Abstract Over 15 million colonoscopies were performed yearly in North America, during which biopsies were taken for pathological examination to identify abnormalities. Distinguishing between true- and pseudo-invasion in colon polyps is critical in treatment planning. Surgical resection of the colon is often the treatment option for true invasion, whereas observation is recommended for pseudo-invasion. The task of identifying true- vs pseudo-invasion, however, could be highly challenging. There is no specialized software tool for this task, and no well-annotated dataset is available. In our work, we obtained (only) 150 whole-slide images (WSIs) from the London Health Science Centre. We built three deep neural networks representing different magnifications in WSIs, mimicking the workflow of pathologists. We also built an online tool for pathologists to annotate WSIs to train our deep neural networks. Results showed that our novel system classifies tissue types with 95.3% accuracy and differentiates true- and pseudo-invasions with 83.9% accuracy. The system’s efficiency is comparable to an expert pathologist. Our system can also be easily adjusted to serve as a confirmatory or screening tool. Our system (available at http://ai4path.ca ) will lead to better, faster patient care and reduced healthcare costs.
This study used hand-collected Greenhouse gas (GHG) emissions data from the Environmental Protection Agency (EPA) and aimed to understand the determinants and incentives of GHG emissions reduction. It explored how companies’ financials, Chief Executive Officer (CEO) compensation, and corporate governance affected GHG emissions. Results showed that companies reporting GHG emissions were wide-spread among the 48 industries represented by two-digit Standard Industrial Classification (SIC) codes. Companies in the industries with high litigation risks and companies with higher profits tended to have lower GHG emissions. Larger property, plant, and equipment values contributed to higher GHG emissions. Furthermore, companies used compensation incentives to reduce the levels of GHG emissions as evidenced by the negative correlation between GHG emissions and executive compensation (including bonus, stock options and restricted stocks). Lastly, corporate governance affected GHG emission levels. Boards with directors of longer tenure and more female directors were more likely to curb GHG emissions. My study contributed to finding ways to incentivize companies to reduce GHG emissions.
5045 Background: SipT is an FDA-approved autologous cellular immunotherapy targeting Prostatic Acid Phosphatase (PAP) that improves survival in patients with mCRPC. Combining immunotherapies could provide opportunities to enhance efficacy. We performed a randomized phase II trial adding CTLA-4 blockade with Ipi following SipT treatment and assessed whether timing of this sequence could modify immune and/or clinical responses to this treatment. Methods: Fifty chemotherapy-naïve mCRPC pts were randomized to receive ipi (4 doses of 3mg/kg every 3 weeks) either immediately (n = 24) or 3 weeks (n = 26) following completion of sipT. Blood was collected at various time points of the study. Immune-related adverse events (irAE) were recorded. The primary endpoint was to determine the proportion of pts who achieved an antibody titer of ³1:400 to PA2024, the targeting cassette in SipT and/or PAP. Clinical response was defined as ³30% reduction in serum prostate specific antigen (PSA) compared to pre-treatment levels. Radiographic progression-free survival (rPFS) and overall survival (OS) were defined as from the date of randomization to the date of radiographic progression and the date of death, respectively, or last follow-up date. Luminex assays for anti-PAP and anti-PA2024 specific serum IgG and ELISpot for IFN-g production against PAP and PA2024 were used to assess antigen-specific B and T cells responses, respectively. Modulation of circulating immune cells was evaluated by CyTOF. Results: SipT + Ipi did not induce any unexpected irAEs. The timing of Ipi did not significantly alter the rates of clinical response, rPFS, OS, toxicity, nor antigen-specific B and T cell responses. Clinical responses were observed in 6 of 50 (12%) pts and were often durable (median 140 days, range 55-689 days). Pts experiencing irAEs were more likely to have a PSA response (P = 0.001). The median rPFS was 5.7 months (mos). The median OS was 31.9 mos. This treatment induced antibody and T cell immune responses irrespective of treatment arm. Single cell assessment bt CyTOF demonstrated that treatment induced CD4 and CD8 T cell activation that was more pronounced with the immediate schedule. Lower frequencies of CTLA-4 positive circulating T cells were associated with better clinical outcomes even at baseline. Lower frequencies of CTLA-4 positive T cells was associated with prior radiation therapy. Prior radiation treatment was associated with improved rPFS (6.5 vs. 3.9 mos, P = 0.004). Conclusions: These findings suggest that pre-existing immunity may help dictate responsiveness to Ipi and SipT combination immunotherapy in mCRPC pts. Prior radiation therapy seems to leave not only a lasting impression on the T cell compartment, but also can associate with improved clinical outcomes with subsequent immunotherapy. Clinical trial information: NCT01804465.
