11 research outputs found
Investigation of endogenous p21 expression and its correlation to therapy resistance in high-risk neuroblastoma
No full textNeuroblastoma (NB) is a childhood cancer with a highly complex nature. High-risk NB patients undergo intensive treatment regimens that are often followed by long-term side effects. This, in addition to the emergence of resistant cancer cells, highlights a need for novel therapeutic targets and treatment strategies to improve outcome in NB. P21 is a cyclin-dependent kinase inhibitor considered to play a role in tumor resistance and aggressiveness due to its involvement in cell cycle and/or apoptosis. This project aimed to explore the expression of endogenous p21 in high-risk NB cell lines and whether p21 could be a therapeutic target for high-risk NB. Endogenous p21 levels were investigated using RT-qPCR and quantitative immunocytochemistry in eight high-risk NB cell lines. A small molecular inhibitor of p21, UC2288, was used in these cell lines to investigate tumour cell viability following p21 inhibition. In addition, combination treatment with UC2288 and the chemotherapy drug cisplatin was performed on resistant NB cell lines. Our results show variable expression of p21, where cell lines with high endogenous p21 expression showed sensitivity to single agent treatment with cisplatin or UC2288. Moreover, resistant NB cell lines showed lower endogenous p21 expression, however, combination treatment with UC2288 and cisplatin showed reduced viability, indicating sensitivity to combination treatment. This project highlights the potential of using p21 as a therapeutic target as well as a predictive biomarker in high-risk NB
(-)-OSU6162 in the treatment of fatigue and other sequelae after aneurysmal subarachnoid hemorrhage: a double-blind, randomized, placebo-controlled study
No full textOBJECTIVE
Fatigue after aneurysmal subarachnoid hemorrhage (aSAH) is common and usually long-lasting, and it has a considerable negative impact on health-related quality of life (HRQOL), social functioning, and the ability to return to work (RTW). No effective treatment exists. The dopaminergic regulator (−)-OSU6162 has shown promising results regarding the mitigation of fatigue in various neurological diseases, and therefore the authors aimed to investigate the efficacy of (−)-OSU6162 in alleviating fatigue and other sequelae after aSAH.
METHODS
A double-blind, randomized, placebo-controlled, single-center trial was performed in which 96 participants with post-aSAH fatigue were administered 30–60 mg/day of (−)-OSU6162 or placebo over a period of 12 weeks. Efficacy was assessed using the Fatigue Severity Scale (FSS), the Mental Fatigue Scale (MFS), the Beck Anxiety Inventory (BAI), the Beck Depression Inventory II (BDI-II), the SF-36 questionnaire, and a neuropsychological test battery. Assessments were performed at baseline, after 1, 4, 8, and 12 weeks of treatment, and at follow-up, 8 weeks after treatment.
RESULTS
The 96 participants with post-aSAH fatigue were randomized to treatment with (−)-OSU6162 (n = 49) or placebo (n = 47). The FSS, MFS, and BDI scores improved significantly in both groups after 12 weeks of treatment, whereas the BAI scores improved in the placebo group only. HRQOL improved significantly in the SF-36 domain “Vitality” in both groups. Neuropsychological test performances were within the normal range at baseline and not affected by treatment. The FSS score was distinctly improved in patients with complete RTW upon treatment with (−)-OSU6162. Concomitant use of antidepressants improved the efficacy of (−)-OSU6162 on the FSS score at week 1 beyond the placebo response, and correspondingly the use of beta- or calcium-channel blockers improved the (−)-OSU6162 efficacy beyond the placebo response in MFS scores at week 4 of treatment. There was a significant correlation between improvement in FSS, BAI, and BDI scores and the plasma concentration of (−)-OSU6162 at the dose of 60 mg/day. No serious adverse events were attributable to the treatment, but dizziness was reported more often in the (−)-OSU6162 group.
