Nuclear size rectification:A potential new therapeutic approach to reduce metastasis in cancer

Research on metastasis has recently regained considerable interest with the hope that single cell technologies might reveal the most critical changes that support tumor spread. However, it is possible that part of the answer has been visible through the microscope for close to 200 years. Changes in nuclear size characteristically occur in many cancer types when the cells metastasize. This was initially discarded as contributing to the metastatic spread because, depending on tumor types, both increases and decreases in nuclear size could correlate with increased metastasis. However, recent work on nuclear mechanics and the connectivity between chromatin, the nucleoskeleton, and the cytoskeleton indicate that changes in this connectivity can have profound impacts on cell mobility and invasiveness. Critically, a recent study found that reversing tumor type-dependent nuclear size changes correlated with reduced cell migration and invasion. Accordingly, it seems appropriate to now revisit possible contributory roles of nuclear size changes to metastasis

Sepelvaltimotauti ja sepelvaltimon kroonisen totaalitukoksen perkutaaninen hoito : merkitys potilaan oirekuvaan ja ennusteeseen

Sepelvaltimotauti on merkittävä kuolleisuuden aiheuttaja maailmalla ja Suomessa. Suomessa tautia sairastaa 50 vuotta täyttäneistä suomalaisista miehistä 14 % ja naisista 7 %. Sepelvaltimon krooninen totaalitukos (engl. chronic total occlusion, CTO) on ahtauma, joka tukkii suonen täysin ja on yli kolme kuukautta vanha. Rekisteritutkimusten perusteella CTO todetaan 15–25% potilaista, joille tehdään koronaariangiografia. CTO voidaan hoitaa erikoistekniikoin toteutetulla pallolaajennuksella (engl. chronic total occlusion percutaneous coronary intervention, CTO-PCI). Tutkimusnäytön perusteella onnistunut toimenpide vähentää potilaiden oireita, mutta vaikutusta ennusteeseen ei luotettavasti ole pystytty osoittamaan. Tutkimus on retrospektiivinen seurantatutkimus, jossa selvitetään Helsingin yliopistollisessa keskussairaalassa (HYKS) tehtyjen CTO-PCI -toimenpiteiden vaikutusta potilaiden oirekuvaan ja ennusteeseen. Tutkimuksessa vertaillaan potilasryhmiä, joilla tukkeuman aukaisu on onnistunut ja joilla se ei ole onnistunut. Tutkimuksen aineistona on Helsingin ja HUS:n Jorvin ja Meilahden sydänasemalla vuosina 2014-2017 CTO-PCI toimenpiteellä hoidettujen potilaiden potilastiedot ja tutkimuksen aikana tehtävä potilaiden haastattelu puhelimitse. Tutkimusta varten kehitettiin CCS ja NYHA -luokituksia mukaileva oirekyselylomake, jonka perusteella voitiin arvioida potilaiden oireisuutta ennen ja jälkeen tutkimuksen. Tuloksista nähdään, että potilaiden oireet lievittyvät onnistuneen toimenpiteen myötä. Kuolleisuuteen toimenpiteellä ei näytä olevan vaikutusta. Nämä tulokset vahvistavat aiempien tutkimusten tuloksia. Toimenpiteestä on myös merkittävää hyötyä potilaille, koska onnistuneen toimenpiteen jälkeen potilaat välttyvät ohitusleikkaukselta todennäköisemmin kuin epäonnistuneen toimenpiteen jälkeen

”Kansan pelin” kauhuvuodet: Heyselin ja Hillsborough’n katsomokatastrofit The Guardianissa vuosina 1985–1990

