tbuckley/cabot-search huggingface dataset:
Enhanced Application of 18F-FDG PET/CT in Bladder Cancer by Adding Early Dynamic Acquisition to a Standard Delayed PET Protocol
Authors: Hai-Jeon Yoon, Jang Yoo, Yemi Kim, Dong Hyeon Lee, Bom Sahn Kim
Journal: Clinical Nuclear Medicine (2017)

We investigated the value of early dynamic (ED) PET for the detection and characterization of bladder cancer.Fifty-two bladder cancer patients were prospectively enrolled. The study protocol was composed of ED, whole-body (WB, 60 minutes after injection), and additional delayed (AD, 120 minutes after injection) PET acquisition. Early dynamic PET was acquired for 10 minutes and reconstructed as 5 frames at 2-minute intervals. A focal radiotracer accumulation confined to the bladder wall was considered as PET positive and referred for further quantitative measurement. SUVmax on ED (SUVmax, SUVmax, SUVmax, SUVmax, and SUVmax for 5 frames), WB (SUVmax), and AD PET (SUVmax) were measured. PET results were correlated with bladder cancer pathology variables.The sensitivities of ED, WB, and AD PET for bladder cancer were 84.6%, 57.7%, and 61.2%, respectively. The sensitivity of ED PET was significantly higher than that of WB (P = 0.002) and AD PET (P = 0.008). On ED PET, SUVmax was significantly correlated with muscle invasiveness, histological grade, and pathological tumor size (P = 0.018, P = 0.030, and P = 0.030). On WB and AD PET, only pathological tumor size showed significant positive correlation with SUVmax and SUVmax (P = 0.043 and P = 0.007).Early dynamic PET can help to detect and characterize bladder cancer.
Abstract 5194: Focal radiation enhances paclitaxel therapy in a mouse model of triple negative breast cancer
Authors: Maryland Franklin, Thomas Dailey, Wilbur Leopold
Journal: Cancer Research (2017)

Abstract Triple negative breast cancer (TNBC) accounts for 15-20% of all breast cancers in the US. In general, patients have poorer prognosis and therapeutic intervention is more challenging due to insensitivity to hormonal and anti-HER2 therapies. Therapeutic options include chemotherapy and/or radiation (RT) treatment. In this work we utilized HCC70, a human TNBC cell line, grown subcutaneously in NSG mice. We investigated whether the combination of focal RT and paclitaxel would improve anti-tumor activity over paclitaxel alone. RT therapy has typically been delivered in low doses over long periods of time. More recently higher fractions of RT are being given in shorter time intervals. Utilizing the Small Animal Radiation Research Platform (SARRP; Xstrahl, Suwanee, GA) we compared a low dose (2.5Gy) fractionated regimen to a higher dose but less frequent regimen (8Gy, QDx3) either as monotherapy or in combination with paclitaxel (15mg/kg weekly). The total cumulative dose of radiation was 24-25Gy in both radiation regimens. Paclitaxel alone produced moderate activity with a 10 day tumor growth delay and no tumor regressions. Treatment with low dose RT resulted in tumor stasis for ≥68 days, but there were no tumor regressions or tumor free survivors (TFS). Treatment with 8Gy, produced a 75% incidence of confirmed partial regressions (PR) and a 25% incidence of complete regressions (CR) with no TFS. In this group we observed slightly more body weight loss (BWL), more frequent clinical signs, and more frequent need for food and water supplementation than with the fractionated RT regimen. Mean BWL was ~10% with a nadir around 8-10 days post first RT dose. BWL was recovered over the next 1-2 week period. The combination of low dose focal RT with paclitaxel produced activity similar to that with high dose radiation (50% PR, 40% CR, and 1 TFS). Treatment with paclitaxel plus 8Gy RT was highly efficacious, producing an 80% incidence of CRs, all of which remained tumor free at study day 108. The remaining mouse experienced tumor stasis in excess of 63 days. Thus, a higher dose of focal RT given in shorter intervals in combination with systemic paclitaxel resulted in the most efficacious therapeutic strategy but at the cost of increased BWL and clinical signs. Citation Format: Maryland Franklin, Thomas Dailey, Wilbur Leopold. Focal radiation enhances paclitaxel therapy in a mouse model of triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5194. doi:10.1158/1538-7445.AM2017-5194
Abstract 1799: CRM1 expression in pancreatic adenocarcinoma correlates with survivin expression and the proliferative activity
Authors: David M. Saulino, Pamela S. Younes, Jennifer M. Bailey, Mamoun Younes
Journal: Cancer Research (2017)

