Open access articles by University of Helsinki researchers. Contains final versions and manuscripts of research articles as well as professional publications and publications aimed at general public.

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  • Pöntinen, Anna K.; Top, Janetta; Arredondo-Alonso, Sergio; Tonkin-Hill, Gerry; Freitas, Ana R.; Novais, Carla; Gladstone, Rebecca A.; Pesonen, Maiju; Meneses, Rodrigo; Pesonen, Henri; Lees, John A.; Jamrozy, Dorota; Bentley, Stephen D.; Lanza, Val F.; Torres, Carmen; Peixe, Luisa; Coque, Teresa M.; Parkhill, Julian; Schurch, Anita C.; Willems, Rob J. L.; Corander, Jukka (2021)
    Enterococcus faecalis is a commensal and nosocomial pathogen, which is also ubiquitous in animals and insects, representing a classical generalist microorganism. Here, we study E. faecalis isolates ranging from the pre-antibiotic era in 1936 up to 2018, covering a large set of host species including wild birds, mammals, healthy humans, and hospitalised patients. We sequence the bacterial genomes using short- and long-read techniques, and identify multiple extant hospital-associated lineages, with last common ancestors dating back as far as the 19th century. We find a population cohesively connected through homologous recombination, a metabolic flexibility despite a small genome size, and a stable large core genome. Our findings indicate that the apparent hospital adaptations found in hospital-associated E. faecalis lineages likely predate the "modern hospital" era, suggesting selection in another niche, and underlining the generalist nature of this nosocomial pathogen.Enterococcus faecalis is a commensal microorganism of animals, insects and humans, but also a nosocomial pathogen. Here, the authors analyse genomic sequences from E. faecalis isolates from animals and humans, and find that the last common ancestors of multiple hospital-associated lineages date to the pre-antibiotic era.
  • Ylösmäki, Erkko; Ylösmäki, Leena; Fusciello, Manlio; Martins, Beatriz; Ahokas, Petra; Cojoc, Hanne; Uoti, Arttu; Feola, Sara; Kreutzman, Anna; Ranki, Tuuli; Karbach, Julia; Viitala, Tapani; Priha, Petri; Jäger, Elke; Pesonen, Sari; Cerullo, Vincenzo (2021)
    Oncolytic viruses (OVs) have been shown to induce anti-cancer immunity and enhance cancer immunotherapies, such as immune checkpoint inhibitor therapies. OV therapies can be further improved by arming OVs with immunostimulatory molecules, including various cytokines or chemokines. Here, we have developed a novel adenovirus encoding two immunostimulatory molecules: cluster of differentiation 40 ligand (CD40L) and tumor necrosis factor receptor superfamily member 4 ligand (OX40L). This novel virus, designated VALOD-102, is designed to activate both innate and adaptive immune responses against tumors. CD40L affects the innate side by licensing antigen-presenting cells to drive CD8(+) T cell responses, and OX40L increases clonal expansion and survival of CD8(+) T cells and formation of a larger pool of memory T cells. VALO-D102 and its murine surrogate VALO-mD901, expressing murine OX40L and CD40L, were used in our previously developed PeptiCRAd cancer vaccine platform. Intratumoral administration of PeptiCRAd significantly increased tumor-specific T cell responses, reduced tumor growth, and induced systemic anti-cancer immunity in two mouse models of melanoma. In addition, PeptiCRAd therapy, in combination with anti-PD-1 immune checkpoint inhibitor therapy, significantly improved tumor growth control as compared to either monotherapy alone.