Pro-gradu -tutkielmani käsittelee brittiläisen The Guardian -sanomalehden uutisointia englantilaisen jalkapallon kahdesta vakavimmasta katsomokatastrofista: vuoden 1985 Heyselistä ja vuoden 1989 Hillsborough’sta. Guardian oli keskustavasemmistolaista politiikkaa kannattanut valtalehti, jonka oikeistohallitukselle esittämä kritiikki heijastui myös lehden jalkapallouutisointiin. Tutkin millaisessa valossa katsomokatastrofit lehdessä näyttäytyivät, miten Guardian suhtautui 1980-luvun suurena yhteiskunnallisena ongelmana pidettyyn jalkapallohuliganismiin, ja miten brittiyhteiskunnan ongelmat yhdistyivät katsomokatastrofeihin. Lisäksi tarkastelen lehden suhdetta jalkapallon kanssa tekemissä olleisiin ihmisiin, kuten jalkapalloviranomaisiin ja poliitikkoihin. Aineistoni koostuu Guardianin journalistisesta materiaalista, kuten pääkirjoituksista, uutisista, kolumneista ja urheilu-uutisista, joita oli yhteensä 525 kappaletta. Tarkastelen aineistoa sisällönanalyysin, sekä kontekstianalyysin ja lähdekritiikin keinoin. Koska katsomokatastrofit eivät olleet identtisiä, vertailen myös Heyseliä ja Hillsborough’ta keskenään löytääkseni yhtäläisyyksiä ja eroja lehden suhtautumisessa niihin. Tutkimuksesta ilmenee katsomokatastrofien olleen vain yksi jalkapallon useista ongelmista. Heyselin jälkeen Guardian syytti erityisesti englantilaisia kannattajia huliganismista, ja vaati heidän vetäytymistään eurooppalaisista turnauksista. Hillsborough’n onnettomuuteen mennessä tilanne muuttui, ja lehden kritiikki siirtyi kannattajista paikallisen poliisin toimintaan ottelupäivänä. Vuosina 1985–88 jalkapallokeskustelu pyörikin pitkälti huligaanikysymyksen ympärillä, mutta Hillsborough’n jälkeen Guardian painotti enemmän lajiolosuhteiden turvallisuuden tärkeyttä. Tutkimusvuodet 1985–1990 olivat englantilaisen jalkapallon kriisiaikaa, jolloin mielikuvat lajista olivat negatiivisia ja se oli jatkuvassa poliittisessa paineessa. Guardian piti jalkapallohuliganismia yhteiskunnallisena ongelmana ja osoituksena Britannian 1980-luvun sosiaalisista paheista. Tutkimuksesta ilmenee lehden pitäneen huligaaniongelmaa seurauksena lajin ulkopuolisista ongelmista eikä lajista itsestään johtuvana. Guardian kritisoi säännöllisesti poliitikkoja ja jalkapallojohtajia. Poliittisesti lehden kritiikki esitettyihin jalkapalloratkaisuihin jyrkkeni sitä mukaa, kun hallituksen omat mielipiteet tiukkenivat. Kokonaisuudessa Guardian muistutti erityisesti Heyselin ja Hillsborough’n uhreista ja vaati parannuksia englantilaisten stadionien rapistuneisiin katsomo-olosuhteisiin. Uhrit unohtamalla vaarana oli katastrofien unohtaminen, ja riski uusille onnettomuuksille

Phase-to-Phase With Nucleoli – Stress Responses, Protein Aggregation and Novel Roles of RNA

Protein- and RNA-containing foci and aggregates are a hallmark of many age- and mutation-related neurodegenerative diseases. This article focuses on the role the nucleolus has as a hub in macromolecule regulation in the mammalian nucleus. The nucleolus has a well-established role in ribosome biogenesis and functions in several types of cellular stress responses. In addition to known reactions to DNA damaging and transcription inhibiting stresses, there is an emerging role of the nucleolus especially in responses to proteotoxic stress such as heat shock and inhibition of proteasome function. The nucleolus serves as an active regulatory site for detention of extranucleolar proteins. This takes place in nucleolar cavities and manifests in protein and RNA collections referred to as intranucleolar bodies (INBs), nucleolar aggresomes or amyloid bodies (A-bodies), depending on stress type, severity of accumulation, and material propensities of the macromolecular collections. These indicate a relevance of nucleolar function and regulation in neurodegeneration-related cellular events, but also provide surprising connections with cancer-related pathways. Yet, the molecular mechanisms governing these processes remain largely undefined. In this article, the nucleolus as the site of protein and RNA accumulation and as a possible protective organelle for nuclear proteins during stress is viewed. In addition, recent evidence of liquid-liquid phase separation (LLPS) and liquid-solid phase transition in the formation of nucleoli and its stress responses, respectively, are discussed, along with the increasingly indicated role and open questions for noncoding RNA species in these events

Virtual reality for 3D histology: multi-scale visualization of organs with interactive feature exploration

Virtual reality (VR) enables data visualization in an immersive and engaging manner, and it can be used for creating ways to explore scientific data. Here, we use VR for visualization of 3D histology data, creating a novel interface for digital pathology. Our contribution includes 3D modeling of a whole organ and embedded objects of interest, fusing the models with associated quantitative features and full resolution serial section patches, and implementing the virtual reality application. Our VR application is multi-scale in nature, covering two object levels representing different ranges of detail, namely organ level and sub-organ level. In addition, the application includes several data layers, including the measured histology image layer and multiple representations of quantitative features computed from the histology. In this interactive VR application, the user can set visualization properties, select different samples and features, and interact with various objects. In this work, we used whole mouse prostates (organ level) with prostate cancer tumors (sub-organ objects of interest) as example cases, and included quantitative histological features relevant for tumor biology in the VR model. Due to automated processing of the histology data, our application can be easily adopted to visualize other organs and pathologies from various origins. Our application enables a novel way for exploration of high-resolution, multidimensional data for biomedical research purposes, and can also be used in teaching and researcher training

