| 1. |
- Bonagas, Nadilly, et al.
(author)
-
Pharmacological targeting of MTHFD2 suppresses acute myeloid leukemia by inducing thymidine depletion and replication stress
- 2022
-
In: NATURE CANCER. - : Springer Science and Business Media LLC. - 2662-1347. ; 3:2, s. 156-
-
Journal article (peer-reviewed)abstract
- The folate metabolism enzyme MTHFD2 (methylenetetrahydrofolate dehydrogenase/cyclohydrolase) is consistently overexpressed in cancer but its roles are not fully characterized, and current candidate inhibitors have limited potency for clinical development. In the present study, we demonstrate a role for MTHFD2 in DNA replication and genomic stability in cancer cells, and perform a drug screen to identify potent and selective nanomolar MTHFD2 inhibitors; protein cocrystal structures demonstrated binding to the active site of MTHFD2 and target engagement. MTHFD2 inhibitors reduced replication fork speed and induced replication stress followed by S-phase arrest and apoptosis of acute myeloid leukemia cells in vitro and in vivo, with a therapeutic window spanning four orders of magnitude compared with nontumorigenic cells. Mechanistically, MTHFD2 inhibitors prevented thymidine production leading to misincorporation of uracil into DNA and replication stress. Overall, these results demonstrate a functional link between MTHFD2-dependent cancer metabolism and replication stress that can be exploited therapeutically with this new class of inhibitors. Helleday and colleagues describe a nanomolar MTHFD2 inhibitor that causes replication stress and DNA damage accumulation in cancer cells via thymidine depletion, demonstrating a potential therapeutic strategy in AML tumors in vivo.
|
|
| 2. |
- Ekeskär, Andreas, 1984-, et al.
(author)
-
Construction logistics in a multi-project context: coopetition among main contractors and the role of third-party logistics providers
- 2022
-
In: Construction Management and Economics. - : Taylor & Francis. - 0144-6193 .- 1466-433X. ; 40:1, s. 25-40
-
Journal article (peer-reviewed)abstract
- As a part of supply chain management (SCM) initiatives to improve performance and productivity in construction projects, the use of construction logistics setups (CLSs) operated by third-party logistics (TPL) providers have increased. CLSs are often used in complex multi-project contexts, such as urban development districts, where extensive coordination of actors, resources, and activities is needed. The purpose of this paper is twofold: to investigate how main contractors engage in horizontal relationships with each other when coordinating activities and resources within and across projects in a multi-project context, and to investigate what role a TPL provider assumes when engaging in relationships with main contractors in a multi-project context. The findings are based on a case study of an urban development district with a mandatory TPL-operated CLS, and we apply the industrial network approach. In this multi-project context, the main contractors engage in coopetitive relationships, coordinating activities and resources within and across projects. The TPL provider coordinates actors, resources, and activities, facilitating smoother production by managing logistics and mediating coopetitive relationships. This can be understood as a multi-project coordination role and extends the role SCM can play in construction. In that role, a TPL provider can minimise tensions between coopetitive actors across a multitude of horizontal relationships and projects.
|
|
| 3. |
- Granheimer, Klara, et al.
(author)
-
Adaptability in Public Procurement of Engineering Services Promoting Carbon Reduction: An Organizational Control Perspective
- 2022
-
In: Sustainability. - : MDPI AG. - 2071-1050. ; 14:10, s. 5958-5958
-
Journal article (peer-reviewed)abstract
- Many studies have emphasized the importance of engineering services and their adaptability to reduce carbon emissions in the construction sector. As public clients procure these services, selecting efficient (procurement-related) control modes is critical. However, studies of control modes and their effect on adaptability are scarce. The purpose of this study is to investigate how, through the choice of control modes, a public client may create incentives for service providers to deliver carbon reduction solutions in the construction phase. In this study, a procurement model and a classification model are developed, and a single case study of an engineering service contract aiming for carbon reduction is used to illustrate the models. The empirical data include 16 interviews with respondents from the 2 contract parties, i.e., the client and service provider. The findings show that it is important to create incentives for adaptability when procuring engineering services with the aim of reducing carbon emissions in the construction phase. The findings also highlight the importance of these incentives being created both in relation to the selection of service providers and to the responsibility between the contract parties. The models developed in the study may serve as important tools for both practitioners and researchers.