  • Vaquero, Lucia; Ramos-Escobar, Neus; Cucurell, David; Francois, Clement; Putkinen, Vesa; Segura, Emma; Huotilainen, Minna; Penhune, Virginia; Rodriguez-Fornells, Antoni (2021)
    The mismatch negativity (MMN) is an event related brain potential (ERP) elicited by unpredicted sounds presented in a sequence of repeated auditory stimuli. The neural sources of the MMN have been previously attributed to a fronto-temporo-parietal network which crucially overlaps with the so-called auditory dorsal stream, involving inferior and middle frontal, inferior parietal, and superior and middle temporal regions. These cortical areas are structurally connected by the arcuate fasciculus (AF), a three-branch pathway supporting the feedback-feedforward loop involved in auditory-motor integration, auditory working memory, storage of acoustic templates, as well as comparison and update of those templates. Here, we characterized the individual differences in the white-matter macrostructural properties of the AF and explored their link to the electrophysiological marker of passive change detection gathered in a melodic multifeature MMN-EEG paradigm in 26 healthy young adults without musical training. Our results show that left fronto-temporal white-matter connectivity plays an important role in the pre-attentive detection of rhythm modulations within a melody. Previous studies have shown that this AF segment is also critical for language processing and learning. This strong coupling between structure and function in auditory change detection might be related to life-time linguistic (and possibly musical) exposure and experiences, as well as to timing processing specialization of the left auditory cortex. To the best of our knowledge, this is the first time in which the relationship between neurophysiological (EEG) and brain whitematter connectivity indexes using DTI-tractography are studied together. Thus, the present results, although still exploratory, add to the existing evidence on the importance of studying the constraints imposed on cognitive functions by the underlying structural connectivity.
  • Wang, Shiqi (2021)
    The intracellular delivery of emerging biomacromolecular therapeutics, such as genes, peptides, and proteins, remains a great challenge. Unlike small hydrophobic drugs, these biotherapeutics are impermeable to the cell membrane, thus relying on the endocytic pathways for cell entry. After endocytosis, they are entrapped in the endosomes and finally degraded in lysosomes. To overcome these barriers, many carriers have been developed to facilitate the endosomal escape of these biomacromolecules. This mini-review focuses on the development of anionic pH-responsive amphiphilic carboxylate polymers for endosomal escape applications, including the design and synthesis of these polymers, the mechanistic insights of their endosomal escape capability, the challenges in the field, and future opportunities.
  • Casarotto, Plinio C.; Girych, Mykhailo; Fred, Senem M.; Kovaleva, Vera; Moliner, Rafael; Enkavi, Giray; Biojone, Caroline; Cannarozzo, Cecilia; Sahu, Madhusmita Pryiadrashini; Kaurinkoski, Katja; Brunello, Cecilia A.; Steinzeig, Anna; Winkel, Frederike; Patil, Sudarshan; Vestring, Stefan; Serchov, Tsvetan; Diniz, Cassiano R. A. F.; Laukkanen, Liina; Cardon, Iseline; Antila, Hanna; Rog, Tomasz; Piepponen, Timo Petteri; Bramham, Clive R.; Normann, Claus; Lauri, Sari E.; Saarma, Mart; Vattulainen, Ilpo; Castren, Eero (2021)
    It is unclear how binding of antidepressant drugs to their targets gives rise to the clinical antidepressant effect. We discovered that the transmembrane domain of tyrosine kinase receptor 2 (TRKB), the brain-derived neurotrophic factor (BDNF) receptor that promotes neuronal plasticity and antidepressant responses, has a cholesterol-sensing function that mediates synaptic effects of cholesterol. We then found that both typical and fast-acting antidepressants directly bind to TRKB, thereby facilitating synaptic localization of TRKB and its activation by BDNF. Extensive computational approaches including atomistic molecular dynamics simulations revealed a binding site at the transmembrane region of TRKB dimers. Mutation of the TRKB antidepressant-binding motif impaired cellular, behavioral, and plasticity-promoting responses to antidepressants in vitro and in vivo. We suggest that binding to TRKB and allosteric facilitation of BDNF signaling is the common mechanism for antidepressant action, which may explain why typical antidepressants act slowly and how molecular effects of antidepressants are translated into clinical mood recovery.
  • Pajulahti, Riikka; Salmela-Aro, Katariina; Lehto, Reetta; Vepsäläinen, Henna; Lehto, Elviira; Nissinen, Kaija; Skaffari, Essi; Sääksjärvi, Katri; Roos, Eva; Sajaniemi, Nina; Erkkola, Maijaliisa; Ray, Carola (2021)
    Consistently linked with children?s food consumption are food availability and accessibility. However, less is known about potential individual differences among young children in their susceptibility to home food environments. The purpose of the study was to examine whether the association between home food availability and accessibility of sugar-rich foods and drinks (SFD) or fruits and vegetables (FV) and children?s consumption of these foods differ according to their temperament. The study used two cross-sectional datasets collected as part of the Increased Health and Wellbeing in Preschools (DAGIS) study: 1) a cross-sectional data of 864 children aged 3?6 years old collected between fall 2015 and spring 2016, and 2) an intervention baseline data of 802 children aged 3?6 collected in fall 2017. Parents reported their children?s temperament, consumption of FV and SFD, and home availability and accessibility of SFD and FV. Examination of whether associations between home availability and accessibility of FV and their consumption differ according to children?s temperament involved using linear regression models. Similar models were used to examine association between home availability and accessibility of SFD and their consumption, and the moderating role of temperament. The association between home accessibility of SFD and their consumption frequency was dependent on the level of children?s negative affectivity. More frequent consumption of SFD was observed with higher home accessibility of SFD. The association was stronger in children with higher scores in negative affectivity. No other interactions were found. Children with higher negative affectivity are possibly more vulnerable to food cues in the home environment than children with lower negative affectivity. Consideration of children?s individual characteristics is necessary in supporting their healthy eating.
