Targeting aberrant sialylation and fucosylation in prostate cancer cells using potent metabolic inhibitors

Aberrant glycosylation is a hallmark of cancer and is not just a consequence, but also a driver of a malignant phenotype. In prostate cancer, changes in fucosylated and sialylated glycans are common and this has important implications for tumor progression, metastasis, and immune evasion. Glycans hold huge translational potential and new therapies targeting tumor-associated glycans are currently being tested in clinical trials for several tumor types. Inhibitors targeting fucosylation and sialylation have been developed and show promise for cancer treatment, but translational development is hampered by safety issues related to systemic adverse effects. Recently, potent metabolic inhibitors of sialylation and fucosylation were designed that reach higher effective concentrations within the cell, thereby rendering them useful tools to study sialylation and fucosylation as potential candidates for therapeutic testing. Here, we investigated the effects of global metabolic inhibitors of fucosylation and sialylation in the context of prostate cancer progression. We find that these inhibitors effectively shut down the synthesis of sialylated and fucosylated glycans to remodel the prostate cancer glycome with only minor apparent side effects on other glycan types. Our results demonstrate that treatment with inhibitors targeting fucosylation or sialylation decreases prostate cancer cell growth and downregulates the expression of genes and proteins important in the trajectory of disease progression. We anticipate our findings will lead to the broader use of metabolic inhibitors to explore the role of fucosylated and sialylated glycans in prostate tumor pathology and may pave the way for the development of new therapies for prostate cancer

Monotonicity of Fitness Landscapes and Mutation Rate Control

A common view in evolutionary biology is that mutation rates are minimised. However, studies in combinatorial optimisation and search have shown a clear advantage of using variable mutation rates as a control parameter to optimise the performance of evolutionary algorithms. Much biological theory in this area is based on Ronald Fisher's work, who used Euclidean geometry to study the relation between mutation size and expected fitness of the offspring in infinite phenotypic spaces. Here we reconsider this theory based on the alternative geometry of discrete and finite spaces of DNA sequences. First, we consider the geometric case of fitness being isomorphic to distance from an optimum, and show how problems of optimal mutation rate control can be solved exactly or approximately depending on additional constraints of the problem. Then we consider the general case of fitness communicating only partial information about the distance. We define weak monotonicity of fitness landscapes and prove that this property holds in all landscapes that are continuous and open at the optimum. This theoretical result motivates our hypothesis that optimal mutation rate functions in such landscapes will increase when fitness decreases in some neighbourhood of an optimum, resembling the control functions derived in the geometric case. We test this hypothesis experimentally by analysing approximately optimal mutation rate control functions in 115 complete landscapes of binding scores between DNA sequences and transcription factors. Our findings support the hypothesis and find that the increase of mutation rate is more rapid in landscapes that are less monotonic (more rugged). We discuss the relevance of these findings to living organisms

Is the Rehbein procedure obsolete in the treatment of Hirschsprung’s disease?

Contains fulltext : 87916.pdf (publisher's version ) (Closed access)PURPOSE: After 25 years of practice and positive results of the Rehbein-procedure (RB) for children with Hirschsprung Disease (HD), we changed to the less invasive transanal endorectal pull through (TERPT). The aim of this study was to compare short- and mid-term complications of these two procedures in our patients with HD. METHODS: Retrospective data of 50 HD patients were analyzed. Of these patients, 25 underwent RB (2000-2006) and in 25 the TERPT was performed (2005-2009). Medical records were reviewed to score complications and outcomes. Differences were analyzed using Chi-Square and Mann-Whitney U tests. RESULTS: All RB patients (100%) were given a colostomy compared with four patients (16%) in the TERPT group (p < 0.001). The average age at surgery in the RB group was 191 days whereas this was 72 days in the TERPT group (p < 0.01). The mean length of time of surgery in the RB group (158 min) was not significantly different from that in the TERPT group (183 min). Ganglion cells were located in all specimens at the proximal end of the specimens. The median time to first feeding significantly decreased from 2 days (range 1-11) in the RB group to 1 day (range 1-3) in the TERPT group (p < 0.01). The median length of hospital stay decreased in the TERPT group (8 days) compared with the RB group (10 days) (p < 0.001). There was a significant reduction in postoperative obstructive symptoms during the first 6 months in the TERPT group (48%) compared with the RB group (84%) (p = 0.016). Postoperative enterocolitis decreased from 40% in the RB group to 24% in the TERPT group although this was not statistically significant. CONCLUSIONS: The introduction of TERPT reduced the need for colostomies; it shortened days to first feeding after surgery and reduced hospital stay. It also improved short-term outcome with less obstructive symptoms. We recommend TERPT surgery as a first choice in children with HD. we consider the RB now to be obsolete.1 november 201

Timing of glioblastoma surgery and patient outcomes: a multicenter cohort study.

BACKGROUND: The impact of time-to-surgery on clinical outcome for patients with glioblastoma has not been determined. Any delay in treatment is perceived as detrimental, but guidelines do not specify acceptable timings. In this study, we relate the time to glioblastoma surgery with the extent of resection and residual tumor volume, performance change, and survival, and we explore the identification of patients for urgent surgery. METHODS: Adults with first-time surgery in 2012–2013 treated by 12 neuro-oncological teams were included in this study. We defined time-to-surgery as the number of days between the diagnostic MR scan and surgery. The relation between time-to-surgery and patient and tumor characteristics was explored in time-to-event analysis and proportional hazard models. Outcome according to time-to-surgery was analyzed by volumetric measurements, changes in performance status, and survival analysis with patient and tumor characteristics as modifiers. RESULTS: Included were 1033 patients of whom 729 had a resection and 304 a biopsy. The overall median time-to-surgery was 13 days. Surgery was within 3 days for 235 (23%) patients, and within a month for 889 (86%). The median volumetric doubling time was 22 days. Lower performance status (hazard ratio [HR] 0.942, 95% confidence interval [CI] 0.893–0.994) and larger tumor volume (HR 1.012, 95% CI 1.010–1.014) were independently associated with a shorter time-to-surgery. Extent of resection, residual tumor volume, postoperative performance change, and overall survival were not associated with time-to-surgery. CONCLUSIONS: With current decision-making for urgent surgery in selected patients with glioblastoma and surgery typically within 1 month, we found equal extent of resection, residual tumor volume, performance status, and survival after longer times-to-surgery

