VE-PTP controls blood vessel development by balancing Tie-2 activity

Vascular endothelial protein tyrosine phosphatase (VE-PTP) is an endothelial-specific receptor-type tyrosine phosphatase that associates with Tie-2 and VE-cadherin. VE-PTP gene disruption leads to embryonic lethality, vascular remodeling defects, and enlargement of vascular structures in extraembryonic tissues. We show here that antibodies against the extracellular part of VE-PTP mimic the effects of VE-PTP gene disruption exemplified by vessel enlargement in allantois explants. These effects require the presence of the angiopoietin receptor Tie-2. Analyzing the mechanism we found that anti–VE-PTP antibodies trigger endocytosis and selectively affect Tie-2–associated, but not VE-cadherin–associated VE-PTP. Dissociation of VE-PTP triggers the activation of Tie-2, leading to enhanced endothelial cell proliferation and enlargement of vascular structures through activation of Erk1/2. Importantly, the antibody effect on vessel enlargement is also observed in newborn mice. We conclude that VE-PTP is required to balance Tie-2 activity and endothelial cell proliferation, thereby controlling blood vessel development and vessel size

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

The ACGME case log: General surgery resident experience in pediatric surgery

BackgroundGeneral surgery (GS) residents in ACGME programs log cases performed during their residency. We reviewed designated pediatric surgery (PS) cases to assess for changes in performed cases over time.MethodsThe ACGME case logs for graduating GS residents were reviewed from academic year (AY) 1989-1990 to 2010-2011 for designated pediatric cases. Overall and designated PS cases were analyzed. Data were combined into five blocks: Period I (AY1989-90 to AY1993-94), Period II (AY1994-95 to AY1998-99), Period III (AY1999-00 to AY2002-03), Period IV (AY2003-04 to AY2006-07), and Period V (AY2007-08 to AY2010-11). Periods IV and V were delineated by implementation of duty hour restrictions. Student t-tests compared averages among the time periods with significance at P &lt; .05.ResultsOverall GS case load remained relatively stable. Of total cases, PS cases accounted for 5.4% in Period I and 3.7% in Period V. Designated pediatric cases declined for each period from an average of 47.7 in Period I to 33.8 in Period V. These changes are due to a decline in hernia repairs, which account for half of cases. All other cases contributed only minimally to the pediatric cases. The only laparoscopic cases in the database were anti-reflux procedures, which increased over time.ConclusionsGS residents perform a diminishing number of designated PS cases. This decline occurred before the onset of work-hour restrictions. These changes have implications on the capabilities of the current graduating workforce. However, the case log does not reflect all cases trainees may be exposed to, so revision of this list is recommended

Impact of the COVID-19 pandemic on the practice of endocrine surgery.

BackgroundThis study investigates the impact of the COVID-19 pandemic on endocrine surgeons.MethodsA survey on the professional, educational, and clinical impact was sent to active and corresponding members of the American Association of Endocrine Surgeons (AAES) in September 2020. Chi-square and paired t-test were used for analysis.Results77 surgeons responded (14.8&nbsp;%). All reported suspension of elective surgeries; 37.7&nbsp;% were reassigned to other duties during this time. The median number of cases backlogged was 30 (IQR 15-50). Most surgeons reported decreased clinical volume (74.6&nbsp;%). The use of virtual platforms for clinical and educational purposes increased from pre-COVID-19 levels (all p&nbsp;&lt;&nbsp;0.001). Use of in-office procedures (p&nbsp;&lt;&nbsp;0.001) and length of observation prior to discharge for thyroid surgery (p&nbsp;&lt;&nbsp;0.05) decreased.ConclusionThe COVID-19 pandemic led to suspension of operations and decreased practice volume for endocrine surgeons. Surgeons increased use of virtual platforms, decreased in-office procedures, and decreased duration of observation for thyroid surgery in response

The ACGME case log: General surgery resident experience in pediatric surgery

BACKGROUND: General surgery (GS) residents in ACGME programs log cases performed during their residency. We reviewed designated pediatric surgery (PS) cases to assess for changes in performed cases over time. METHODS: The ACGME case logs for graduating GS residents were reviewed from academic year (AY) 1989–1990 to 2010–2011 for designated pediatric cases. Overall and designated PS cases were analyzed. Data were combined into five blocks: Period I (AY1989–90 to AY1993–94), Period II (AY1994–95 to AY1998–99), Period III (AY1999–00 to AY2002–03), Period IV (AY2003–04 to AY2006–07), and Period V (AY2007–08 to AY2010–11). Periods IV and V were delineated by implementation of duty hour restrictions. Student t-tests compared averages among the time periods with significance at P < .05. RESULTS: Overall GS case load remained relatively stable. Of total cases, PS cases accounted for 5.4% in Period I and 3.7% in Period V. Designated pediatric cases declined for each period from an average of 47.7 in Period I to 33.8 in Period V. These changes are due to a decline in hernia repairs, which account for half of cases. All other cases contributed only minimally to the pediatric cases. The only laparoscopic cases in the database were anti-reflux procedures, which increased over time. CONCLUSIONS: GS residents perform a diminishing number of designated PS cases. This decline occurred before the onset of work-hour restrictions. These changes have implications on the capabilities of the current graduating workforce. However, the case log does not reflect all cases trainees may be exposed to, so revision of this list is recommended