| 1. |
- Arlien-Søborg, Mai C., et al.
(författare)
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Acromegaly management in the nordic countries : a Delphi consensus survey
- 2024
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Ingår i: Clinical Endocrinology. - : John Wiley & Sons. - 0300-0664 .- 1365-2265.
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Acromegaly is associated with increased morbidity and mortality if left untreated. The therapeutic options include surgery, medical treatment, and radiotherapy. Several guidelines and recommendations on treatment algorithms and follow-up exist. However, not all recommendations are strictly evidence-based. To evaluate consensus on the treatment and follow-up of patients with acromegaly in the Nordic countries.Methods: A Delphi process was used to map the landscape of acromegaly management in Denmark, Sweden, Norway, Finland, and Iceland. An expert panel developed 37 statements on the treatment and follow-up of patients with acromegaly. Dedicated endocrinologists (n = 47) from the Nordic countries were invited to rate their extent of agreement with the statements, using a Likert-type scale (1−7). Consensus was defined as ≥80% of panelists rating their agreement as ≥5 or ≤3 on the Likert-type scale.Results: Consensus was reached in 41% (15/37) of the statements. Panelists agreed that pituitary surgery remains first line treatment. There was general agreement to recommend first-generation somatostatin analog (SSA) treatment after failed surgery and to consider repeat surgery. In addition, there was agreement to recommend combination therapy with first-generation SSA and pegvisomant as second- or third-line treatment. In more than 50% of the statements, consensus was not achieved. Considerable disagreement existed regarding pegvisomant monotherapy, and treatment with pasireotide and dopamine agonists.Conclusion: This consensus exploration study on the management of patients with acromegaly in the Nordic countries revealed a relatively large degree of disagreement among experts, which mirrors the complexity of the disease and the shortage of evidence-based data.
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| 2. |
- Beck, Halfdan, et al.
(författare)
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Regulators of cyclin-dependent kinases are crucial for maintaining genome integrity in S phase
- 2010
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Ingår i: Journal of Cell Biology. - : Rockefeller University Press. - 0021-9525 .- 1540-8140. ; 188:5, s. 629-638
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Tidskriftsartikel (refereegranskat)abstract
- Maintenance of genome integrity is of critical importance to cells. To identify key regulators of genomic integrity, we screened a human cell line with a kinome small interfering RNA library. WEE1, a major regulator of mitotic entry, and CHK1 were among the genes identified. Both kinases are important negative regulators of CDK1 and -2. Strikingly, WEE1 depletion rapidly induced DNA damage in S phase in newly replicated DNA, which was accompanied by a marked increase in single-stranded DNA. This DNA damage is dependent on CDK1 and -2 as well as the replication proteins MCM2 and CDT1 but not CDC25A. Conversely, DNA damage after CHK1 inhibition is highly dependent on CDC25A. Furthermore, the inferior proliferation of CHK1-depleted cells is improved substantially by codepletion of CDC25A. We conclude that the mitotic kinase WEE1 and CHK1 jointly maintain balanced cellular control of Cdk activity during normal DNA replication, which is crucial to prevent the generation of harmful DNA lesions during replication.
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| 3. |
- Cumming, Joshua, 1991-
(författare)
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The identification and functional evaluation of novel cancer-associated fibroblast subtypes and matrisome proteins in pancreatic cancer
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy characterized by an extensive desmoplastic stroma. The stroma is the site of intricate communication between malignant cells and their surrounding environment. This tissue microenvironment (TME) is populated by a heterogenous mixture of cell types and extracellular matrix proteins. Distinct stromal elements confer tumour-restraining or tumour-promoting influences on tumorigenesis. Characterizing stromal composition therefore represents an opportunity to identify candidates for therapeutic intervention to facilitate improved clinical outcomes. In this thesis we identify galectin-4 as an extracellular matrix protein which is upregulated in PDAC. We find that galectin-4 exerts a pro-tumorigenic influence in PDAC through promoting immune suppression, highlighting its potential as a novel therapeutic target. We subsequently provide a comprehensive characterization of mesenchymal cell diversity in PDAC including cancer-associated fibroblasts (CAFs) which represent one of the dominant stromal cellular components. We identify inflammatory CAF (iCAF) and myofibroblastic CAF (myCAF) subtypes in addition to defining a novel interferon-response CAF (ifCAF) subtype. In addition, we demonstrate that pancreatic stellate cells (PSCs) are capable of forming iCAFs, myCAFs and ifCAFs in response to tumour-derived signals using an organoid-based co-culture model and define biological pathways regulating CAF subtype formation. We then perform a high-throughput drug-screen using this co-culture model to identify compounds which can suppress tumour growth indirectly through modifying CAFs. One such compound is GNF-5 which we show can suppress cancer cell proliferation indirectly through manipulating CAF phenotype. Taken together, this thesis augments our understanding of the composition of the PDAC stroma and identifies potential therapeutic targets as well as developing an approach to discover drugs which yield a therapeutic benefit through targeting the PDAC stroma.
