Role of Ubiquitin and SUMO in Intracellular Trafficking

Precise location of proteins at a given time within a cell is essential to convey specific signals and result in a relevant functional outcome. Small ubiquitin-like modifications, such as ubiquitin and SUMO, represent a delicate and diverse way to transiently regulate intracellular trafficking events of existing proteins in cells. Trafficking of multiple proteins is controlled reversibly by ubiquitin and/or SUMO directly or indirectly via regulation of transport machinery components. Regulation is dynamic and multilayered, involving active crosstalk and interdependence between post-translational modifications. However, in most cases regulation appears very complex, and the mechanistic details regarding how ubiquitin and SUMO control protein location in cells are not yet fully understood. Moreover, most of the findings still lack in vivo evidence in multicellular organisms.</p

Individual Differences in Moral Disgust Do Not Predict Utilitarian Judgments, Sexual and Pathogen Disgust Do

The role of emotional disgust and disgust sensitivity in moral judgment and decision-making has been debated intensively for over 20 years. Until very recently, there were two main evolutionary narratives for this rather puzzling association. One of the models suggest that it was developed through some form of group selection mechanism, where the internal norms of the groups were acting as pathogen safety mechanisms. Another model suggested that these mechanisms were developed through hygiene norms, which were piggybacking on pathogen disgust mechanisms. In this study we present another alternative, namely that this mechanism might have evolved through sexual disgust sensitivity. We note that though the role of disgust in moral judgment has been questioned recently, few studies have taken disgust sensitivity to account. We present data from a large sample (N=1300) where we analyzed the associations between The Three Domain Disgust Scale and the most commonly used 12 moral dilemmas measuring utilitarian/deontological preferences with Structural Equation Modeling. Our results indicate that of the three domains of disgust, only sexual disgust is associated with more deontological moral preferences. We also found that pathogen disgust was associated with more utilitarian preferences. Implications of the findings are discussed.Peer reviewe

Ex vivo -mallit ja nestebiopsia yksilöllistetyssä syövänhoidossa

Vertaisarvioitu. Teema : geeniohjatun syövän hoidon työryhmä.Syövän tutkimus- ja hoitomenetelmät kehittyvät jatkuvasti yksilöllistetympään suuntaan. Syynä ovat molekyyliprofiloinnin menetelmien kehitys, siitä saatava tieto ja geenidiagnostiikkaan perustuvat lääkkeet. Hoidon valitsemiseksi tarvitaan ja käytetään yhä useammin vastetta ennakoivia biomarkkereita. Potilaskohtaiset ex vivo -syöpämallit mahdollistavat tulevaisuudessa yksilöllistetyn, systeemibiologian periaatteita hyödyntävän syövänhoidon tutkimuksen, biomarkkereiden identifioinnin ja uusien hoitostrategioiden testaamisen. Ex vivo -mallien avulla voitaneen ohjata myös suoraan hoidon valintaa, luultavasti ensin hematologisissa syöpätaudeissa. Nestebiopsiasta tehtävä molekyyliprofilointi mahdollistaa ajantasaisen geenidiagnostiikan, jolloin hoitojen aiheuttamassa evoluutiopaineessa alati tapahtuva syövän muuntuminen voidaan huomata. Jotta syövän systeemibiologisen perustutkimuksen havaintoja päästään hyödyntämään potilastyössä, tarvitaan kliiniseen työhön niveltyvää yksilöllistä syövänhoidon tutkimusta, koulutusta ja osaamista.Peer reviewe

Socio‐cognitive biases in folk AI ethics and risk discourse

Peer reviewe

Ex vivo -mallit ja nestebiopsia yksilöllistetyssä syövänhoidossa

Syövän tutkimus- ja hoitomenetelmät kehittyvät jatkuvasti yksilöllistetympään suuntaan. Syynä ovat molekyyliprofiloinnin menetelmien kehitys, siitä saatava tieto ja geenidiagnostiikkaan perustuvat lääkkeet. Hoidon valitsemiseksi tarvitaan ja käytetään yhä useammin vastetta ennakoivia biomarkkereita. Potilaskohtaiset ex vivo -syöpämallit mahdollistavat tulevaisuudessa yksilöllistetyn, systeemibiologian periaatteita hyödyntävän syövänhoidon tutkimuksen, biomarkkereiden identifioinnin ja uusien hoitostrategioiden testaamisen. Ex vivo -mallien avulla voitaneen ohjata myös suoraan hoidon valintaa, luultavasti ensin hematologisissa syöpätaudeissa. Nestebiopsiasta tehtävä molekyyliprofilointi mahdollistaa ajantasaisen geenidiagnostiikan, jolloin hoitojen aiheuttamassa evoluutiopaineessa alati tapahtuva syövän muuntuminen voidaan huomata. Jotta syövän systeemibiologisen perustutkimuksen havaintoja päästään hyödyntämään potilastyössä, tarvitaan kliiniseen työhön niveltyvää yksilöllistä syövänhoidon tutkimusta, koulutusta ja osaamista

Treatments approved, boosts eschewed : Moral limits of neurotechnological enhancement

In six vignette-based experiments, we assessed people's moral reactions towards various cognition-enhancing brain implants, including their overall approval and perceived fairness, as well as the dehumanization of brain-implanted agents. Across the domains of memory (Studies 1-4, 6), general intelligence (Study 5A), and emotional stability (Study 5B), people in general approved of alleviating ailments, and even of attaining optimal human performance, but expressed greater opposition towards superhuman levels of enhancement. Further analyses of individual differences indicated that the tendency to condemn transhumanist technologies, such as brain implants, was linked to sexual disgust sensitivity and the binding moral foundations - two characteristic correlates of a conservative worldview. In turn, exposure to science fiction was tied to greater approval of brain implants. We also examined potential idiosyncrasies associated with our stimulus materials and did not find reliable effects of any secondary factors on moral attitudes. Taken together, our studies reveal certain moral boundaries to neurotechnological enhancement, strong among those with conservative affective and moral dispositions but relaxed among those familiar with science fiction themes.Peer reviewe