|
|
| 4. |
- Granheimer, Klara, 1989-
(author)
-
Public procurement of engineering services : Task characteristics, control modes and effects on adaptability
- 2022
-
Licentiate thesis (other academic/artistic)abstract
- Previous research has emphasized the importance of engineering services and adaptability in the early stages of construction projects. Public clients usually procure engineering services from private companies, which makes their procurement strategies important in creating incentives for adaptability and innovation for the service providers. Due to the high uncertainty and clients’ lack of understanding of the tasks they procure, the procurement of services is argued to be challenging – especially for public clients. Despite this, studies on the procurement of engineering services are scarce, as is research on the effects on adaptability. The purpose of this thesis, therefore, is to increase the understanding of organizational control in the public procurement of engineering services, by focusing on task characteristics, control modes and their effects on adaptability.A single case study of the Swedish Transport Administration was analyzed using the three models developed in the appended papers, i.e., the expanded control model, the procurement model for services and the classification model. The empirical data, consisting of interviews, observations and documents, were analyzed using visual mapping and flexible pattern matching.The findings illustrate that uncertainty is the task characteristic that differs between the early phase of construction (i.e., physical planning) and subsequent stages (i.e., tender document), while knowledge of the transformation process is the task characteristic that differs between a standard contract and an environmentally sustainable contract. Thus, when procuring engineering services including carbon reduction goals where new solutions are needed, new procurement strategies are necessary. In order to cope with the high uncertainty and low knowledge of the transformation process, social control is preferable. In addition, using social control will enhance the service providers’ willingness to adapt. These findings are important in the procurement of engineering services because uncertainty and the client’s understanding of the tasks are two of the main aspects that make engineering services difficult to procure.By combining task characteristics, control modes and their effects on adaptability, this thesis illustrates the importance of focusing on the entirety of organizational control. For example, even though process control and social control both incentivize the service provider to adapt to change, process control is less suitable for a public client when uncertainties are high. In addition, when choosing control modes related to the specification and reward system, it seems more efficient to provide the same incentives (i.e., process control may be combined with social control), whereas output control should not be combined with any other control mode. This shows the importance of combining the three variables and that the three main models of this thesis can be important tools. This knowledge and the models may therefore be useful to academics as well as practitioners. The results contribute to the scarce research on the procurement of engineering services for construction projects, as well as to the control literature.
|
|
| 5. |
- Granheimer, Klara, et al.
(author)
-
Public procurement of engineering services: the influence of task characteristics on organisational control
- 2022
-
In: Engineering Construction and Architectural Management. - : Emerald Group Publishing Limited. - 0969-9988 .- 1365-232X.
-
Journal article (peer-reviewed)abstract
- Prior research has emphasised the importance of the early phases of construction projects, as well as the difficulties of procuring engineering services – especially due to the uncertainties. Despite that, studies on the public procurement of engineering services are scarce. Although scholars have shown that uncertainty may affect the choice of control modes, the level of uncertainty that characterises services is not addressed by the two task characteristics: knowledge of the transformation process and output measurability. The purpose is to investigate organisational control in public procurement of engineering services.Design/methodology/approachThe existing control model was adjusted in this study by conceptually adding uncertainty as a third aspect to the two task characteristics. A single case study of the Swedish Transport Administration was used. The empirical data, comprising 14 interviews with managers from the client and engineering consulting companies, were analysed using flexible pattern matching and visual mapping approaches and then illustrated using the model.FindingsThe public client did not base its choice of control modes on uncertainty, but rather on the other two task characteristics. Consequently, the service providers argued that the chosen control modes reduced their creativity, increased their financial risks and caused unclear responsibilities. This study therefore shows that uncertainty is an important factor to consider in the choice of control modes, both from a theoretical perspective and from the service providers' point of view. The developed model may therefore be useful for researchers as well as practitioners.Originality/valueThis study is the first attempt to add uncertainty as a task characteristic when choosing control modes. The results contribute to the scarce control literature regarding the procurement of engineering services for construction projects and the procurement of other services with high uncertainty.
|
|
| 6. |
- Larsson, Johan, 1979-, et al.