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| 4. |
- Hansen, Jacob B, et al.
(författare)
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Retinoblastoma protein functions as a molecular switch determining white versus brown adipocyte differentiation.
- 2004
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424. ; 101:12, s. 4112-7
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Tidskriftsartikel (refereegranskat)abstract
- Adipocyte precursor cells give raise to two major cell populations with different physiological roles: white and brown adipocytes. Here we demonstrate that the retinoblastoma protein (pRB) regulates white vs. brown adipocyte differentiation. Functional inactivation of pRB in wild-type mouse embryo fibroblasts (MEFs) and white preadipocytes by expression of simian virus 40 large T antigen results in the expression of the brown fat-specific uncoupling protein 1 (UCP-1) in the adipose state. Retinoblastoma gene-deficient (Rb-/-) MEFs and stem cells, but not the corresponding wild-type cells, differentiate into adipocytes with a gene expression pattern and mitochondria content resembling brown adipose tissue. pRB-deficient MEFs exhibit an increased expression of the Forkhead transcription factor Foxc2 and its target gene cAMP-dependent protein kinase regulatory subunit RIalpha, resulting in increased cAMP sensitivity. Suppression of cAMP-dependent protein kinase activity in Rb(-/-)MEFs blocked the brown adipocyte-like gene expression pattern without affecting differentiation per se. Immunohistochemical studies revealed that pRB is present in the nuclei of white but not brown adipocyte precursor cells at a developmental stage where both cell types begin to accumulate lipid and brown adipocytes express UCP-1. Furthermore, pRB rapidly undergoes phosphorylation upon cold-induced neodifferentiation and up-regulation of UCP-1 expression in brown adipose tissue. Finally, down-regulation of pRB expression accompanies transdifferentiation of white into brown adipocytes in response to beta3-adrenergic receptor agonist treatment. We propose that pRB acts as a molecular switch determining white vs. brown adipogenesis, suggesting a previously uncharacterized function of this key cell cycle regulator in adipocyte lineage commitment and differentiation.
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| 5. |
- Jacobsen, Mette, et al.
(författare)
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Characterisation of five candidate genes within the ETEC F4ab/ac candidate region in pigs
- 2011
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Ingår i: BMC Research Notes. - : Springer Science and Business Media LLC. - 1756-0500. ; 4
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundEnterotoxigenic Escherichia coli (ETEC) that express the F4ab and F4ac fimbriae is a major contributor to diarrhoea outbreaks in the pig breeding industry, infecting both newborn and weaned piglets. Some pigs are resistant to this infection, and susceptibility is inherited as a simple dominant Mendelian trait. Indentifying the genetics behind this trait will greatly benefit pig welfare as well as the pig breeding industry by providing an opportunity to select against genetically susceptible animals, thereby reducing the number of diarrhoea outbreaks. The trait has recently been mapped by haplotype sharing to a 2.5 Mb region on pig chromosome 13, a region containing 18 annotated genes.FindingsThe coding regions of five candidate genes for susceptibility to ETEC F4ab/ac infection (TFRC, ACK1, MUC20, MUC4 and KIAA0226), all located in the 2.5 Mb region, were investigated for the presence of possible causative mutations. A total of 34 polymorphisms were identified in either coding regions or their flanking introns. The genotyping data for two of those were found to perfectly match the genotypes at the ETEC F4ab/ac locus, a G to C polymorphism in intron 11 of TFRC and a C to T silent polymorphism in exon 22 of KIAA0226. Transcriptional profiles of the five genes were investigated in a porcine tissue panel including various intestinal tissues. All five genes were expressed in intestinal tissues at different levels but none of the genes were found differentially expressed between ETEC F4ab/ac resistant and ETEC F4ab/ac susceptible animals in any of the tested tissues.ConclusionsNone of the identified polymorphisms are obvious causative mutations for ETEC F4ab/ac susceptibility, as they have no impact on the level of the overall mRNA expression nor predicted to influence the composition of the amino acids composition. However, we cannot exclude that the five tested genes are bona fide candidate genes for susceptibility to ETEC F4ab/ac infection since the identified polymorphism might affect the translational apparatus, alternative splice forms may exist and post translational mechanisms might contribute to disease susceptibility.