  • Hokajärvi, Anna-Maria; Rytkönen, Annastiina; Tiwari, Ananda; Kauppinen, Ari; Oikarinen, Sami; Lehto, Kirsi-Maarit; Kankaanpää, Aino; Gunnar, Teemu; Al-Hello, Haider; Blomqvist, Soile; Miettinen, Ilkka T.; Savolainen-Kopra, Carita; Pitkänen, Tarja (2021)
    Analysis of the particulate matter of the sample, in addition to the water fraction, can improve the detection frequency. (C) 2021 The Author(s). Published by Elsevier B.V.Wastewater-based surveillance of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is used to monitor the population-level prevalence of the COVID-19 disease. In many cases, due to lockdowns or analytical delays, the analysis of wastewater samples might only be possible after prolonged storage. In this study, the effect of storage conditions on the RNA copy numbers of the SARS-CoV-2 virus in wastewater influent was studied and compared to the persistence of norovirus over time at 4 degrees C, -20 degrees C, and -75 degrees C using the reverse-transcription quantitative PCR (RT-qPCR) assays E-Sarbeco, N2, and norovirus GII. For the first time in Finland, the presence of SARS-CoV-2 RNA was tested in 24 h composite influent wastewater samples collected from Viikinmaki wastewater treatment plant, Helsinki, Finland. The detected and quantified SARS-CoV-2 RNA copy numbers of the wastewater sample aliquots taken during 19-20 April 2020 and stored for 29, 64, and 84 days remained surprisingly stable. In the stored samples, the SARS betacoronavirus and SARS-CoV-2 copy numbers, but not the norovirus GII copy numbers, seemed slightly higher when analyzed from the pre-centrifuged pellet-that is, the particulate matter of the influent-as compared with the supernatant (i.e., water fraction) used for ultrafiltration, although the difference was not statistically significant. Furthermore, when wastewater was spiked with SARS-CoV-2, linear decay at 4 degrees C was observed on the first 28 days, while no decay was visible within 58 days at -20 degrees C or -75 degrees C. In conclusion, freezing temperatures should be used for storage when immediate SARS-CoV-2 RNA analysis from the wastewater influent is not possible. Analysis of the particulate matter of the sample, in addition to the water fraction, can improve the detection frequency. (C) 2021 The Author(s). Published by Elsevier B.V.
  • Abdelrehiem, Dina Ahmed Mosselhy; Virtanen, Jenni Maaret Elina; Kant, Ravi; He, Wei; Elbahri, Mady; Sironen, Tarja (2021)
    Every day, new information is presented with respect to how to best combat the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This manuscript sheds light on such recent findings, including new co-factors (i.e., neuropilin-1) and routes (i.e., olfactory transmucosal) allowing cell entry of SARS-CoV-2 and induction of neurological symptoms, as well as the new SARS-CoV-2 variants. We highlight the SARS-CoV-2 human-animal interfaces and elaborate containment strategies using the same vaccination (i.e., nanoparticle "NP" formulations of the BNT162b2 and mRNA-1273 vaccines) for humans, minks, raccoon dogs, cats, and zoo animals. We investigate the toxicity issues of anti-CoV NPs (i.e., plasmonic NPs and quantum dots) on different levels. Namely, nano-bio interfaces (i.e., protein corona), in vitro (i.e., lung cells) and in vivo (i.e., zebrafish embryos) assessments, and impacts on humans are discussed in a narrative supported by original figures. Ultimately, we express our skeptical opinion on the comprehensive administration of such antiviral nanotheranostics, even when integrated into facemasks, because of their reported toxicities and the different NP parameters (e.g., size, shape, surface charge, and purity and chemical composition of NPs) that govern their end toxicity. We believe that more toxicity studies should be performed and be presented, clarifying the odds of the safe administration of nanotoxocological solutions and the relief of a worried public.