CONCLUSIONS
Fatigue and other sequelae after aSAH were similarly alleviated by treatment with (−)-OSU6162 and placebo. (−)-OSU6162 improved fatigue, as measured with the FSS score, significantly in patients with complete RTW. There seemed to be synergetic effects of (−)-OSU6162 and medications interfering with dopaminergic pathways that should be explored further. The strong placebo response may be exploited in developing nonpharmacological treatment programs for post-aSAH fatigue
Fit Minded College Edition-Podcasts: Feasibility of using a Facebook page to promote physical activity in female college students as compared to a website discussion board
No full textabstract: Background: The purpose of this study was to determine the feasibility of using Facebook as compared to a discussion board in an online, web-based intervention, Fit Minded College Edition-Podcasts (FMCEP), to improve physical activity and self-worth in female college students.
Methods: Participants (n=55) were randomly assigned to either a private Facebook group (FB) or the Fit Minded discussion board (DB) to participate in discussion of health and wellness related podcasts. FMCEP was a 6-week intervention guided by the self-determination theory (SDT) to target autonomy, relatedness and competence. Each week participants were instructed to complete three tasks: (1) listen to an assigned podcast, (2) complete a workbook assignment, and (3) participate in FB or DB online discussion. Participants completed assessments at baseline and post-intervention (6-weeks).
Results: Self-reported physical activity (p=0.032, η2= 0.193) and physical self-worth (p<0.001, η2=0.747) increased significantly over time, but no difference was seen between the groups for both physical activity (p=0.266, η2= 0.056) and physical self-worth (p=0.485, η2=0.024). Website use (measured by mean number of engagements per day, each week) declined across the 6-week intervention in the DB group but was consistent in the FB group.
Conclusion: These findings suggest web-based interventions, guided by SDT, can improve physical activity and physical self-worth among female college students, and the Facebook group may be more feasible and effective. Future studies are needed to optimize web-based physical activity interventions in college females
Hydrodynamic-sea ice couplings in the Barents Sea and their consequences for marine productivity
No full textNo abstracts are to be cited without prior reference to the author. During the past decades the Barents Sea experienced pronounced changes in hydrodynamic-, biogeochemical and higher trophic level conditions. The sea ice cover showed a long-term decreasing trend, which seems to have slightly stabilized during the recent years (Karaskov et al., 2013). Barents Sea temperature is characterized by significant multidecadal variability, which correlates to the Atlantic Multidecadal Oscillation AMO (e.g. Levitus, et al., 2009) and covariations with cyclone activity have been identified in earlier studies (e.g. Sorteberg and Kvingedal, 2006). These long-term variations in oceanographic conditions are accompanied by pronounced variations in the ecosystem with a.o. an increase in fish abundance and an expansion of key stocks northwards (e.g. Stiansen et al., 2009). Based on model simulations of contrasting years, it has earlier been suggested that sea ice retreat will result in increasing primary production in the Barents Sea (e.g. Wassmann et al., 2006). We investigate long-term variations in bottom up controls on the lower trophic level production in the Barents Sea by employing a regional physical-biological model for a multi-decadal simulation. We will illustrate the impact of climatic forcing on lower trophic level production in the Barents Sea and discuss the variations in dominant climatic drivers over the decades
Hepatic Progenitor Specification from Pluripotent Stem Cells Using a Defined Differentiation System
