| 1. |
- Dongre, Mitesh, et al.
(författare)
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Flagella-mediated secretion of a novel Vibrio cholerae cytotoxin affecting both vertebrate and invertebrate hosts
- 2018
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Ingår i: Communications Biology. - : Springer Nature Publishing AG. - 2399-3642. ; 1
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Tidskriftsartikel (refereegranskat)abstract
- Using Caenorhabditis elegans as an infection host model for Vibrio cholerae predator interactions, we discovered a bacterial cytotoxin, MakA, whose function as a virulence factor relies on secretion via the flagellum channel in a proton motive force-dependent manner. The MakA protein is expressed from the polycistronic makDCBA (motility-associated killing factor) operon. Bacteria expressing makDCBA induced dramatic changes in intestinal morphology leading to a defecation defect, starvation and death in C. elegans. The Mak proteins also promoted V. cholerae colonization of the zebrafish gut causing lethal infection. A structural model of purified MakA at 1.9 Å resolution indicated similarities to members of a superfamily of bacterial toxins with unknown biological roles. Our findings reveal an unrecognized role for V. cholerae flagella in cytotoxin export that may contribute both to environmental spread of the bacteria by promoting survival and proliferation in encounters with predators, and to pathophysiological effects during infections.
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| 2. |
- Flodbring Larsson, Per, et al.
(författare)
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FcγRIIIa receptor interacts with androgen receptor and PIP5K1α to promote growth and metastasis of prostate cancer
- 2022
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Ingår i: Molecular Oncology. - : John Wiley & Sons. - 1574-7891 .- 1878-0261.
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Tidskriftsartikel (refereegranskat)abstract
- Low-affinity immunoglobulin gamma Fc region receptor III-A (FcγRIIIa) is a cell surface protein that belongs to a family of Fc receptors that facilitate the protective function of the immune system against pathogens. However, the role of FcγRIIIa in prostate cancer (PCa) progression remained unknown. In this study, we found that FcγRIIIa expression was present in PCa cells and its level was significantly higher in metastatic lesions than in primary tumors from the PCa cohort (P = 0.006). PCa patients with an elevated level of FcγRIIIa expression had poorer biochemical recurrence (BCR)-free survival compared with those with lower FcγRIIIa expression, suggesting that FcγRIIIa is of clinical importance in PCa. We demonstrated that overexpression of FcγRIIIa increased the proliferative ability of PCa cell line C4-2 cells, which was accompanied by the upregulation of androgen receptor (AR) and phosphatidylinositol-4-phosphate 5-kinase alpha (PIP5Kα), which are the key players in controlling PCa progression. Conversely, targeted inhibition of FcγRIIIa via siRNA-mediated knockdown or using its inhibitory antibody suppressed growth of xenograft PC-3 and PC-3M prostate tumors and reduced distant metastasis in xenograft mouse models. We further showed that elevated expression of AR enhanced FcγRIIIa expression, whereas inhibition of AR activity using enzalutamide led to a significant downregulation of FcγRIIIa protein expression. Similarly, inhibition of PIP5K1α decreased FcγRIIIa expression in PCa cells. FcγRIIIa physically interacted with PIP5K1α and AR via formation of protein-protein complexes, suggesting that FcγRIIIa is functionally associated with AR and PIP5K1α in PCa cells. Our study identified FcγRIIIa as an important factor in promoting PCa growth and invasion. Further, the elevated activation of FcγRIII and AR and PIP5K1α pathways may cooperatively promote PCa growth and invasion. Thus, FcγRIIIa may serve as a potential new target for improved treatment of metastatic and castration-resistant PCa.
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| 3. |
- Fuhrman, Barbara J, et al.
