Anticancer activity of the protein kinase C modulator HMI-1a3 in 2D and 3D cell culture models of androgen-responsive and androgen-unresponsive prostate cancer

Prostate cancer is one of the most common cancers in men. Although it has a relatively high 5-year survival rate, development of resistance to standard androgen-deprivation therapy is a significant clinical problem. Therefore, novel therapeutic strategies are urgently needed. The protein kinase C (PKC) family is a putative prostate cancer drug target, but so far no PKC-targeting drugs are available for clinical use. By contrast to the standard approach of developing PKC inhibitors, we have developed isophthalate derivatives as PKC agonists. In this study, we have characterized the effects of the most potent isophthalate, 5-(hydroxymethyl) isophthalate 1a3 (HMI-1a3), on three prostate cancer cell lines (LNCaP, DU145, and PC3) using both 2D and 3D cell culture models. In 2D cell culture, HMI-1a3 reduced cell viability or proliferation in all cell lines as determined by the metabolic activity of the cells (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide assay) and thymidine incorporation. However, the mechanism of action in LNCaP cells was different to that in DU145 or PC3 cells. In LNCaP cells, HMI-1a3 induced a PKC-dependent activation of caspase 3/7, indicating an apoptotic response, whereas in DU145 and PC3 cells, it induced senescence, which was independent of PKC. This was observed as typical senescent morphology, increased beta-galactosidase activity, and upregulation of the senescence marker p21 and downregulation of E2F transcription factor 1. Using a multicellular spheroid model, we further showed that HMI-1a3 affects the growth of LNCaP and DU145 cells in a 3D culture, emphasizing its potential as a lead compound for cancer drug development.Peer reviewe

1.5 °C carbon budget dependent on carbon cycle uncertainty and future non-CO2 forcing

Estimates of the 1.5 °C carbon budget vary widely among recent studies, emphasizing the need to better understand and quantify key sources of uncertainty. Here we quantify the impact of carbon cycle uncertainty and non-CO2 forcing on the 1.5 °C carbon budget in the context of a prescribed 1.5 °C temperature stabilization scenario. We use Bayes theorem to weight members of a perturbed parameter ensemble with varying land and ocean carbon uptake, to derive an estimate for the fossil fuel (FF) carbon budget of 469 PgC since 1850, with a 95% likelihood range of (411,528) PgC. CO2 emissions from land-use change (LUC) add about 230 PgC. Our best estimate of the total (FF + LUC) carbon budget for 1.5 °C is therefore 699 PgC, which corresponds to about 11 years of current emissions. Non-CO2 greenhouse gas and aerosol emissions represent equivalent cumulative CO2 emissions of about 510 PgC and −180 PgC for 1.5 °C, respectively. The increased LUC, high non-CO2 emissions and decreased aerosols in our scenario, cause the long-term FF carbon budget to decrease following temperature stabilization. In this scenario, negative emissions would be required to compensate not only for the increasing non-CO2 climate forcing, but also for the declining natural carbon sinks

Effect of major trauma on the expected number of births in Finnish women : A nationwide population-based public data and register analysis

Background: The effect of major trauma on subsequent fertility is poorly described. If women have lower fertility after trauma, they would have a lower risk of anti-D mediated hemolytic disease of the fetus and newborn in a future pregnancy following the transfusion of RhD-positive blood to RhD-negative women during their resuscitation. Study Design and Methods: Data was obtained from the Care Register for Health Care, National Medical Birth Register, and open access data from Statistic Finland to evaluate the effect of major trauma (traumatic brain injuries, spine, pelvic, hip/thigh fractures) on the age-specific number of births during years 1998–2018. The total number of births before a specific maternal age for different trauma populations was calculated and these were compared to the corresponding number of births in the general population. Results: There were 50,923 injured women in this study. All injured women, including when analyzed by the nature of their injury, demonstrated lower expected numbers of births starting at approximately 28 years of age compared to the general population of women in Finland. At age 49, the expected number of births in the general population was approximately 1.8, whereas for all injured women 0.6, women with TBIs and spine fractures 0.6, women with pelvic fractures 0.5, and women with hip or thigh fractures 0.3. Discussion: Injured women are predicted to have lower fertility rates compared to the general population of Finnish women. The lower fertility rate should be considered when planning a blood product resuscitation strategy for injured women.Peer reviewe

Identification of 17 novel mutations in 40 Argentinean unrelated families with mucopolysaccharidosis type II (Hunter syndrome)