No full textLiver disease is an escalating global health issue. While liver transplantation is an effective mode of therapy, patient mortality has increased due to shortages in donor organ availability. Organ scarcity also affects the routine supply of human hepatocytes for basic research and the clinic. Therefore, the development of renewable sources of human liver progenitor cells is desirable and is the goal of this study. To be able to effectively generate and deploy human liver progenitors on a large scale, a reproducible hepatic progenitor differentiation system was developed that can be used with both human embryonic and induced pluripotent stem cell lines. This protocol aids experimental reproducibility between users in a range of cell cultureware formats. These are important advantages over current differentiation systems that will enhance the basic research and may pave the way towards clinical product development
Translational studies on antimetabolic therapies in paediatric oncology
No full textCure rates for paediatric and adult cancer patients have improved within the last decades. This can partly be explained by implementation of new technologies and methodologies such as the identification of new mutations after sequencing that can be directly targeted for treatment or the introduction of immunotherapy. However, there is an urgent need for improvement of survival particularly for patients with relapsed metastatic disease.More than 20 years ago, SAMHD1 was discovered and even though its key role in preventing viral HIV-1 infections was initially established, it was only later classified as the first deoxynucleoside triphosphate triphosphohydrolase that can remove the three phosphogroups of the dNTPs in a single reaction, which contributes to the dNTP pool homoeostasis by limiting potentially hazardous expansion of the intracellular dNTP pool. SAMHD1 is a homotetramer that is strictly regulated by the dNTP levels, with two allosteric sites (AS1 and AS2) and one catalytic site responsible for the dNTPase activity.Cancer cells are, among other hallmarks, characterized by loss of proliferation inhibition. It is therefore not surprising that in many cancer types, deregulation, or mutations of SAMHD1 have been reported that allow cells to circumvent dNTP shortage to permit further DNA replication. Many chemotherapeutic drugs target uncontrolled cancer proliferation. For example, a large group of these compounds are analogues of physiological nucleosides leading to inhibition of DNA replication. SAMHD1 has the capacity to use many of these analogues as substrates and through its dNTPase activity, it dephosphorylates them and prevents their incorporation into the nascent DNA chain. This can lead to treatment resistance effectively inactivating chemotherapy. One of these analogues frequently used in regimens against haematological malignancies is cytarabine. However, its active metabolite ara-CTP is a substrate for SAMHD1, hence SAMHD1- positive cancers might limit its cytotoxic efficacy. Therefore, SAMHD1 represents a promising therapeutic target, and its inhibition might enhance cytarabine efficacy.In the present thesis, we aimed to investigate whether there is an association between SAMHD1 expression and response to treatment with nucleoside analogues in two different haematological malignancies and whether SAMHD1 inhibition can improve current treatment protocols.In paper I, we performed a phenotypic screen of more than 33000 small molecules and discovered non-competitive inhibitors of ribonucleotide reductase to potentiate cytarabine in a SAMHD1-dependent manner. Inhibition of SAMHD1 activity towards ara- CTP occurred in an indirect manner as RNR inhibition led to dNTP ratio imbalances affecting SAMHD1 substrate specificity. As dCTP outcompeted dATP as dominant AS2 activator, SAMHD1 activity towards ara-CTP was gradually lost. Functionally, the RNR inhibitors hydroxyurea or gemcitabine acted synergistically with cytarabine, and sensitized cells to treatment in a SAMHD1-dependent manner, both in cell lines and in patient derived AML blasts. Furthermore, combination treatment prolonged survival in murine AML models. As a result, with this study we discovered already clinically available drugs that could act synergistically with cytarabine and improve treatment outcome. Hence, SAMHD1 can act as a biomarker for AML patients and combining cytarabine with RNR inhibitors might overcome SAMHD1-mediated resistance.In paper II, we showed that another nucleoside analogue, nelarabine, that is specifically cytotoxic against malignant T-cells was both an allosteric activator and a substrate for SAMHD1, thus limiting its cytotoxic efficacy. SAMHD1 depletion led