A systematic comparison of data- and knowledge-driven approaches to disease subtype discovery

bbab314Typical clustering analysis for large-scale genomics data combines two unsupervised learning techniques: dimensionality reduction and clustering (DR-CL) methods. It has been demonstrated that transforming gene expression to pathway-level information can improve the robustness and interpretability of disease grouping results. This approach, referred to as biological knowledge-driven clustering (BK-CL) approach, is often neglected, due to a lack of tools enabling systematic comparisons with more established DR-based methods. Moreover, classic clustering metrics based on group separability tend to favor the DR-CL paradigm, which may increase the risk of identifying less actionable disease subtypes that have ambiguous biological and clinical explanations. Hence, there is a need for developing metrics that assess biological and clinical relevance. To facilitate the systematic analysis of BK-CL methods, we propose a computational protocol for quantitative analysis of clustering results derived from both DR-CL and BK-CL methods. Moreover, we propose a new BK-CL method that combines prior knowledge of disease relevant genes, network diffusion algorithms and gene set enrichment analysis to generate robust pathway-level information. Benchmarking studies were conducted to compare the grouping results from different DR-CL and BK-CL approaches with respect to standard clustering evaluation metrics, concordance with known subtypes, association with clinical outcomes and disease modules in co-expression networks of genes. No single approach dominated every metric, showing the importance multi-objective evaluation in clustering analysis. However, we demonstrated that, on gene expression data sets derived from TCGA samples, the BK-CL approach can find groupings that provide significant prognostic value in both breast and prostate cancers.Peer reviewe

Organisation of cross-sector collaboration and its influence on crisis management effectiveness among pharmaceutical supply chain stakeholders during the COVID-19 pandemic

Objectives: To investigate the organisation of cross-sector collaboration and how it influenced crisis management effectiveness among pharmaceutical supply chain stakeholders in Finland during the COVID-19 pandemic. Study design: Qualitative semi-structured interview study. Methods: Purposeful selection was used to obtain the study sample consisting of leaders and specialists from the pharmaceutical industry and wholesalers (n = 9), community pharmacy owners (n = 9), hospital pharmacy heads (n = 6), government agency directors and officials (n = 5) and advocacy organisation representatives (n = 2). Inductive content analysis was performed to examine the data from the semi-structured individual (n = 29) and paired (n = 2) interviews in March–May 2021. Results: A new conceptual model was developed to describe the organisation of collaborative crisis management. Without a predefined crisis management organisation, cross-sector collaboration was organised based on previous collaboration structures, channels and relationships and through the establishment of issue-specific groups by government agencies as per legal mandates. Crisis dynamics and related issues guided the group formation and meeting frequency. Advocacy organisations and government agencies acted in bridging role between stakeholders. Shared knowledge among pharmaceutical supply chain stakeholders enabled anticipation and preparedness during crisis; shared resources fostered maintenance of core functions; and shared problem-solving facilitated cross-sectoral solutions. Conclusion: This was the first study exploring cross-sector collaboration among pharmaceutical supply chain stakeholders during a crisis. Sharing knowledge, resources and problem-solving increased the crisis management effectiveness. The study presented a new illustration of organising for collaborative crisis management and added knowledge about private-third sector collaboration and issue-specific groups to the cross-sector collaboration and crisis management literature

A fluorescence based sensor assay that monitors general protein aggregation in human cells

Protein conformational disorders are characterized by disruption of protein folding and toxic accumulation of protein aggregates. Here we describe a sensitive and simple method to follow and monitor general protein aggregation in human cells. Heat shock protein 27 (HSP27) is an oligomeric small heat shock protein that binds and keeps unfolded proteins in a folding competent state. This high specificity of HSP27 for aggregated proteins can be explored to monitor aggregation in living cells by fusing it to a fluorescent protein as Green Fluorescent Protein (GFP). We have constructed a HeLa stable cell line expressing a HSP27:GFP chimeric reporter protein and after validation, this stable cell line is exposed to different agents that interfere with proteostasis, namely Arsenite, MG132, and Aβ-peptide. Exposure to proteome destabilizers lead to re-localization of HSP27:GFP fluorescence to foci, confirming that our reporter system is functional and can be used to detect and follow protein aggregation in living cells. This reporter is a valuable tool to setup wide-genetic screens to identify genes and pathways involved in protein misfolding and aggregation.publishe

Deformation equivariant cross-modality image synthesis with paired non-aligned training data

Cross-modality image synthesis is an active research topic with multiple medical clinically relevant applications. Recently, methods allowing training with paired but misaligned data have started to emerge. However, no robust and well-performing methods applicable to a wide range of real world data sets exist. In this work, we propose a generic solution to the problem of cross-modality image synthesis with paired but non-aligned data by introducing new deformation equivariance encouraging loss functions. The method consists of joint training of an image synthesis network together with separate registration networks and allows adversarial training conditioned on the input even with misaligned data. The work lowers the bar for new clinical applications by allowing effortless training of cross-modality image synthesis networks for more difficult data sets