Mucopolysaccharidosis type II (MPSII) is an X-linked lysosomal storage disorder caused by deficiency of the enzyme iduronate-2-sulfatase (IDS). The human IDS gene is located in chromosome Xq28. This is the first report of genotype and phenotype characterization of 49 Hunter patients from40 families of Argentina. Thirty different alleles have been identified, and 57%were novel. The frequency of de novomutationswas 10%. Overall, the percentage of private mutations in our series was 75%.Facultad de Ciencias Exacta

Fabrication of Phononic-Isolated Kinetic Inductance Detectors

Kinetic inductance detectors (KID) have received increased interest due to their relative ease of fabrication, low noise, and scalability to large format arrays required by next generation of astronomical telescopes. The development of KIDs has progressed rapidly, with very low noise equivalent power demonstrated by several groups and KIDs arrays implemented in several ground-based and air-borne instruments. In this paper, we describe a new fabrication process which consists of a membrane isolated KID incorporating a phononic bandgap structure tuned to block recombination phonons from escaping to the thermal bath. This architecture is designed to increase the quasi-particle lifetime and results in increased responsivity to signal photons and lower noise. These devices have been fabricated as lumped-element resonators with hafnium inductors and Nb capacitors on low stress silicon nitride and silicon-on-insulator membranes. We discuss the fabrication process, which uses a combination of sub-micron laser based direct write lithography and nanoscale electron beam lithography

Impacts of sea spray geoengineering on ocean biogeochemistry

We used an earth system model of intermediate complexity to study the effects of Solar Radiation Management (SRM) by sea spray geoengineering on ocean biogeochemistry. SRM slightly decreased global ocean net primary productivity (NPP) relative to the control run. The lower temperatures in the SRM run decreased NPP directly but also indirectly increased NPP in some regions due to changes in nutrient availability resulting from changes in ocean stratification and circulation. Reduced light availability had a minor effect on global total NPP but a major regional effect near the nutrient rich upwelling region off the coast of Peru, where light availability is the main limiting factor for phytoplankton growth in our model. Unused nutrients from regions with decreased NPP also fueled NPP elsewhere. In the context of RCP4.5 simulation used here, SRM decreased ocean carbon uptake due to changes in atmospheric CO2 concentrations, seawater chemistry, NPP, temperature, and ocean circulation

WtF-Nano : One-Pot Dewatering and Water-Free Topochemical Modification of Nanocellulose in Ionic Liquids or gamma-Valerolactone

Ionic liquids are used to dewater a suspension of birch Kraft pulp cellulose nanofibrils (CNF) and as a medium for water-free topochemical modification of the nanocellulose (a process denoted as "WtF-Nano"). Acetylation was applied as a model reaction to investigate the degree of modification and scope of effective ionic liquid structures. Little difference in reactivity was observed when water was removed, after introduction of an ionic liquid or molecular co-solvent. However, the viscoelastic properties of the CNF suspended in two ionic liquids show that the more basic, but non-dissolving ionic liquid, allows for better solvation of the CNF. Vibrio fischeri bacterial tests show that all ionic liquids in this study were harmless. Scanning electron microscopy and wide-angle X-ray scattering on regenerated samples show that the acetylated CNF is still in a fibrillar form. 1D and 2D NMR analyses, after direct dissolution in a novel ionic liquid electrolyte solution, indicate that both cellulose and residual xylan on the surface of the nanofibrils reacts to give acetate esters.Peer reviewe

Toisiolaki - lääketieteellisen tutkimuksen mahdollistaja vai tukahduttaja?

Vertaisarvioitu.Lähtökohdat : Suomessa tuli 1.5.2019 voimaan niin sanottu toisiolaki eli Laki sosiaali- ja terveys¬tietojen toissijaisesta käytöstä. Kyselytutkimuksemme tarkoitus oli selvittää kliinikkotutkijoiden kokemuksia toisiolain vaikutuksista ja käytännön toteutuksesta. Menetelmät : Suomalaisia kliinikkotutkijoita pyydettiin arvioimaan Webropol-alustalla toisiolain aiheuttamia aikataulumuutoksia, talousvaikutuksia, tutkimusyhteistyössä tapahtuneita muutoksia, mahdollisia esteitä ja hyötyjä lain voimaantuloon liittyen sekä muita lain aiheuttamia positiivisia ja negatiivisia vaikutuksia. Tulokset : Vastaajista (n = 430) 64,4 % raportoi, että tutkimustoiminnan kustannukset ovat nousseet toisiolain mukana. Vastaajista 38,4–45,6 % oli jättänyt tutkimusprojekteja käynnistämättä joko lupahakemuksen hinnan tai etäkäyttöympäristön kustannusten sekä sen käyttövaatimuksen vuoksi. Päätelmät :Tutkimuksemme perusteella on syytä epäillä, että toisiolain soveltaminen vaikuttaa heikentävästi julkaisujen määrään ja laatuun ja heikentää Suomen kilpailukykyä etenkin tutkija¬lähtöisessä tutkimuksessa. Toisiolain seuraukset kohdistuvat erityisesti suomalaisiin potilaisiin, heidän hoitonsa laatuun sekä hoidon tasavertaisuuteen.Peer reviewe