to treatment sensitization and addition of hydroxyurea in SAMHD1 expressing cells, inhibited SAMHD1 catalytic activity and increased intracellular levels of the active metabolite ara-GTP. Finally, in T-ALL patient derived cells, addition of HU improved the efficacy of nelarabine treatment. All in all, we showed that SAMHD1 expression is a resistance factor in nelarabine treatment and inhibition with HU could have a potential clinical use.In paper III, based on our preclinical data we performed a small phase 1 clinical trial to validate the efficacy and safety of adding hydroxyurea to cytarabine-based treatment of AML patients. A total of nine patients were enrolled and they received a minimum of two cycles of treatment including daunorubicin, cytarabine and hydroxyurea. Analysis of blood mononuclear cells of patients showed that adding HU increased ara-CTP levels in vivo. All patients achieved complete remission (CR) without unexpected or unacceptable toxicities and MRD was negative in all eight patients that could be evaluated. Thus, CR of all patients combined with the pharmacokinetic studies, suggested that adding HU to alleviate the SAMHD1-based resistance barrier can be a rational strategy to improve treatment outcomes with cytarabine-based treatments,In paper IV, we investigated the correlation between SAMHD1 expression and its impact on induction and consolidation therapy of AML. In two independent patient cohorts (n=98 and n=124), SAMHD1 protein expression levels were assessed via immunohistochemistry. SAMHD1 was differentially expressed in AML blasts but was not expressed in several physiological hematopoietic cells. Based on their SAMHD1 expression, samples were allocated to three different groups and although no effect of SAMHD1 expression was evident during induction therapy, patients with low SAMHD1 levels at diagnosis had significantly prolonged event-free and overall survival rates. Therefore, evaluation of SAMHD1 levels can serve as a prognostic marker and might stratify personalized treatment strategies including SAMHD1 inhibitors.In summary, the results of this thesis show that SAMHD1 can be used as a prognostic biomarker for AML treated with cytarabine-based regimens and might stratify patients for enhanced treatment protocols adding the SAMHD1 inhibitor hydroxyurea to cytarabine. SAMHD1 might have a similar role for the nucleoside analogue nelarabine in Tlymphoblastic malignancies. Hence, SAMHD1 might constitute a universal resistance factor for a group of nucleoside analogues, irrespective of the specific oncological diagnosis. Targeting SAMHD1 thus promises to improve outcomes for a large group of cancers.List of scientific papersI. Sean G Rudd#, Nikolaos Tsesmetzis#, Kumar Sanjiv#, Cynthia Bj Paulin, Lakshmi Sandhow, Juliane Kutzner, Ida Hed Myrberg, Sarah S Bunten, Hanna Axelsson, Si Min Zhang, Azita Rasti, Petri Mäkelä, Si'Ana A Coggins, Sijia Tao, Sharda Suman, Rui M Branca, Georgios Mermelekas, Elisée Wiita, Sun Lee, Julian Walfridsson, Raymond F Schinazi, Baek Kim, Janne Lehtiö, Georgios Z Rassidakis, Katja Pokrovskaja Tamm, Ulrika Warpman-Berglund, Mats Heyman, Dan Grandér, Sören Lehmann, Thomas Lundbäck, Hong Qian, Jan-Inge Henter, Torsten Schaller, Thomas Helleday, Nikolas Herold. Ribonucleotide reductase inhibitors suppress SAMHD1 ara-CTPase activity enhancing cytarabine efficacy. EMBO Molecular Medicine. (2020) 12: e10419. # Denotes equal first author contribution. https://doi.org/10.15252/emmm.201910419 II. Nikolaos Tsesmetzis, Agnes L. Sorteberg, Sijia Tao, Ingrid Lilienthal, Hala Habash, Rakan Naboulsi, Magdelena Barbachowska, Miriam Yagüe-Capilla, Sean G. Rudd, Hong Qian, Georgios Z. Rassidakis, Leonie Saft, Joel Joelsson, Katja Prokovskaja Tamm, Raymond F Schinazi, Baek Kim, Torsten Schaller, David T Teachey, Nikolas Herold. SAMHD1 inhibition sensitises T-lymphoblastic acute leukaemia to nelarabine. [Manuscript]III. Martin Jädersten, Ingrid Lilienthal, Nikolaos Tsesmetzis, Magda Lourda, Sofia Bengtzén, Anna Bohlin, Cornelia Arnroth, Tom Erkers, Brinton Seashore-Ludlow, Géraldine Giraud, Giti S Barkhordar, Sijia Tao, Linda Fogelstrand, Leonie Saft, Päivi Östling, Raymond F Schinazi, Baek Kim, Torsten Schaller, Gunnar Juliusson, Stefan Deneberg, Sören Lehmann, Georgios Z Rassidakis, Martin Höglund, Jan-Inge Henter, Nikolas Herold. Targeting SAMHD1 with hydroxyurea in first-line cytarabine-based therapy of newly diagnosed acute myeloid leukaemia: Results from the HEAT-AML trial. Journal of Internal Medicine. 