  • University of Helsinki, Helsinki Collegium for Advanced Studies; University of Helsinki, Department of Social Research (2010-2017); Wrede, Sirpa; Näre, Lena; ; ; (De Gruyter Poland, 2013)
    Nordic Journal of Migration Research
  • Taheri, Shirin; Naimi, Babak; Rahbek, Carsten; Araujo, Miguel B. (2021)
    Studies have documented climate change-induced shifts in species distributions but uncertainties associated with data and methods are typically unexplored. We reviewed 240 reports of climate-related species-range shifts and classified them based on three criteria. We ask whether observed distributional shifts are compared against random expectations, whether multicausal factors are examined on equal footing, and whether studies provide sufficient documentation to enable replication. We found that only similar to 12.1% of studies compare distributional shifts across multiple directions, similar to 1.6% distinguish observed patterns from random expectations, and similar to 19.66% examine multicausal factors. Last, similar to 75.5% of studies report sufficient data and results to allow replication. We show that despite gradual improvements over time, there is scope for raising standards in data and methods within reports of climate-change induced shifts in species distribution. Accurate reporting is important because policy responses depend on them. Flawed assessments can fuel criticism and divert scarce resources for biodiversity to competing priorities.
  • Heinonen, Jussi S.; Luttinen, Arto V.; Spera, Frank J.; Vuori, Saku K.; Bohrson, Wendy A. (2021)
    Two subvertical gabbroic dikes with widths of similar to 350 m (East-Muren) and >= 500 m (West-Muren) crosscut continental flood basalts in the Antarctic extension of the similar to 180 Ma Karoo large igneous province (LIP) in Vestfjella, western Dronning Maud Land. The dikes exhibit unusual geochemical profiles; most significantly, initial (at 180 Ma) epsilon(Nd) values increase from the dike interiors towards the hornfelsed wallrock basalts (from - 15.3 to - 7.8 in East-Muren and more gradually from - 9.0 to - 5.5 in West-Muren). In this study, we utilize models of partial melting and energy-constrained assimilation-fractional crystallization in deciphering the magmatic evolution of the dikes and their contact aureoles. The modeling indicates that both gabbroic dikes acquired the distinctly negative epsilon(Nd) values recorded by their central parts by varying degrees of assimilation of Archean crust at depth. This first phase of deep contamination was followed by a second event at or close to the emplacement level and is related to the interaction of the magmas with the wallrock basalts. These basalts belong to a distinct Karoo LIP magma type having initial epsilon(Nd) from - 2.1 to + 2.5, which provides a stark contrast to the epsilon(Nd) composition of the dike parental magmas (- 15.3 for East-Muren, - 9.0 for West-Muren) previously contaminated by Archean crust. For East-Muren, the distal hornfelses represent partially melted wallrock basalts and the proximal contact zones represent hybrids of such residues with differentiated melts from the intrusion; the magmas that were contaminated by the partial melts of the wallrock basalts were likely transported away from the currently exposed parts of the conduit before the magma-wallrock contact was sealed and further assimilation prevented. In contrast, for West-Muren, the assimilation of the wallrock basalt partial melts is recorded by the gradually increasing epsilon(Nd) of the presently exposed gabbroic rocks towards the roof contact with the basalts. Our study shows that primitive LIP magmas release enough sensible and latent heat to partially melt and potentially assimilate wallrocks in multiple stages. This type of multi-stage assimilation is difficult to detect in general, especially if the associated wallrocks show broad compositional similarity with the intruding magmas. Notably, trace element and isotopic heterogeneity in LIP magmas can be homogenized by such processes (basaltic cannibalism). If similar processes work at larger scales, they may affect the geochemical evolution of the crust and influence the generation of, for example, massif-type anorthosites and "ghost plagioclase" geochemical signature.