(author)
-
Innovation outcomes and processes in infrastructure projects–a co mparative study of Design-Build and Design-Build-Maintenance contracts
- 2022
-
In: Construction Management and Economics. - : Informa UK Limited. - 0144-6193 .- 1466-433X. ; 40:2, s. 142-156
-
Journal article (peer-reviewed)abstract
- Innovation is often seen as essential for long-term development in the construction industry, but its actual outcomes and processes in construction projects require more attention. Many studies on procurement strategies and delivery systems have focussed on the public transport infrastructure sector, whereas most construction innovation scholars have addressed the innovation phenomenon in construction generally. Thus, the purpose of this study is to compare how two delivery systems, design-build (DB) and design-build-maintenance (DBM), influence project-level innovation. Findings are based on empirical data from a multiple case study of six infrastructure projects, three with DB contracts and three with DBM contracts, in which 12 innovations are identified, described, and compared. The findings show that various kinds of innovations in terms of outcomes and processes are implemented in infrastructure projects, and that the delivery system do effect both dimensions. Long maintenance responsibilities tend to spur contractors to engage in early exploration of sustainable solutions that could be of long-term benefit. The research contributes to procurement literature by exemplifying how delivery systems influence both the outcomes and processes of project-level innovations. It also increases our knowledge about construction innovation as a multi-dimensional phenomenon.
|
|
| 7. |
- Suur, Bianca E., et al.
(author)
-
Therapeutic potential of the Proprotein Convertase Subtilisin/Kexin family in vascular disease
- 2022
-
In: Frontiers in Pharmacology. - : Frontiers Media SA. - 1663-9812. ; 13
-
Journal article (peer-reviewed)abstract
- Proprotein convertase subtilisin/kexins (PCSKs) constitute a family of nine related proteases: PCSK1-7, MBTPS1, and PCSK9. Apart from PCSK9, little is known about PCSKs in cardiovascular disease. Here, we aimed to investigate the expression landscape and druggability potential of the entire PCSK family for CVD. We applied an integrative approach, combining genetic, transcriptomic and proteomic data from three vascular biobanks comprising carotid atherosclerosis, thoracic and abdominal aneurysms, with patient clinical parameters and immunohistochemistry of vascular biopsies. Apart from PCSK4, all PCSK family members lie in genetic regions containing variants associated with human cardiovascular traits. Transcriptomic analyses revealed that FURIN, PCSK5, MBTPS1 were downregulated, while PCSK6/7 were upregulated in plaques vs. control arteries. In abdominal aneurysms, FURIN, PCSK5, PCSK7, MBTPS1 were downregulated, while PCSK6 was enriched in diseased media. In thoracic aneurysms, only FURIN was significantly upregulated. Network analyses of the upstream and downstream pathways related to PCSKs were performed on the omics data from vascular biopsies, revealing mechanistic relationships between this protein family and disease. Cell type correlation analyses and immunohistochemistry showed that PCSK transcripts and protein levels parallel each other, except for PCSK9 where transcript was not detected, while protein was abundant in vascular biopsies. Correlations to clinical parameters revealed a positive association between FURIN plaque levels and serum LDL, while PCSK6 was negatively associated with Hb. PCSK5/6/7 were all positively associated with adverse cardiovascular events. Our results show that PCSK6 is abundant in plaques and abdominal aneurysms, while FURIN upregulation is characteristic for thoracic aneurysms. PCSK9 protein, but not the transcript, was present in vascular lesions, suggesting its accumulation from circulation. Integrating our results lead to the development of a novel 'molecular' 5D framework. Here, we conducted the first integrative study of the proprotein convertase family in this context. Our results using this translational pipeline, revealed primarily PCSK6, followed by PCSK5, PCSK7 and FURIN, as proprotein convertases with the highest novel therapeutic potential.