2022 Dec;292(6):925-940. https://doi.org/10.1111/joim.13553 IV. George Z Rassidakis#, Nikolas Herold#, Ida Hed Myrberg#, Nikolaos Tsesmetzis, Sean G Rudd, Jan-Inge Henter, Torsten Schaller, Siok-Bian Ng, Wee Joo Chng, Benedict Yan, Chin Hin Ng, Farhad Ravandi, Michael Andreeff, Hagop M Kantarjian, L Jeffrey Medeiros, Ioanna Xagoraris, Joseph D Khoury. Low-level expression of SAMHD1 in acute myeloid leukaemia (AML) blasts correlates with improved outcome upon consolidation chemotherapy with high-dose cytarabine-based regimens. Blood Cancer Journal. 2018 Oct 19;8(11):98. # Denotes equal first author contribution. https://doi.org/10.1038/s41408-018-0134-z </p
Unveiling the cellular heterogeneity of cancer metastasis [Elektronisk resurs]
No full textTechnologies within single-cell omics have revolutionized our ability to explore cellular heterogeneity with remarkable precision. Encompassing a range of methods that can analyze the molecular characteristics of individual cells, single- cell omics promise to provide valuable insights into the DNA, RNA, and protein levels at a single-cell resolution. In particular, single-cell RNA-sequencing (scRNA- seq) and spatial-omics stand out as pivotal tools providing insights into gene expression profiles, transcriptional states, and the spatial organization of cancer cells thereby providing leveraged to reveal the cellular heterogeneity of cancer cells and the tumour microenvironment (TME). Especially in the context of cancer metastasis, which remains a therapeutic enigma, the use of scRNA-seq and spatial-omics can be used to delineate the complex cellular landscapes of tumours and identify the interactions within the TME, providing crucial information for developing targeted therapies and improving patient outcomes. In Paper I we investigate clear cell renal cell carcinoma (ccRCC) using scRNA-seq to analyze primary tumours and their metastatic counterparts. A distinct transcriptional signature was identified in tumour cells that predict metastatic potential and patient survival and highlights the role of the TME, particularly vascular remodelling and an immunosuppressive microenvironment in promoting metastasis. Finally, we highlight potential therapeutic targets, such as the CXCL9/CXCL10-CXCR3 and CD70-CD27 axes, as potential targets for treatments. In Paper II, building on the insights of Paper I, we use scRNA-seq to analyze the TME of primary and bone metastatic ccRCC with a unique comparison to tumour involved-, benign- and healthy- bone marrow. Our findings highlight a population of tumour-associated mesenchymal stromal cells promoting epithelial-to- mesenchymal transition and bone remodelling as well as an immunosuppressive microenvironment with exhausted CD8+ T cells and tumour-associated macrophages that aids the metastatic process to bone. Finally, we show that tumour-associated mesenchymal cells exert their effects on bone remodelling via the RANK/RANKL/OPG signalling pathway, crucial for regulating bone resorption and remodelling in metastatic sites and suggest the pathway as a therapeutic target. In Paper III, we investigated spatially resolved chromosomal aberrations in high- risk neuroblastoma (NB) patient samples and cell lines using spatial omics. We describe the tumour clonal landscape in patient samples and the evolutionary trajectories of cells in response to chemotherapy in NB cell lines. We reveal that targeting both proliferation and DNA damage response pathways via a combination treatment with doxorubicin, gemcitabine, and an ATM inhibitor, can effectively reduce tumour growth and inhibit regrowth both in vitro and in vivo, highlighting the importance of addressing genetic and phenotypic heterogeneity in NB. Overall, this thesis provides novel insights into the intricate cellular landscape of primary and metastatic tumours as well as their surrounding microenvironments, revealing potential culprits of the metastatic process. Using high-resolution single-cell omics technologies, we enable the identification of key therapeutic targets and the development of more effective, personalized treatment strategies to combat cancer metastasis. List of