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| 6. |
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| 7. |
- Jensen, Christian Fuglesang S., et al.
(författare)
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Microdissection Testicular Sperm Extraction Versus Multiple Needle-pass Percutaneous Testicular Sperm Aspiration in Men with Nonobstructive Azoospermia : A Randomized Clinical Trial
- 2022
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Ingår i: European Urology. - : Elsevier BV. - 0302-2838. ; 82:4, s. 377-384
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Tidskriftsartikel (refereegranskat)abstract
- Background: Surgical extraction of testicular spermatozoa is needed in men with nonobstructive azoospermia (NOA) who wish to become biological fathers. Based on available uncontrolled studies with unspecific patient selection, microdissection testicular sperm extraction (mTESE), having a sperm retrieval rate (SRR) of 50%, is considered the most efficient sperm retrieval procedure. However, no randomized clinical trials for comparison of different sperm retrieval procedures exist. Testicular sperm aspiration (TESA) is simple and commonly used, and we hypothesized that this technique using multiple needle passes would give similar SRRs to mTESE. Objective: To compare mTESE and multiple needle-pass TESA in men with NOA. Design, setting, and participants: A randomized clinical trial was performed between June 2017 and April 2021, with inclusion of 100 men with NOA from four centers in Denmark and Sweden. All participants received treatment at the same institution. Intervention: Participants were randomized to mTESE (n = 49) or multiple needle-pass TESA (n = 51). Patients with failed multiple needle-pass TESA proceeded directly to salvage mTESE. Outcome measurements and statistical analysis: The primary outcome was SRR. Secondary outcomes included complications and changes in reproductive hormones after surgery. Results and limitations: Spermatozoa were retrieved in 21/49 (43%) men after mTESE and in 11/51 (22%) men after multiple needle-pass TESA (rate difference –0.21; 95% confidence interval –0.39 to –0.03; p = 0.02). The combined SRR for multiple needle-pass TESA + salvage mTESE was 15/51 (29%). No complications occurred after multiple needle-pass TESA only, while 5/89 (6%) men having mTESE experienced a complication requiring surgical intervention. Overall, no statistically significant differences in reproductive hormones were observed between groups after 6 mo. Limitations include the low number of patients in secondary outcome data. Conclusions: In direct comparison, SRR was higher in mTESE than in multiple needle-pass TESA. Patient summary: Men with azoospermia need surgical extraction of spermatozoa to become biological fathers. In this randomized trial, we compared two surgeries (microdissection testicular sperm extraction [mTESE] and testicular sperm aspiration [TESA]) and found that mTESE gives a higher sperm retrieval rate than multiple needle-pass TESA.
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| 8. |
- Jensen, Christian Fuglesang S., et al.
(författare)
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Results from the first autologous grafting of adult human testis tissue : A case report
- 2024
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Ingår i: Human Reproduction. - 0268-1161. ; 39:2, s. 303-309
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Tidskriftsartikel (refereegranskat)abstract
- Fertility restoration using autologous testicular tissue transplantation is relevant for infertile men surviving from childhood cancer and, possibly, in men with absent or incomplete spermatogenesis resulting in the lack of spermatozoa in the ejaculate (non-obstructive azoospermia, NOA). Currently, testicular tissue from pre-pubertal boys extracted before treatment with gonadotoxic cancer therapy can be cryopreserved with good survival of spermatogonial stem cells. However, strategies for fertility restoration, after successful cancer treatment, are still experimental and no clinical methods have yet been developed. Similarly, no clinically available treatments can help men with NOA to become biological fathers after failed attempts of testicular surgical sperm retrieval. We present a case of a 31-year-old man with NOA who had three pieces of testis tissue (each ∼2 × 4 × 2 mm3) extracted and cryopreserved in relation to performing microdissection testicular sperm extraction (mTESE). Approximately 2 years after mTESE, the thawed tissue pieces were engrafted in surgically created pockets bilaterally under the scrotal skin. Follow-up was performed after 2, 4, and 6 months with assessment of reproductive hormones and ultrasound of the scrotum. After 6 months, all engrafted tissue was extracted and microscopically analyzed for the presence of spermatozoa. Furthermore, parts of the extracted tissue were analyzed histologically and by immunohistochemical analysis. Active blood flow in the engrafted tissue was demonstrated by doppler ultrasound after 6 months. No spermatozoa were found in the extracted tissue. Histological and immunohistochemical analysis demonstrated graft survival with intact clear tubules and normal cell organization. Sertoli cells and spermatocytes with normal morphology were located near the basement membrane. MAGE-A and VASA positive spermatogonia/spermatocytes were detected together with SOX9 positive Sertoli cells. Spermatocytes and/or Sertoli cells positive for γH2AX was also detected. In summary, following autologous grafting of frozen-thawed testis tissue under the scrotal skin in a man with NOA, we demonstrated graft survival after 6 months. No mature spermatozoa were detected; however, this is likely due to the pre-existing spermatogenic failure.
