA velocity was a stronger predictor of upgrading (hazard ratio [HR] 2.47, 95% confidence interval [CI] 1.93-2.99) than the PSA level (HR 0.99, 95% CI 0.89-1.11). Our model had a moderate area under the receiver operating characteristic curve (0.6-0.7) in the validation cohorts. The prediction error was moderate (0.1-0.2) in theGAP3 cohorts where the impact of the PSA level and velocity on upgrading risk was similar to PRIAS, but large (0.2-0.3) otherwise. Our model required re-calibration of baseline upgrading risk in the validation cohorts. We implemented the validated models and the methodology for personalised schedules in a web-application (http://tiny.cc/biopsy).ConclusionsWe successfully developed and validated a model for predicting upgrading risk, and providing risk-based personalised biopsy decisions in AS of prostate cancer. Personalised prostate biopsies are a novel alternative to fixed one-size-fits-all schedules, which may help to reduce unnecessary prostate biopsies, while maintaining cancer control. The model and schedules made available via a web-application enable shared decision-making on biopsy schedules by comparing fixed and personalised schedules on total biopsies and expected time delay in detecting upgrading

Comparison of outcomes of different biopsy schedules among men on active surveillance for prostate cancer: An analysis of the G.A.P.3 global consortium database.

BackgroundThe optimal interval for repeat biopsy during active surveillance (AS) for prostate cancer is yet to be defined. This study examined whether risk of upgrading (to grade group ≥ 2) or risk of converting to treatment varied according to intensity of repeat biopsy using data from the GAP3 consortium's global AS database.Materials and methodsIntensity of surveillance biopsy schedules was categorized according to centers' protocols: (a) Prostate Cancer Research International Active Surveillance project (PRIAS) protocols with biopsies at years 1, 4, and 7 (10 centers; 7532 men); (b) biennial biopsies, that is, every other year (8 centers; 4365 men); and (c) annual biopsy schedules (4 centers; 1602 men). Multivariable Cox regression was used to compare outcomes according to biopsy intensity.ResultsOut of the 13,508 eligible participants, 56% were managed according to PRIAS protocols (biopsies at years 1, 4, and 7), 32% via biennial biopsy, and 12% via annual biopsy. After adjusting for baseline characteristics, risk of converting to treatment was greater for those on annual compared with PRIAS biopsy schedules (hazard ratio [HR] = 1.66; 95% confidence interval [CI] = 1.51-1.83; p < 0.001), while risk of upgrading did not differ (HR = 0.96; 95% CI = 0.84-1.10).ConclusionResults suggest more frequent biopsy schedules may deter some men from continuing AS despite no evidence of grade progression

Active Surveillance for Men Younger than 60 Years or with Intermediate-risk Localized Prostate Cancer. Descriptive Analyses of Clinical Practice in the Movember GAP3 Initiative.

BackgroundActive surveillance (AS) is a management option for men diagnosed with low-risk prostate cancer. Opinions differ on whether it is safe to include young men (≤60 yr) or men with intermediate-risk disease.ObjectiveTo assess whether reasons for discontinuation, treatment choice after AS, and adverse pathology at radical prostatectomy (RP; N1, or ≥GG3, or ≥pT3) differ for men ≤60 yr or those with European Association of Urology (EAU) intermediate-risk disease from those for men >60 yr or those with EAU low-risk disease.Design setting and participantsWe analyzed data from 5411 men ≤60 yr and 14 959 men >60 yr, 14 064 men with low-risk cancer, and 2441 men with intermediate-risk cancer, originating from the GAP3 database (21 169 patients/27 cohorts worldwide).Outcome measurements and statistical analysisCumulative incidence curves were used to estimate the rates of AS discontinuation and treatment choice.Results and limitationsThe probability of discontinuation of AS due to disease progression at 5 yr was similar for men aged ≤60 yr (22%) and those >60 yr (25%), as well as those of any age with low-risk disease (24%) versus those with intermediate-risk disease (24%). Men with intermediate-risk disease are more prone to discontinue AS without evidence of progression than men with low-risk disease (at 1/5 yr: 5.9%/14.2% vs 2.0%/8.8%). Adverse pathology at RP was observed in 32% of men ≤60 yr compared with 36% of men >60 yr (p = 0.029), and in 34% with low-risk disease compared with 40% with intermediate-risk disease (p = 0.048).ConclusionsOur descriptive analysis of AS practices worldwide showed that the risk of progression during AS is similar across the age and risk groups studied. The proportion of adverse pathology was higher among men >60 yr than among men ≤60 yr. These results suggest that men ≤60 yr and those with EAU intermediate-risk disease should not be excluded from opting for AS as initial management.Patient summaryData from 27 international centers reflecting daily clinical practice suggest that younger men or men with intermediate-risk prostate cancer do not hold greater risk for disease progression during active surveillance