scientific papers I. Adele M. Alchahin*, Shenglin Mei*, Ioanna Tsea, Taghreed Hirz, Youmna Kfoury, Douglas Dahl, Chin-Lee Wu, Alexander O. Subtelny, Shulin Wu, David T. Scadden, John H. Shin, Philip J. Saylor, David B. Sykes, Peter V. Kharchenko & Ninib Baryawno. A transcriptional metastatic signature predicts survival in clear cell renal cell carcinoma. Nat Commun 13, 5747 (2022). https://doi.org/10.1038/s41467-022-33375-w II. Shenglin Mei*, Adele M. Alchahin*, Ioanna Tsea*, Youmna Kfoury, Taghreed Hirz, Nathan Elias Jeffries, Ting Zhao, Yanxin Xu, Hanyu Zhang, Hirak Sarkar, Shulin Wu, Alexander O. Subtelny, John Inge Johnsen, Yida Zhang, Keyan Salari, Chin-Lee Wu, Mark A. Randolph, David T. Scadden, Douglas M. Dahl, John Shin, Peter V. Kharchenko, Philip J. Saylor, David B. Sykes & Ninib Baryawno. Single-cell analysis of immune and stroma cell remodelling in renal cell carcinoma primary tumours and bone metastatic lesions. Genome Med 16, 1 (2024). https://doi.org/10.1186/s13073-023-01272-6 III. Ioanna Tsea*, Xiaoze Li Wang*, Yuwei Lin, Sen Li, Agnes Luise Sorteberg, Maja Lundström, Alexandra Johannesson, Pranauti Panshikar, Eleonor O'Brien, Kristina Ihrmark Lundberg, Ingrid Lilienthal, Quentin Verron, Nikolas Herold, Susanne Fransson, Tommy Martinsson, Per Kogner, Jacob Stenman, Malin Wickström, John Inge Johnsen, Ninib Baryawno, Charlotte Stadler, Magda Bienko & Shahrzad Shirazi Fard. Spatially resolved chromosomal aberrations are sensitive towards targeted therapy against proliferation and DNA damage response. [Manuscript] *Equal contributio
Unveiling the cellular heterogeneity of cancer metastasis
No full textTechnologies within single-cell omics have revolutionized our ability to explore cellular heterogeneity with remarkable precision. Encompassing a range of methods that can analyze the molecular characteristics of individual cells, single- cell omics promise to provide valuable insights into the DNA, RNA, and protein levels at a single-cell resolution. In particular, single-cell RNA-sequencing (scRNA- seq) and spatial-omics stand out as pivotal tools providing insights into gene expression profiles, transcriptional states, and the spatial organization of cancer cells thereby providing leveraged to reveal the cellular heterogeneity of cancer cells and the tumour microenvironment (TME). Especially in the context of cancer metastasis, which remains a therapeutic enigma, the use of scRNA-seq and spatial-omics can be used to delineate the complex cellular landscapes of tumours and identify the interactions within the TME, providing crucial information for developing targeted therapies and improving patient outcomes.In Paper I we investigate clear cell renal cell carcinoma (ccRCC) using scRNA-seq to analyze primary tumours and their metastatic counterparts. A distinct transcriptional signature was identified in tumour cells that predict metastatic potential and patient survival and highlights the role of the TME, particularly vascular remodelling and an immunosuppressive microenvironment in promoting metastasis. Finally, we highlight potential therapeutic targets, such as the CXCL9/CXCL10-CXCR3 and CD70-CD27 axes, as potential targets for treatments.In Paper II, building on the insights of Paper I, we use scRNA-seq to analyze the TME of primary and bone metastatic ccRCC with a unique comparison to tumour involved-, benign- and healthy- bone marrow. Our findings highlight a population of tumour-associated mesenchymal stromal cells promoting epithelial-to- mesenchymal transition and bone remodelling as well as an immunosuppressive microenvironment with exhausted CD8+ T cells and tumour-associated macrophages that aids the metastatic process to bone. Finally, we show that tumour-associated mesenchymal cells exert their effects on bone remodelling via the RANK/RANKL/OPG signalling pathway, crucial for regulating bone resorption and remodelling in metastatic sites and suggest the pathway as a therapeutic target.In Paper III, we investigated spatially resolved chromosomal aberrations in high- risk neuroblastoma (NB) patient samples and cell lines using spatial omics. We describe the tumour clonal landscape in patient samples and the evolutionary trajectories of cells in response to chemotherapy in NB cell lines. We reveal that targeting both proliferation and DNA damage