  • Taipale, Jaakko; Hautamäki, Lotta (2021)
    This article examines clinical practice guidelines (CPG) in the courtroom. The guidelines in question are Finnish national current care guidelines for brain injuries, and the case context is traffic insurance compensation cases contested in the Helsinki district court. We analyse 11 case verdicts qualitatively, drawing from earlier socio-logical and theoretical accounts of clinical practice guidelines and evidence-based medicine. What makes the case-type relevant for studying clinical practice guidelines is the fact that the cases, which feature a medical dispute concerning traumatic brain injury, involve highly specialized expertise and contradictory expert claims, but the cases are decided in a generalist court by non-expert judges. What we show in the article is how the guidelines structure, sequence and initiate temporal reworking in the judges’ representation of medical evidence and testimony, and how the plaintiffs’ delayed diagnoses complicate the application of the CPG in the evaluation. We further discuss the guidelines’ epistemic authority in the verdicts and finish by comparing the 2008 and 2017 editions of Finnish CPGs for brain injuries, suggesting a multifaceted, courtroom-mediated feedback loop be-tween the patient-plaintiffs and the clinical practice guidelines.
  • Meitz, Mika; Saikkonen, Pentti (2021)
    Testing for regime switching when the regime switching probabilities are specified either as constants ('mixture models') or are governed by a finite-state Markov chain ('Markov switching models') are long-standing problems that have also attracted recent interest. This paper considers testing for regime switching when the regime switching probabilities are time-varying and depend on observed data ('observation-dependent regime switching'). Specifically, we consider the likelihood ratio test for observation-dependent regime switching in mixture autoregressive models. The testing problem is highly nonstandard, involving unidentified nuisance parameters under the null, parameters on the boundary, singular information matrices, and higher-order approximations of the log-likelihood. We derive the asymptotic null distribution of the likelihood ratio test statistic in a general mixture autoregressive setting using high-level conditions that allow for various forms of dependence of the regime switching probabilities on past observations, and we illustrate the theory using two particular mixture autoregressive models. The likelihood ratio test has a nonstandard asymptotic distribution that can easily be simulated, and Monte Carlo studies show the test to have good finite sample size and power properties. (C) 2020 The Authors. Published by Elsevier B.V.
  • Yagodin, Dmitry (2021)
    This article investigates the policy implications of national and regional climate change denial in Russia. While in general Russia has lagged behind in its climate mitigation policy, its key fossil-fuel regions are actively responding to external initiatives and pressures. As the country generally lacks substantial climate policy initiatives, the focus of this study is on the symbolic policy reactions operationalized as the media coverage of climate change at the national and regional levels in Russia during 2017-2018. Following the theoretical perspective of disproportionate policy response, the analysis elaborates on one of the suggested causes of policy over and underreactions, namely, the level of public demand for policy action. The findings indicate potential for disproportionate policy response research to conceive of public demand in broader terms, distinguishing between local, national and international domains.
  • Oksanen, Eljas; Lewis, Michael (2020)
    This paper explores some 220,000 medieval objects recorded in the Portable Antiquities Scheme (PAS) online database of archaeological small finds through Geographic Information System analysis of their relationship with contemporary market sites. First, an overview of the contents of the PAS database is presented in terms of its spatial and ‘object type’ distribution. Second, the relationship of the medieval finds data against documentary evidence of commercial activity is investigated at a national level. Finally, PAS data is contextualised in its historical landscape context through case studies. It is argued that the distribution of PAS finds on the national scale can be linked with patterns of commercial activity, and that while rural and urban finds scatters have distinguishing trends, the countryside population enjoyed access to a range of sophisticated metalwork culture; also, that certain assemblages can be analysed statistically to yield new data and perspectives on local historical development.
  • Lucendo, Estefania; Sancho, Monica; Lolicato, Fabio; Javanainen, Matti; Kulig, Waldemar; Leiva, Diego; Duart, Gerard; Andreu-Fernandez, Vicente; Mingarro, Ismael; Orzaez, Mar (2020)
    The Bcl-2 protein family comprises both proand antiapoptotic members that control the permeabilization of the mitochondrial outer membrane, a crucial step in the modulation of apoptosis. Recent research has demonstrated that the carboxyl-terminal transmembrane domain (TMD) of some Bcl-2 protein family mem-bers can modulate apoptosis; however, the transmembrane interactome of the antiapoptotic protein Mcl-1 remains largely unexplored. Here, we demonstrate that the Mcl-1 TMD forms homooligomers in the mitochondrial membrane, competes with full-length Mcl-1 protein with regards to its antiapoptotic function, and induces cell death in a Bok-dependent manner. While the Bok TMD oligomers locate preferentially to the endoplasmic reticulum (ER), heterooligomerization between the TMDs of Mcl-1 and Bok predominantly takes place at the mitochondrial membrane. Strikingly, the coexpression of Mcl-1 and Bok TMDs produces an increase in ER mitochondrial-associated membranes, suggesting an active role of Mcl-1 in the induced mitochondrial targeting of Bok. Finally, the introduction of Mcl-1 TMD somatic mutations detected in cancer patients alters the TMD interaction pattern to provide the Mcl-1 protein with enhanced antiapoptotic activity, thereby highlighting the clinical relevance of Mcl-1 TMD interactions.