(författare)
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Association of the Age at Menarche with Site-Specific Cancer Risks in Pooled Data from Nine Cohorts
- 2021
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Ingår i: Cancer Research. - : American Association for Cancer Research (AACR). - 0008-5472 .- 1538-7445. ; 81:8, s. 2246-2255
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Tidskriftsartikel (refereegranskat)abstract
- The average age at menarche declined in European and U.S. populations during the 19th and 20th centuries. The timing of pubertal events may have broad implications for chronic disease risks in aging women. Here we tested for associations of recalled menarcheal age with risks of 19 cancers in 536,450 women [median age, 60 years (range, 31-39 years)] in nine prospective U.S. and European cohorts that enrolled participants from 1981 to 1998. Cox regression estimated multivariable-adjusted HRs and 95% confidence intervals (CI) for associations of the age at menarche with risk of each cancer in each cohort and random-effects meta-analysis was used to generate summary estimates for each cancer. Over a median 10 years of follow-up, 60,968 women were diagnosed with a first primary incident cancer. Inverse linear associations were observed for seven of 19 cancers studied. Each additional year in the age at menarche was associated with reduced risks of endometrial cancer (HR = 0.91; 95% CI, 0.89-0.94), liver cancer (HR = 0.92; 95% CI, 0.85-0.99), melanoma (HR = 0.95; 95% CI, 0.93-0.98), bladder cancer (HR = 0.96; 95% CI, 0.93-0.99), and cancers of the colon (HR = 0.97; 95% CI, 0.96-0.99), lung (HR = 0.98; 95% CI, 0.96-0.99), and breast (HR = 0.98; 95% CI, 0.93-0.99). All but one of these associations remained statistically significant following adjustment for baseline body mass index. Similarities in the observed associations between menarche and seven cancers suggest shared underlying causes rooted early in life. We propose as a testable hypothesis that early exposure to sex hormones increases mid-life cancer risks by altering functional capacities of stem cells with roles in systemic energy balance and tissue homeostasis. SIGNIFICANCE: Age at menarche is associated with risk for seven cancers in middle-aged women, and understanding the shared underlying causal pathways across these cancers may suggest new avenues for cancer prevention.
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| 4. |
- Genkinger, Jeanine M., et al.
(författare)
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A pooled analysis of 14 cohort studies of anthropometric factors and pancreatic cancer risk
- 2011
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Ingår i: International Journal of Cancer. - : WILEY. - 0020-7136 .- 1097-0215. ; 129:7, s. 1708-1717
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Tidskriftsartikel (refereegranskat)abstract
- Epidemiologic studies of pancreatic cancer risk have reported null or nonsignificant positive associations for obesity, while associations for height have been null. Waist and hip circumference have been evaluated infrequently. A pooled analysis of 14 cohort studies on 846,340 individuals was conducted; 2,135 individuals were diagnosed with pancreatic cancer during follow-up. Study-specific relative risks (RRs) and 95% confidence intervals (CIs) were calculated by Cox proportional hazards models, and then pooled using a random effects model. Compared to individuals with a body mass index (BMI) at baseline between 21-22.9 kg/m(2), pancreatic cancer risk was 47% higher (95% CI:23-75%) among obese (BMI >= 30 kg/m(2)) individuals. A positive association was observed for BMI in early adulthood (pooled multivariate [MV]RR = 1.30, 95%CI = 1.09-1.56 comparing BMI >= 25 kg/m(2) to a BMI between 21 and 22.9 kg/m(2)). Compared to individuals who were not overweight in early adulthood (BMI < 25 kg/m(2)) and not obese at baseline (BMI < 30 kg/m(2)), pancreatic cancer risk was 54% higher (95%CI = 24-93%) for those who were overweight in early adulthood and obese at baseline. We observed a 40% higher risk among individuals who had gained BMI >= 10 kg/m(2) between BMI at baseline and younger ages compared to individuals whose BMI remained stable. Results were either similar or slightly stronger among never smokers. A positive association was observed between waist to hip ratio (WHR) and pancreatic cancer risk (pooled MVRR = 1.35 comparing the highest versus lowest quartile, 95%CI = 1.03-1.78). BMI and WHR were positively associated with pancreatic cancer risk. Maintaining normal body weight may offer a feasible approach to reducing morbidity and mortality from pancreatic cancer.
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| 5. |
- Karlsson, Richard, et al.
