Resolving the evolutionary paradox of genetic instability: a cost–benefit analysis of DNA repair in changing environments

AbstractLoss of genetic stability is a critical phenomenon in cancer and antibiotic resistance, and the prevailing dogma is that unstable cells survive because instability provides adaptive mutations. Challenging this view, we have argued that genetic instability arises because DNA repair may be a counterproductive strategy in mutagenic environments. This paradoxical relationship has also been confirmed by explicit experiments, but the underlying evolutionary principles remain controversial. This paper aims to clarify the issue, and presents a model that explains genetic instability from the basic perspective of molecular evolution and information processing

Does prolonged labor affect the birth experience and subsequent wish for cesarean section among first-time mothers? A quantitative and qualitative analysis of a survey from Norway

Background: Prolonged labor might contribute to a negative birth experience and influence first-time mothers’ attitudes towards future pregnancies. Previous studies have not adjusted for possible confounding factors, such as operative delivery, induction and postpartum hemorrhage. We aimed to determine the impact of prolonged labor on birth experience and a wish for cesarean section in subsequent pregnancies. Methods: A survey including the validated “Childbirth Experience Questionnaire”. First-time mothers giving birth between 2012 and 2014 at a Norwegian university hospital participated. Data from deliveries were collected. Regression analysis and thematic content analysis were performed. Results: 459 (71%) women responded. Women with labor duration > 12 h had significantly lower scores on two out of four sub-items of the questionnaire: own capacity (p = 0.040) and perceived safety (p = 0.023). Other factors contributing to a negative experience were: Cesarean section vs vaginal birth: own capacity (p = 0.001) and perceived safety (p = 0.007). Operative vaginal vs spontaneous birth: own capacity (p = 0.001), perceived safety (p < 0.001) and participation (p = 0.047). Induced vs spontaneous start: own capacity (p = 0.039) and participation (p = 0.050). Postpartum hemorrhage ≥500 ml vs < 500 ml: perceived safety (p = 0.002) and participation (p = 0.031). In the unadjusted analysis, prolonged labor more than doubled the risk (odds ratio (OR) 2.66, 95%CI 1.42–4.99) of a subsequent wish for cesarean delivery. However, when adjustments were made for mode of delivery and induction, emergency cesarean section (OR 8.86,95%CI 3.85–20.41) and operative vaginal delivery (OR 3.05, 95%CI 1.46–6.38) remained the only factors significantly increasing the probability of wanting a cesarean section in subsequent pregnancies. The written comments on prolonged labor (n = 46) indicated four main themes: – Difficulties gaining access to the labor ward. – Being left alone during the unexpectedly long, painful early stage of labor. – Stressful operative deliveries and worse pain than imagined. – Lack of support and too little or contradictory information from the staff. Conclusions: Women with prolonged labors are at risk of a negative birth experience. Prolonged labor per se did not predict a wish for a cesarean section in a subsequent pregnancy. However, women with long labors more often experience operative delivery, which is a risk factor of a later wish for a cesarean section.publishedVersio

Vaccination of patients with cutaneous melanoma with telomerase-specific peptides

Purpose: A phase I study was conducted to investigate the safety, tolerability, and immunological responses to vaccination with a combination of telomerase-derived peptides GV1001 (hTERT: 611-626) and p540 (hTERT: 540-548) using granulocyte-macrophage colony-stimulating factor (GM-CSF) or tuberculin as adjuvant in patients with cutaneous melanoma. Experimental design: Ten patients with melanoma stages UICC IIb-IV were vaccinated 8times intradermally with either 60 or 300nmole of GV1001 and p540 peptide using GM-CSF as adjuvant. A second group of patients received only 300nmole GV1001 in combination with tuberculin PPD23 injections. HLA typing was not used as an inclusion criterion. Peptide-specific immune responses were measured by delayed-type hypersensitivity (DTH) reactions, in vitro T cell proliferation assays, and cytotoxicity (51-Chromium release) assays for a selected number of clones subsequently generated. Results: Vaccination was well tolerated in all patients. Peptide-specific immune response measured by DTH reactions and in vitro response could be induced in a dose-dependent fashion in 7 of 10 patients. Cloned T cells from the vaccinated patients showed proliferative responses against both vaccine peptides GV1001 and p540. Furthermore, T cell clones were able to specifically lyse p540-pulsed T2 target cells and various pulsed and unpulsed tumor cell lines. Conclusion: These results demonstrate that immunity to hTERT can be generated safely and effectively in patients with advanced melanoma and therefore encourage further trial

Identification of nucleolar protein No55 as a tumour-associated autoantigen in patients with prostate cancer

Four different genes were identified by immunoscreening of a cDNA expression library from the human prostate cancer cell line DU145 with allogeneic sera from four prostate cancer patients. A cDNA encoding the nucleolar protein No55 was further analysed and shown to be expressed at the mRNA level in several normal tissues, including ovaries, pancreas and prostate and in human prostate cancer cell lines PC-3, PC-3m and LNCaP. By reverse transcriptase/polymerase chain reaction, expression of No55 was several-fold higher in two out of nine prostate cancer primary tumours and two out of two metastatic lesions, compared to normal prostate tissue. Antibodies to No55 were detected in sera from seven out of 47 prostate cancer patients but not in sera from 20 healthy male controls. Sequence analysis of the No55 open reading frame from normal and tumour tissues revealed no tumour-specific mutations. The No55 gene was located to chromosome 17q21, a region reported to be partially deleted in prostate cancer. Considering the immunogenicity of the No55 protein in the tumour host, the expression profile and chromosomal localization of the corresponding gene, studies evaluating No55 as a potential antigen for immunological studies in prostate cancer may be warranted. © 2000 Cancer Research Campaig