  • Kokko, Marjut; Takala, Marjatta; Pihlaja, Päivi (2021)
    Co-teaching has become a well-known way of working among Finnish teachers in recent years. Teachers' collaboration is becoming increasingly important in light of the rising number of diverse students in regular classes. In an ideal co-teaching context, teachers collaborate as equals, recognise and respect each other's skills and competencies, and strengthen and support each other. In this study, we examine teachers' views on co-teaching and investigate which background factors explain teachers' views concerning the benefits and the challenges of co-teaching. The data obtained from Finnish basic education teachers' (N = 694) responses to an online questionnaire are analysed quantitatively. The results show some differences among the teachers' views. Subject teachers perceive more challenges in co-teaching than class and special education teachers. Class teachers perceive the fewest challenges. Although teachers are generally interested in co-teaching and some of them co-teach regularly, they also report several barriers to its application. The explanatory factors concerning the differences in teachers' views are gender, teachers' co-teaching experiences, the amount of co-teaching per week and working as a class teacher.
  • Siddiqui, Farid Ahmad; Parkkola, Hanna; Vukic, Vladimir; Oetken-Lindholm, Christina; Jaiswal, Alok; Kiriazis, Alexandros; Pavic, Karolina; Aittokallio, Tero; Salminen, Tiina A.; Abankwa, Daniel (2021)
    Simple Summary The correct folding of proteins is essential for their activity. Therefore, cells have evolved protein-folding chaperones, such as Hsp90. Interestingly, in several cancer cells, Hsp90 appears to have a role that is more important than normal. The current working model suggests that, with the help of its co-chaperone, Cdc37, it stabilizes mutant kinases. However, Hsp90, together with Cdc37, assists additional proteins that may be relevant in cancer. We demonstrate that the Hsp90-dependent stability of the transcription factor HIF-1 alpha and one of its downstream transcriptional targets, galectin-3, is important to maintain the elevated activity of the major oncogene KRAS. This is because galectin-3 stabilizes the MAPK-signaling complexes of K-Ras, which is called a nanocluster. In addition, we identified six drug-like small molecules that inhibit the Hsp90/Cdc37 protein interface at low micro molar concentrations. Given the co-occurrence of mutant KRAS with high HIF-1 alpha and high galectin-3 levels in pancreatic cancer, our results suggest an application of Hsp90 inhibitors in this cancer type. The ATP-competitive inhibitors of Hsp90 have been tested predominantly in kinase addicted cancers; however, they have had limited success. A mechanistic connection between Hsp90 and oncogenic K-Ras is not known. Here, we show that K-Ras selectivity is enabled by the loss of the K-Ras membrane nanocluster modulator galectin-3 downstream of the Hsp90 client HIF-1 alpha. This mechanism suggests a higher drug sensitivity in the context of KRAS mutant, HIF-1 alpha-high and/or Gal3-high cancer cells, such as those found, in particular, in pancreatic adenocarcinoma. The low toxicity of conglobatin further indicates a beneficial on-target toxicity profile for Hsp90/Cdc37 interface inhibitors. We therefore computationally screened >7 M compounds, and identified four novel small molecules with activities of 4 mu M-44 mu M in vitro. All of the compounds were K-Ras selective, and potently decreased the Hsp90 client protein levels without inducing the heat shock response. Moreover, they all inhibited the 2D proliferation of breast, pancreatic, and lung cancer cell lines. The most active compounds from each scaffold, furthermore, significantly blocked 3D spheroids and the growth of K-Ras-dependent microtumors. We foresee new opportunities for improved Hsp90/Cdc37 interface inhibitors in cancer and other aging-associated diseases.

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