(författare)
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Establishment of Prostate Tumor Growth and Metastasis Is Supported by Bone Marrow Cells and Is Mediated by PIP5K1α Lipid Kinase
- 2020
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Ingår i: Cancers. - : MDPI. - 2072-6694. ; 12:9
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Tidskriftsartikel (refereegranskat)abstract
- Cancer cells facilitate growth and metastasis by using multiple signals from the cancer-associated microenvironment. However, it remains poorly understood whether prostate cancer (PCa) cells may recruit and utilize bone marrow cells for their growth and survival. Furthermore, the regulatory mechanisms underlying interactions between PCa cells and bone marrow cells are obscure. In this study, we isolated bone marrow cells that mainly constituted populations that were positive for CD11b and Gr1 antigens from xenograft PC-3 tumor tissues from athymic nu/nu mice. We found that the tumor-infiltrated cells alone were unable to form tumor spheroids, even with increased amounts and time. By contrast, the tumor-infiltrated cells together with PCa cells formed large numbers of tumor spheroids compared with PCa cells alone. We further utilized xenograft athymic nu/nu mice bearing bone metastatic lesions. We demonstrated that PCa cells were unable to survive and give rise to colony-forming units (CFUs) in media that were used for hematopoietic cell colony-formation unit (CFU) assays. By contrast, PC-3M cells survived when bone marrow cells were present and gave rise to CFUs. Our results showed that PCa cells required bone marrow cells to support their growth and survival and establish bone metastasis in the host environment. We showed that PCa cells that were treated with either siRNA for PIP5K1α or its specific inhibitor, ISA-2011B, were unable to survive and produce tumor spheroids, together with bone marrow cells. Given that the elevated expression of PIP5K1α was specific for PCa cells and was associated with the induced expression of VEGF receptor 2 in PCa cells, our findings suggest that cancer cells may utilize PIP5K1α-mediated receptor signaling to recruit growth factors and ligands from the bone marrow-derived cells. Taken together, our study suggests a new mechanism that enables PCa cells to gain proliferative and invasive advantages within their associated host microenvironment. Therapeutic interventions using PIP5K1α inhibitors may not only inhibit tumor invasion and metastasis but also enhance the host immune system.
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| 6. |
- Kloss, Frank, et al.
(författare)
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The role of oxygen termination of nanocrystalline diamond on immobilisation of BMP-2 and subsequent bone formation
- 2008
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Ingår i: Biomaterials. - : Elsevier BV. - 0142-9612 .- 1878-5905. ; 29:16, s. 2433-2442
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Tidskriftsartikel (refereegranskat)abstract
- Medical implants are increasingly often inserted into bone of frail patients, who are advanced in years. Due to age, severe trauma or pathology-related bone changes, osseous healing at the implant site is frequently limited. We were able to demonstrate that coating of endosseous implants with nanocrystalline diamond (NCD) allows stable functionalization by means of physisorption with BMP-2. Strong physisorption was shown to be directly related to the unique properties of NCD, and BMP-2 in its active form interacted strongly when NCD was oxygen-terminated. The binding of the protein was monitored under physiological conditions by single molecule force spectroscopy, and the respective adsorption energies were further substantiated by force-field-calculations. Implant surfaces refined in such a manner yielded enhanced osseointegration in vivo, when inserted into sheep calvaria. Our results further suggest that this technical advancement can be readily applied in clinical therapies with regard to bone healing, since primary human mesenchymal stromal cells strongly activated the expression of osteogenic markers when being cultivated on NCD physisorbed with physiological amounts of BMP-2.
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| 7. |
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| 8. |
- Larsson, Elin, et al.