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| 9. |
- Jensen, Christian Fuglesang Skjødt, et al.
(författare)
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Sertoli and Germ Cells Within Atrophic Seminiferous Tubules of Men With Non-Obstructive Azoospermia
- 2022
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Ingår i: Frontiers in Endocrinology. - : Frontiers Media SA. - 1664-2392. ; 13
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Tidskriftsartikel (refereegranskat)abstract
- Background: Infertile men with non-obstructive azoospermia (NOA) have impaired spermatogenesis. Dilated and un-dilated atrophic seminiferous tubules are often present in the testes of these patients, with the highest likelihood of active spermatogenesis in the dilated tubules. Little is known about the un-dilated tubules, which in NOA patients constitute the majority. To advance therapeutic strategies for men with NOA who fail surgical sperm retrieval we aimed to characterize the spermatogonial stem cell microenvironment in atrophic un-dilated tubules. Methods: Testis biopsies approximately 3x3x3 mm3 were obtained from un-dilated areas from 34 patients. They were classified as hypospermatogenesis (HS) (n=5), maturation arrest (MA) (n=14), and Sertoli cell only (SCO) (n= 15). Testis samples from five fertile men were included as controls. Biopsies were used for histological analysis, RT-PCR analysis and immunofluorescence of germ and Sertoli cell markers. Results: Anti-Müllerian hormone mRNA and protein expression was increased in un-dilated tubules in all three NOA subtypes, compared to the control, showing an immature state of Sertoli cells (p<0.05). The GDNF mRNA expression was significantly increased in MA (P=0.0003). The BMP4 mRNA expression showed a significant increase in HS, MA, and SCO (P=0.02, P=0.0005, P=0.02, respectively). The thickness of the tubule wall was increased 2.2-fold in the SCO-NOA compared to the control (p<0.05). In germ cells, we found the DEAD-box helicase 4 (DDX4) and melanoma-associated antigen A4 (MAGE-A4) mRNA and protein expression reduced in NOA (MAGE-A: 46% decrease in HS, 53% decrease in MA, absent in SCO). In HS-NOA, the number of androgen receptor positive Sertoli cells was reduced 30% with a similar pattern in mRNA expression. The γH2AX expression was increased in SCO as compared to HS and MA. However, none of these differences reached statistical significance probably due to low number of samples. Conclusions: Sertoli cells were shown to be immature in un-dilated tubules of three NOA subtypes. The increased DNA damage in Sertoli cells and thicker tubule wall in SCO suggested a different mechanism for the absence of spermatogenesis from SCO to HS and MA. These results expand insight into the differences in un-dilated tubules from the different types of NOA patients.
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| 10. |
- Jørgensen, Claus, et al.
(författare)
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Global offshoring - knowledge journeys of three SMEs
- 2012
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Ingår i: International Journal of Globalisation and Small Business. - 1479-3067 .- 1479-3059. ; 4:3/4, s. 360-379
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Tidskriftsartikel (refereegranskat)abstract
- This paper analyses three small and medium sized enterprises (SMEs) in the textile industry involved in manufacturing, design sales and procurement offshoring. Adopting the knowledge-based theory of the firm andthe theory of knowledge integration leads to identification of ‘direction’ and ‘organisational routines’, which are important for the integration of knowledge between entities dispersed in time and space.The companies were followed over a period of four years, with annual interviews that show that, to differing degrees, offshoring of manufacturing becomes a journey for the companies involved to take back outsourced activities when it proves difficult to create the appropriate managerial direction and organisational routines. Travelling experts, virtual interaction through IT, and training of employees abroad are three central elements encountered. Changes in the globalised upstream setups challenge the companies’ manufacturing and innovative capabilities, since innovation,knowledge and activities prove less transferable and robust, leading to a need for re-integration in the restructured upstream sourcing setups.
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