Toisiolaki - lääketieteellisen tutkimuksen mahdollistaja vai tukahduttaja?

Lähtökohdat : Suomessa tuli 1.5.2019 voimaan niin sanottu toisiolaki eli Laki sosiaali- ja terveys­tietojen toissijaisesta käytöstä. Kyselytutkimuksemme tarkoitus oli selvittää kliinikkotutkijoiden kokemuksia toisiolain vaikutuksista ja käytännön toteutuksesta. Menetelmät : Suomalaisia kliinikkotutkijoita pyydettiin arvioimaan Webropol-alustalla toisiolain aiheuttamia aikataulumuutoksia, talousvaikutuksia, tutkimusyhteistyössä tapahtuneita muutoksia, mahdollisia esteitä ja hyötyjä lain voimaantuloon liittyen sekä muita lain aiheuttamia positiivisia ja negatiivisia vaikutuksia. Tulokset : Vastaajista (n = 430) 64,4 % raportoi, että tutkimustoiminnan kustannukset ovat nousseet toisiolain mukana. Vastaajista 38,4–45,6 % oli jättänyt tutkimusprojekteja käynnistämättä joko lupahakemuksen hinnan tai etäkäyttöympäristön kustannusten sekä sen käyttövaatimuksen vuoksi. Päätelmät :Tutkimuksemme perusteella on syytä epäillä, että toisiolain soveltaminen vaikuttaa heikentävästi julkaisujen määrään ja laatuun ja heikentää Suomen kilpailukykyä etenkin tutkija­lähtöisessä tutkimuksessa. Toisiolain seuraukset kohdistuvat erityisesti suomalaisiin potilaisiin, heidän hoitonsa laatuun sekä hoidon tasavertaisuuteen.publishedVersionPeer reviewe

Glial cell line-derived neurotrophic factor receptor REarranged during transfection agonist supports dopamine neurons in Vitro and enhances dopamine release In Vivo

Background Motor symptoms of Parkinson's disease (PD) are caused by degeneration and progressive loss of nigrostriatal dopamine neurons. Currently, no cure for this disease is available. Existing drugs alleviate PD symptoms but fail to halt neurodegeneration. Glial cell line-derived neurotrophic factor (GDNF) is able to protect and repair dopamine neurons in vitro and in animal models of PD, but the clinical use of GDNF is complicated by its pharmacokinetic properties. The present study aimed to evaluate the neuronal effects of a blood-brain-barrier penetrating small molecule GDNF receptor Rearranged in Transfection agonist, BT13, in the dopamine system. Methods We characterized the ability of BT13 to activate RET in immortalized cells, to support the survival of cultured dopamine neurons, to protect cultured dopamine neurons against neurotoxin-induced cell death, to activate intracellular signaling pathways both in vitro and in vivo, and to regulate dopamine release in the mouse striatum as well as BT13's distribution in the brain. Results BT13 potently activates RET and downstream signaling cascades such as Extracellular Signal Regulated Kinase and AKT in immortalized cells. It supports the survival of cultured dopamine neurons from wild-type but not from RET-knockout mice. BT13 protects cultured dopamine neurons from 6-Hydroxydopamine (6-OHDA) and 1-methyl-4-phenylpyridinium (MPP+)-induced cell death only if they express RET. In addition, BT13 is absorbed in the brain, activates intracellular signaling cascades in dopamine neurons both in vitro and in vivo, and also stimulates the release of dopamine in the mouse striatum. Conclusion The GDNF receptor RET agonist BT13 demonstrates the potential for further development of novel disease-modifying treatments against PD. (c) 2019 International Parkinson and Movement Disorder SocietyPeer reviewe