The World Health Organization (WHO) 2010 has classified GI neuroendocrine neoplasms into neuroendocrine tumor (NET) and high-grade neuroendocrine carcinoma (NEC). The genetic underpinnings of NEC are poorly understood. The aim of the study was to perform genomic profiling of NEC to better characterize this aggressive disease.We identified nine patients with colonic NEC between January 1, 2005 and June 30, 2013. Whole exome sequencing (WES) was performed on tumor DNA from two patients with ≥80% tumor cellularity and matched normal tissue available. Focused BRAF mutational analysis was performed on an additional seven patients via sanger sequencing of BRAF exons 11 and 15.We identified BRAF exon 15 mutations (c.A1781G: p.D594G and c.T1799A: p.V600E) by WES in two patients. Upon additional screening of seven colonic NECs for BRAF exon 11 and 15 mutations, we identified BRAF V600E mutations in two of seven specimens (29%). Overall, BRAF exon 15 mutations were present in four of nine colonic NECs.Colonic NEC is a rare but aggressive tumor with high frequency (44%) of BRAF mutations. Further investigation is warranted to ascertain the incidence of BRAF mutations in a larger population as BRAF inhibition may be a potential avenue of targeted treatment for these patients.
The increasing incidence of diabetes requires a better understanding of the pathogenesis of the clinical disease. Studies in prevention and treatment have been hampered by the single end-point of diagnosis of diabetes and hyperglycemia. The common pathology in both type 1 and type 2 diabetes is insufficient beta-cell mass to meet the metabolic demand. Unfortunately, current diagnostic methods rely on metabolic responses that do not accurately reflect true beta-cell mass. Recent advances in beta-cell imaging have utilized multiple modalities in experimental and clinical settings. While no gold-standard exists to measure beta-cell mass, modalities such as single photon emission computed tomography, optical and fluorescent imaging, magnetic resonance imaging, and positron emission tomography have been used with mixed success. Many of the methods are limited by the inability to translate to the clinical setting, poor discrimination between the exocrine and endocrine pancreas, or a poor measurement of beta-cell mass. However, promising new neurofunctional imaging approaches have emerged as improved measures of beta-cell mass. We review the current understanding of the pathogenesis and evaluation of diabetes, as well as experimental approaches to assessing beta-cell mass.
As the semiconductor industry continues to push the limits of integrated circuit fabrication, reliance on extreme ultraviolet lithography (EUVL) has increased. Additionally, it has become clear that new techniques and methods are needed to mitigate pattern defectivity and roughness at lithography and etch process and eliminate film-related defects. These approaches require improvements to the process chemicals and the lithography process equipment to achieve finer patterns. ESPERTTM (Enhanced Sensitivity develoPER TechnologyTM) technique has been developed and optimized to fulfil this novel development need. ESPERTTM has demonstrated a capability that can enhance the developing contrast between the EUV exposed and unexposed areas. This paper reviews 23 nm pitch line and space and sub-40 nm pitch pillars which were realized by optimized illuminators with 0.33 NA single exposure, and we will show how ESPERTTM helped improve the minimum critical dimension size, defectivity, roughness and electrical yield at the finer patterns.
<p>Supplementary Figure 1: Manual gating strategy A representative patient sample was used to illustrate the gating strategy on Cytobank to create pre-determined landmark nodes for scaffold analysis and clustering.</p>