|
|
| 8. |
- Tano, Hanna
(author)
-
PNA and affinity protein tools for selective tumor targeting of radiopharmaceuticals
- 2022
-
Doctoral thesis (other academic/artistic)abstract
- Targeted radiotherapy of cancer intends to selectively deliver cytotoxic radionuclides to tumor cells. Affinity proteins of various kinds are explored for this task, and depending on the affinity protein used, different challenges arise. Full-length antibodies are typically associated with long serum half-life, leading to high systemic toxicity, while smaller affinity ligands such as engineered scaffold proteins, antibody fragments or peptides, usually demonstrate high radioactive uptake in kidneys. The smallest affinity ligands furthermore suffer from low therapeutic efficacy due to their fast wash-out, thus demanding frequent administrations of the radio-conjugate to reach a therapeutic effect. These issues were addressed in this thesis, where small affinity ligands (an Affibody molecule, a single domain antibody fragment and a peptide) have been explored as targeting agents for the cancer targets HER2, CD38 and GRPR, respectively. The Affibody molecule and the single domain antibody fragment were used in a pretargeting setting where high selective hybridization are used as recognition tags between peptide nucleic acid (PNA) strands on the tumor targeting primary agent and the radiolabelled secondary agent. In papers I and II, different sets of PNA hybridization probes were evaluated, in vitro and in vivo. In paper I, we demonstrate that the shortest tested secondary PNA probe (the 9-mer HP16) had the most favourable biodistribution profile with high tumor uptake along with the lowest kidney uptake. In paper II, we produced a set of shorter primary PNA probes, aiming for simplified production, and new sets of even shorter secondary PNA probes. A secondary 8-mer was identified as suitable for testing in cell assays and in vivo together with HER2-binding Affibody-PNA conjugates with varying length of the primary PNA probe, in order to determine if the smaller hydrodynamic range would further improve the biodistribution properties. In paper III, the Affibody-mediated PNA-based pretargeting strategy was evaluated as a monotherapy and as a co-treatment strategy with trastuzumab, to treat mice bearing HER2-positive tumors. Mice treated with the co-treatment strategy had significantly longer survival compared to other groups. In paper IV, the feasibility of using the PNA pretargeting strategy in combination with another affinity protein (a single domain antibody fragment) was evaluated in a CD38-expressing cell line. In paper V, the GRPR-binding peptide RM26 was conjugated to an albumin-binding domain, with the aim to achieve a high tumor uptake over time. The RM26-ABD conjugate did demonstrate good tumor uptake over time. However, the conjugate also demonstrated high kidney uptake, limiting its use as a therapeutic construct. In conclusion, the work presented in this thesis shows strategies for selective tumor targeting of radiopharmaceuticals using affinity proteins and PNA-mediated pretargeting.
|
|
| 9. |
- Yang, Muyi, et al.
(author)
-
Novel loss-of-function variant in DENND5A impedes melanosomal cargo transport and predisposes to familial cutaneous melanoma
- 2022
-
In: Genetics in Medicine. - : Elsevier BV. - 1098-3600 .- 1530-0366. ; 24:1, s. 157-169
-
Journal article (peer-reviewed)abstract
- Purpose: More than half of the familial cutaneous melanomas have unknown genetic predisposition. This study aims at characterizing a novel melanoma susceptibility gene. Methods: We performed exome and targeted sequencing in melanoma-prone families without any known melanoma susceptibility genes. We analyzed the expression of candidate gene DENND5A in melanoma samples in relation to pigmentation and UV signature. Functional studies were carried out using microscopic approaches and zebrafish model. Results: We identified a novel DENND5A truncating variant that segregated with melanoma in a Swedish family and 2 additional rare DENND5A variants, 1 of which segregated with the disease in an American family. We found that DENND5A is significantly enriched in pigmented melanoma tissue. Our functional studies show that loss of DENND5A function leads to decrease in melanin content in vitro and pigmentation defects in vivo. Mechanistically, harboring the truncating variant or being suppressed leads to DENND5A losing its interaction with SNX1 and its ability to transport the SNX1-associated vesicles from melanosomes. Consequently, untethered SNX1-premelanosome protein and redundant tyrosinase are redirected to lysosomal degradation by default, causing decrease in melanin content. Conclusion: Our findings provide evidence of a physiological role of DENND5A in the skin context and link its variants to melanoma susceptibility.
|
|