Neutrophils in cancer: neutral no more

Neutrophils are indispensable antagonists of microbial infection and facilitators of wound healing. In the cancer setting, a newfound appreciation for neutrophils has come into view. The traditionally held belief that neutrophils are inert bystanders is being challenged by the recent literature. Emerging evidence indicates that tumours manipulate neutrophils, sometimes early in their differentiation process, to create diverse phenotypic and functional polarization states able to alter tumour behaviour. In this Review, we discuss the involvement of neutrophils in cancer initiation and progression, and their potential as clinical biomarkers and therapeutic targets

Cost-utility analysis of genetic screening in families of patients with germline MUTYH mutations

<p>Abstract</p> <p>Background</p> <p>MUTYH associated polyposis (MAP) is an autosomal recessive inherited disorder. Carriers of bi-allelic <it>MUTYH </it>germline mutations have a risk of approximately 60% to develop colorectal carcinoma (CRC). In the general population about 1.5% is a heterozygous <it>MUTYH </it>mutation carrier. Children of MAP patients have an increased risk of inheriting two <it>MUTYH </it>mutations compared to the general population, implicating an increased risk for developing CRC.</p> <p>Methods</p> <p>Using data from the literature and Dutch MAP patients (n = 40), we constructed a Markov model to perform a societal cost-utility analysis of genetic screening in MAP families. Genetic screening was done by testing the spouse first and, in case of a heterozygous spouse, also testing of the children.</p> <p>Results</p> <p>The cost of genetic screening of families of MAP patients, when compared to no genetic screening, was estimated at €25,000 per quality-adjusted life year (QALY). The presence of Fecal Occult Blood testing (FOBT) population screening only slightly increased this cost-utility ratio to €25,500 per QALY. For a MUTYH heterozygote index-patient, the ratio was €51,500 per QALY. The results of our analysis were sensitive to several of the parameters in the model, including the cost assumed for molecular genetic testing.</p> <p>Conclusion</p> <p>The costs per QALY of genetic screening in families of MAP patients are acceptable according to international standards. Therefore, genetic testing of spouses and/or children should be discussed with and offered to counselees.</p

Development of a questionnaire to assess sedentary time in older persons -- a comparative study using accelerometry

Background: There is currently no validated questionnaire available to assess total sedentary time in older adults. Most studies only used TV viewing time as an indicator of sedentary time. The first aim of our study was to investigate the self-reported time spent by older persons on a set of sedentary activities, and to compare this with objective sedentary time measured by accelerometry. The second aim was to determine what set of self-reported sedentary activities should be used to validly rank people's total sedentary time. Finally we tested the reliability of our newly developed questionnaire using the best performing set of sedentary activities. Methods. The study sample included 83 men and women aged 65-92 y, a random sample of Longitudinal Aging Study Amsterdam participants, who completed a questionnaire including ten sedentary activities and wore an Actigraph GT3X accelerometer for 8 days. Spearman correlation coefficients were calculated to examine the association between self-reported time and objective sedentary time. The test-retest reliability was calculated using the intraclass correlation coefficient (ICC). Results: Mean total self-reported sedentary time was 10.4 (SD 3.5) h/d and was not significantly different from mean total objective sedentary time (10.2 (1.2) h/d, p = 0.63). Total self-reported sedentary time on an average day (sum of ten activities) correlated moderately (Spearman's r = 0.35, p < 0.01) with total objective sedentary time. The correlation improved when using the sum of six activities (r = 0.46, p < 0.01), and was much higher than when using TV watching only (r = 0.22, p = 0.05). The test-retest reliability of the sum of six sedentary activities was 0.71 (95% CI 0.57-0.81). Conclusions: A questionnaire including six sedentary activities was moderately associated with accelerometry-derived sedentary time and can be used to reliably rank sedentary time in older persons. © 2013 Visser and Koster; licensee BioMed Central Ltd

Overdetection, overtreatment and costs in prostate-specific antigen screening for prostate cancer

Background:Prostate cancer screening with prostate-specific antigen (PSA) has shown to reduce prostate cancer mortality in the European Randomised study of Screening for Prostate Cancer (ERSPC) trial. Overdetection and overtreatment are substantial unfavourable side effects with consequent healthcare costs. In this study the effects of introducing widespread PSA screening is evaluated.Methods:The MISCAN model was used to simulate prostate cancer growth and detection in a simulated cohort of 100 000 men (European standard population) over 25 years. PSA screening from age 55 to 70 or 75, with 1, 2 and 4-year-intervals is simulated. Number of diagnoses, PSA tests, biopsies, treatments, deaths and corresponding costs for 100 000 men and for United Kingdom and United States are compared.Results:Without screening 2378 men per 100 000 were predicted to be diagnosed with prostate cancer compared with 4956 men after screening at 4-year intervals. By introducing screening, the costs would increase with 100% to \[euro]60 695 000. Overdetection is related to 39% of total costs (\[euro]23 669 000). Screening until age 75 is relatively most expensive because of the costs of overtreatment.Conclusion:Introduction of PSA screening will increase total healthcare costs for prostate cancer substantially, of which the actual screening costs will be a small part