PARP Inhibitors in Prostate Cancer-the Preclinical Rationale and Current Clinical Development

Prostate cancer is globally the second most commonly diagnosed cancer type in men. Recent studies suggest that mutations in DNA repair genes are associated with aggressive forms of prostate cancer and castration resistance. Prostate cancer with DNA repair defects may be vulnerable to therapeutic targeting by Poly(ADP-ribose) polymerase (PARP) inhibitors. PARP enzymes modify target proteins with ADP-ribose in a process called PARylation and are in particular involved in single strand break repair. The rationale behind the clinical trials that led to the current use of PARP inhibitors to treat cancer was to target the dependence of BRCA-mutant cancer cells on the PARP-associated repair pathway due to deficiency in homologous recombination. However, recent studies have proposed therapeutic potential for PARP inhibitors in tumors with a variety of vulnerabilities generating dependence on PARP beyond the synthetic lethal targeting of BRCA1/BRCA2 mutated tumors, suggesting a wider potential than initially thought. Importantly, PARP-associated DNA repair pathways are also closely connected to androgen receptor (AR) signaling, which is a key regulator of tumor growth and a central therapeutic target in prostate cancer. In this review, we provide an extensive overview of published and ongoing trials exploring PARP inhibitors in treatment of prostate cancer and discuss the underlying biology. Several clinical trials are currently studying PARP inhibitor mono-and combination therapies in the treatment of prostate cancer. Integration of drugs targeting DNA repair pathways in prostate cancer treatment modalities allows developing of more personalized care taking also into account the genetic makeup of individual tumors

More Than Meets the Eye: Scientific Rationale behind Molecular Imaging and Therapeutic Targeting of Prostate-Specific Membrane Antigen (PSMA) in Metastatic Prostate Cancer and Beyond

Simple SummaryProstate-specific membrane antigen (PSMA) is a transmembrane protein that is overexpressed in prostate cancer and correlates with the aggressiveness of the disease. PSMA is a promising target for imaging and therapeutics in prostate cancer patients validated in prospective trials. However, the role of PSMA in prostate cancer progression is poorly understood. In this review, we discuss the biology and scientific rationale behind the use of PSMA and other targets in the detection and theranostics of metastatic prostate cancer.Prostate cancer is the second most common cancer type in men globally. Although the prognosis for localized prostate cancer is good, no curative treatments are available for metastatic disease. Better diagnostic methods could help target therapies and improve the outcome. Prostate-specific membrane antigen (PSMA) is a transmembrane glycoprotein that is overexpressed on malignant prostate tumor cells and correlates with the aggressiveness of the disease. PSMA is a clinically validated target for positron emission tomography (PET) imaging-based diagnostics in prostate cancer, and during recent years several therapeutics have been developed based on PSMA expression and activity. The expression of PSMA in prostate cancer can be very heterogeneous and some metastases are negative for PSMA. Determinants that dictate clinical responses to PSMA-targeting therapeutics are not well known. Moreover, it is not clear how to manipulate PSMA expression for therapeutic purposes and develop rational treatment combinations. A deeper understanding of the biology behind the use of PSMA would help the development of theranostics with radiolabeled compounds and other PSMA-based therapeutic approaches. Along with PSMA several other targets have also been evaluated or are currently under investigation in preclinical or clinical settings in prostate cancer. Here we critically elaborate the biology and scientific rationale behind the use of PSMA and other targets in the detection and therapeutic targeting of metastatic prostate cancer

Radium-223 dichloride treatment in metastatic castration-resistant prostate cancer in Finland : A real-world evidence multicenter study

Background Radium-233 dichloride is an alpha emitter that specifically targets bone metastases in prostate cancer. Results of a previously reported phase III randomized trial showed survival benefit for radium-223 compared to best supportive care in castration-resistant prostate cancer (CRPC) with bone metastases. However, real-world data are also needed with wider inclusion criteria. Methods We report results of a retrospective multicenter study including all patients with metastatic CRPC treated with radium-223 in all five university hospitals in Finland since the introduction of the treatment. We identified 160 patients who had received radium-223 in Finland in 2014-2019. Results The median overall survival (OS) was 13.8 months (range 0.5-57 months), and the median real-world progression-free survival (rwPFS) was 4.9 months (range 0.5-29.8 months). Alkaline phosphatase (ALP) values within the normal range before and during the radium-223 treatment or the reduction of elevated ALP to normal range during treatment were associated with better OS when compared to elevated ALP values before and during treatment (p = 100 mu g/L) before radium-223 treatment was associated with poor OS compared to low PSA level (Peer reviewe

Therapeutic Potential of Targeting the SUMO Pathway in Cancer

The small ubiquitin-like modifier (SUMO) pathway regulates the hallmark properties of cancer cells. Moreover, alterations in activity and in levels of SUMO machinery components have been observed in human cancer. Due to the reversible nature of this post-translational protein modification, the balance between SUMOylation and the removal of SUMO is critical. Early-phase clinical trials are currently evaluating the safety and efficacy of SUMO pathway inhibition in cancer patients. In this comprehensive review, we critically discuss the potential of targeting the SUMO pathway as a therapeutic option for cancer. </p