PTEN regulates glutamine flux to pyrimidine synthesis and sensitivity to dihydroorotate dehydrogenase inhibition

Metabolic changes induced by oncogenic drivers of cancer contribute to tumor growth and are attractive targets for cancer treatment. Here, we found that increased growth of PTEN mutant cells was dependent on glutamine flux through the de novo pyrimidine synthesis pathway, which created sensitivity to inhibition of dihydroorotate dehydrogenase, a rate limiting enzyme for pyrimidine ring synthesis. S-phase PTEN mutant cells showed increased numbers of replication forks, and inhibitors of dihydroorotate dehydrogenase led to chromosome breaks and cell death due to inadequate ATR activation and DNA damage at replication forks. Our findings indicate that enhanced glutamine flux generates vulnerability to dihydroorotate dehydrogenase inhibition, which then causes synthetic lethality in PTEN deficient cells due to inherent defects in ATR activation. Inhibition of dihydroorotate dehydrogenase could thus be a promising therapy for patients with PTEN mutant cancers

50 years experience with Dupuytren's contracture in the Erlangen University Hospital – A retrospective analysis of 2919 operated hands from 1956 to 2006

<p>Abstract</p> <p>Background</p> <p>Dupuytren's disease (DD) is a hand disorder mainly among the northern population. In contrast it is rare in the mediterranean population. Therefore typical habits and dietetic influences have been discussed as well as genetic predisposition. Still, since the first description by Dupuytren in 1834 only little is known about the etiology and pathogenesis of this disease. Some hints were found for a higher prevalence among people with diabetes, alcohol abuse or smoking. Also, intensive manual work or hand injuries have been discussed to have an influence on DD. To our knowledge this is the largest retrospectively evaluated series of symptomatic patients published to date. The study includes patients from the last 50 years. It was performed to show possible correlations between DD and typical risk factors such as diabetes, alcohol consumption, and smoking.</p> <p>Methods</p> <p>We retrospectively analysed all patient records with DD documented between 1956 and 2006 in the Surgical University Hospital in Erlangen. Data acquisition was conducted by reviewing the medical records from 1956 to 2006 including data from all patients who were surgically treated because of DD.</p> <p>Results</p> <p>We reviewed 2579 male and 340 female surgically treated patients with DD. More than 80% of the patients were between 40 and 70 years old. In 28.9% only the right hand was effected by DD, in 25.3% only the left hand and in 45.8% both hands. In 10.3% of all Patients suffered from Diabetes mellitus. Statistical analysis revealed no significant correlation between diabetes, alcoholism or smoking on the degree of DD in our patients.</p> <p>Conclusion</p> <p>Most data are consistent with previously published results from smaller, comparable retrospective studies with regard to right- or left handedness. We could not confirm a statistically significant correlation of DD with diabetes mellitus, severe alcohol consumption, heavy smoking or epilepsy and the stage of the disease as described in other studies. However, in the whole cohort of our operated patients during the last 50 years the prevalence of the above mentioned risk factors is slightly higher than in the normal population.</p

Golf in Singapore: a cultural perspective

There are currently 12 private golf clubs in Singapore with a total of 17 golf courses. On record, there are an estimated 36,000 golfers with a registered handicap in the database of the Singapore Golf Association (SGA). However, within the next 15 years, there will be a significant reduction in the number of golf courses left in Singapore. With the impending closure of more golf courses over the coming years, what impact will it potentially have on the future of golf in Singapore? The aim of this study is to explore the various subgroups within the golfing community in Singapore and gain insight into the current perceptions towards golf in Singapore. Using Ingham’s Criteria for sport as a theoretical framework for analysis, this study will mainly focus on the action- orientation and normative framework associated with the culture of golf in Singapore. Data collected for the study was obtained through the use of open-ended surveys. Semi-structured interviews were conducted with two officials from SGA and a third interview was also conducted with a participant from outside the SGA. With regards to action-orientation, social influence, personal enjoyment and health benefits were key motivators for participation in golf. With regards to the normative framework, findings suggest a mix of both positive and negative perceptions towards golf in SingaporeBachelor of Science (Sport Science and Management

Tumoral and immune heterogeneity in an anti-PD-1 responsive glioblastoma: a case study

Clinical benefit of immune checkpoint blockade in glioblastoma (GBM) is rare, and we hypothesize that tumor clonal evolution and the immune microenvironment are key determinants of response. Here, we present a detailed molecular characterization of the intratumoral and immune heterogeneity in an IDH wild-type, MGMT-negative GBM patient who plausibly benefited from anti-PD-1 therapy with an unusually long 25-mo overall survival time. We leveraged multiplex immunohistochemistry, RNA-seq, and whole-exome data from the primary tumor and three resected regions of recurrent disease to survey regional tumor-immune interactions, genomic instability, mutation burden, and expression profiles. We found significant regional heterogeneity in the neoantigenic and immune landscape, with a differential T-cell signature among recurrent sectors, a uniform loss of focal amplifications in EGFR, and a novel subclonal EGFR mutation. Comparisons with recently reported correlates of checkpoint blockade in GBM and with TCGA-GBM revealed appreciable intratumoral heterogeneity that may have contributed to a differential PD-1 blockade response