(författare)
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Nerve growth factor R221W responsible for insensitivity to pain is defectively processed and accumulates as proNGF
- 2009
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Ingår i: Neurobiology of Disease. - San Diego : Academic P.. - 0969-9961 .- 1095-953X. ; 33:2, s. 221-228
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Tidskriftsartikel (refereegranskat)abstract
- We have previously identified a homozygous missense (R221W) mutation in the NGFB gene in patients with loss of deep pain perception. NGF is important not only for the survival of sensory neurons but also for the sympathetic neurons and cholinergic neurons of the basal forebrain; however, it is the sensory neurons that are mainly affected in patients with mutant NGFB. In this report, we describe the effects of the mutation on the function of NGF protein and the molecular mechanisms that may underlie the pain insensitivity phenotype in these patients. We show that the mutant NGF has lost its ability to mediate differentiation of PC12 cells into a neuron-like phenotype. We also show that the inability of PC12 cells to differentiate is due to a markedly reduced secretion of mature R221W NGF. The R221W NGF is found mainly as proNGF, in contrast to wild-type NGF which is predominantly in the mature form in both undifferentiated and differentiated PC12 cells. The reduction in numbers of sensory fibers observed in the patients is therefore probably due to loss of trophic support as a result of drastically reduced secretion of NGF from the target organs. Taken together, these data show a clear decrease in the availability of mutant mature NGF and also an accumulation of proNGF in both neuronal and non-neuronal cells. The differential loss of NGF-dependent neurons in these patients, mainly affecting sensory neurons, may depend on differences in the roles of mature NGF and proNGF in different cells and tissues.
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| 9. |
- Larsson, Kjerstin, 1952-
(författare)
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Quality of Life and Coping with Ulcerative colitis and Crohn's disease
- 2007
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The aim of this thesis was to investigate health-related quality of life (HRQoL) and coping strategies for individuals with ulcerative colitis (UC) or Crohn’s disease (CD), and to study the effect of a group-based patient information on anxiety/depression and HRQoL. HRQoL and anxiety/depression were investigated (n=492) (Study I). In Study II, anxiety/depression, HRQoL, satisfaction with information and evaluation of the patient information were studied (n=49). Coping with disease activity was investigated in 166 patients reporting current exacerbation (Study III). Fifteen patients were interviewed about disease-related stress, how this is managed and the need of support from the health care (Study IV). Patients with UC reported better HRQoL and less anxiety/depression than did patients with CD during both remission and exacerbation. Satisfaction with information had increased at follow-up 6 months after patient information. The information and the possibility to discuss with lecturers and group members were valued as most important. No change was found in anxiety/depression or HRQoL at follow-up. Both problem-focused and emotion-focused strategies were employed to cope with disease activity, with no difference between patients with UC or CD. The urgent need of toilet availability and stress associated to social situations were the major disease-related stressors. This stress was managed by finding out the location of toilets, bringing toilet paper and extra underwear and emptying bowel before an activity. The patients wanted information and possibilities to talk to experienced staff and to other patients about how to live with the disease. This thesis shows that HRQoL for some patients with UC, and primarily for patients with CD, is impaired. Thus medical staff should be observant of the psychosocial well-being of patients with CD and also of patients with relapse. Methods to identify and support patients with anxiety/depression and poor HRQoL need to be developed. Interventions should target the patient’s specific problems and at appropriate times.
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| 10. |
- Larsson, Regina, et al.
(författare)
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Properties of electrolytes under pressure : PPG400 and PPG4000 complexed with LiCF3SO3
- 2003
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Ingår i: Electrochimica Acta. - : Elsevier. - 0013-4686 .- 1873-3859. ; 48:23, s. 3481-3489
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Tidskriftsartikel (refereegranskat)abstract
- High-pressure electrical conductivity measurements and differential thermal analysis have been carried out on poly(propylene glycol) (PPG) complexed with LiCF3SO3 (composition O:Li = 20:1) for pressures up to 1 GPa. The temperature and pressure dependence of the conductivity were analyzed in terms of the recently presented generalized Vogel equation as well as the well-known Vogel-Tamman-Fulcher equation, and the former provides an improved description of the data. The conductivity results show that the apparent activation volumes for the conduction process at room temperature and atmospheric pressure are 48 and 42 cm3 mol-1 for electrolyte based on PPG4000 (molecular weight = 4000) and PPG400, respectively. The temperature variation of the activation volume as well as the molecular weight dependence are described well within the free volume theory, which also provide a reasonable description of the pressure dependence. Differential thermal analysis was used to determine the pressure dependence of the glass transition temperature Tg for the electrolyte based on PPG400. The result for the initial slope dTg/dp = 140 K GPa-1 agrees well with that for the pure host PPG, but Tg is shifted up 6 K.
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