response pathways via a combination treatment with doxorubicin, gemcitabine, and an ATM inhibitor, can effectively reduce tumour growth and inhibit regrowth both in vitro and in vivo, highlighting the importance of addressing genetic and phenotypic heterogeneity in NB.Overall, this thesis provides novel insights into the intricate cellular landscape of primary and metastatic tumours as well as their surrounding microenvironments, revealing potential culprits of the metastatic process. Using high-resolution single-cell omics technologies, we enable the identification of key therapeutic targets and the development of more effective, personalized treatment strategies to combat cancer metastasis.List of scientific papersI. Adele M. Alchahin*, Shenglin Mei*, Ioanna Tsea, Taghreed Hirz, Youmna Kfoury, Douglas Dahl, Chin-Lee Wu, Alexander O. Subtelny, Shulin Wu, David T. Scadden, John H. Shin, Philip J. Saylor, David B. Sykes, Peter V. Kharchenko & Ninib Baryawno. A transcriptional metastatic signature predicts survival in clear cell renal cell carcinoma. Nat Commun 13, 5747 (2022). https://doi.org/10.1038/s41467-022-33375-wII. Shenglin Mei*, Adele M. Alchahin*, Ioanna Tsea*, Youmna Kfoury, Taghreed Hirz, Nathan Elias Jeffries, Ting Zhao, Yanxin Xu, Hanyu Zhang, Hirak Sarkar, Shulin Wu, Alexander O. Subtelny, John Inge Johnsen, Yida Zhang, Keyan Salari, Chin-Lee Wu, Mark A. Randolph, David T. Scadden, Douglas M. Dahl, John Shin, Peter V. Kharchenko, Philip J. Saylor, David B. Sykes & Ninib Baryawno. Single-cell analysis of immune and stroma cell remodelling in renal cell carcinoma primary tumours and bone metastatic lesions. Genome Med 16, 1 (2024). https://doi.org/10.1186/s13073-023-01272-6III. Ioanna Tsea*, Xiaoze Li Wang*, Yuwei Lin, Sen Li, Agnes Luise Sorteberg, Maja Lundström, Alexandra Johannesson, Pranauti Panshikar, Eleonor O'Brien, Kristina Ihrmark Lundberg, Ingrid Lilienthal, Quentin Verron, Nikolas Herold, Susanne Fransson, Tommy Martinsson, Per Kogner, Jacob Stenman, Malin Wickström, John Inge Johnsen, Ninib Baryawno, Charlotte Stadler, Magda Bienko & Shahrzad Shirazi Fard. Spatially resolved chromosomal aberrations are sensitive towards targeted therapy against proliferation and DNA damage response. [Manuscript] *Equal contribution</p
Iowa History and Culture : A Bibliography of Materials Published Between 1952 and 1986, 1989
No full textThis bibliography was compiled by two reference librarians, Patricia Dawson and David Hudson with the goal of making it easier of tracking down material on Iowa history and culture. This supplements the Iowa History Reference Guide published in 1952 by William Petersen
SOX11 is a novel binding partner and endogenous inhibitor of SAMHD1 ara-CTPase activity in mantle cell lymphoma.
No full textThe sterile alpha motif and histidine-aspartate (HD) domain containing protein 1 (SAMHD1) is a deoxynucleoside triphosphate triphosphohydrolase with ara-CTPase activity that confers cytarabine (ara-C) resistance in several haematological malignancies. Targeting SAMHD1's ara-CTPase activity has recently been demonstrated to enhance ara-C efficacy in acute myeloid leukemia. Here, we identify the transcription factor SRY-related HMG-box containing protein 11 (SOX11) as a novel direct binding partner and first known endogenous inhibitor of SAMHD1. SOX11 is aberrantly expressed not only in mantle cell lymphoma (MCL), but also in some Burkitt lymphomas. Co-immunoprecipitation of SOX11 followed by mass spectrometry in MCL cell lines identified SAMHD1 as the top SOX11 interaction partner which was validated by proximity ligation assay. In vitro, SAMHD1 bound to the HMG box of SOX11 with low-micromolar affinity. In situ crosslinking studies further indicated that SOX11-SAMHD1 binding resulted in a reduced tetramerization of SAMHD1. Functionally, expression of SOX11 inhibited SAMHD1 ara-CTPase activity in a dose-dependent manner resulting in ara-C sensitization in cell lines and in a SOX11-inducible mouse model of MCL. In SOX11-negative MCL, SOX11-mediated ara-CTPase inhibition could be mimicked by adding the recently identified SAMHD1 inhibitor hydroxyurea. Taken together, our results identify SOX11 as a novel SAMHD1 interaction partner and its first known endogenous inhibitor with potentially important implications for clinical therapy stratification.</p