Abstract Introduction: CRM1 is a nuclear export chaperone that mediates the export of proteins essential to growth regulation and tumor suppression. Its overexpression in tumors was found to be associated with poor prognosis. Selective inhibitors of nuclear export are in phase I and II clinical trials for several tumor types. The expression of CRM1 in human pancreatic adenocarcinoma (PAC) and its relation to survivin expression and tumor proliferative activity is largely unknown. Experimental procedures: Sections of tissue microarray containing 77 formalin fixed and paraffin embedded PAC were stained by immunohistochemistry (IHC) for CRM1, survivin, and Cyclin A. Expression levels of CRM1 and survivin in tumor cells was determined using a quantitative digital image analysis solution (OTMIAS). The tumor proliferative activity was determined by measuring the S-phase fraction (SPF) in sections stained for Cyclin A, also using OTMIAS. Summary: Sixty-six of the 77 (86%) PAC showed at least some positive staining for CRM1, and 11 (14%) were completely negative. The mean CRM1 expression levels ranged from 0.3 to 53 units and the median from 0.3 to 45 units. There was significant positive correlation between the mean and median expression levels of CRM1 in tumor cells with the mean and median levels of survivin (p&amp;lt;0.001). Moreover, there was positive correlation between the mean and median CRM1 levels in tumor cells the SPF (p=0.005). Conclusions: CRM1 is expressed in a significant proportion of PAC, and increased CRM1 expression correlates with increased survivin expression and increased proliferative activity, suggesting that selective inhibitors of nuclear export may be effective against PAC. Note: This abstract was not presented at the meeting. Citation Format: David M. Saulino, Pamela S. Younes, Jennifer M. Bailey, Mamoun Younes. CRM1 expression in pancreatic adenocarcinoma correlates with survivin expression and the proliferative activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1799. doi:10.1158/1538-7445.AM2017-1799
Abstract LB-129: NDAT and P-bi-TAT formulations of tetraiodothyroacetic acid (tetrac) induce devascularization, necrosis and apoptosis in glioblastoma xenografts
Authors: Paul J. Davis, Sudha Thangirala, Stewart Sell, Aleck Hercbergs, Shaker A. Mousa
Journal: Cancer Research (2017)

Abstract Thyroid hormone as L-thyroxine (T4) has been reported to stimulate proliferation of multiple glioma cell lines in vitro and there is clinical evidence that medical induction of hypothyroidism slows growth of glioblastoma multiforme (GBM). The proliferative action of T4 on glioma cells is initiated at a cell surface receptor for thyroid hormone on the extracellular domain of integrin αvβ3. Tetraiodothyroacetic acid (tetrac) is a thyroid hormone (T4) derivative that blocks T4 action at αvβ3 and has anticancer and anti-angiogenic activity. Tetrac has been covalently bonded via a linker to a nanoparticle (Nanotetrac, Nano-diamino-tetrac, NDAT) or to two polyethylene glycol (PEG) molecules (P-bi-TAT) that increase the potency of tetrac and broadens the anticancer properties of the drug. In the present studies of U87 MG GBM xenografts, NDAT administered daily for 10 days s.c. as 1 mg tetrac equivalent/kg reduced tumor xenograft weight at animal sacrifice by 50%, compared to untreated control lesions (p &amp;lt;0.01). Histopathological analysis of tumors revealed a 95% loss of the vascularity of treated tumors compared to controls at 10 days (p &amp;lt;0.001). There was no intratumoral hemorrhage. There was extensive cellular necrosis in treated tumors attributable to devascularization. Cells not necrotic in treated xenografts exhibited apoptosis, so that 80% of cells were either necrotic or apoptotic, compared to controls (p &amp;lt;0.001). Induction of apoptosis in cancer cells is a well-described quality of NDAT. P-bi-TAT treatment resulted in similar results after 20 days of treatment, but included a 21-day off-treatment follow-up after therapy. Xenografts achieved a 95% volume loss in the off-treatment, follow-up phase (P &amp;lt; 0.001). In summary, systemic NDAT and P-bi-TAT have been shown to be effective by multiple mechanisms in treatment of GBM xenografts. Citation Format: Paul J. Davis, Sudha Thangirala, Stewart Sell, Aleck Hercbergs, Shaker A. Mousa. NDAT and P-bi-TAT formulations of tetraiodothyroacetic acid (tetrac) induce devascularization, necrosis and apoptosis in glioblastoma xenografts [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-129. doi:10.1158/1538-7445.AM2017-LB-129
Abstract 541: A comprehensive analysis delineating the immunotherapeutic terrain of cancer-related clinical trials
Authors: Cara M. Statz, Sara E. Patterson, Taofei Yin, Susan M. Mockus
Journal: Cancer Research (2017)

Abstract Technological innovations have facilitated a greater understanding of how the tumor microenvironment contributes to cancer, leading to rapid FDA approval of four immunotherapies. To assess how these therapies are being further investigated in combination with other therapies and in tumor types outside of the current FDA approval, we performed a comprehensive analysis of the curated clinical trials in the JAX Clinical Knowledgebase (JAX-CKB). In brief, clinical trials investigating Atezolizumab, Nivolumab, Pembrolizumab, and Ipilimumab, curated from clinicaltrials.gov, were queried in the JAX-CKB and then analyzed for comparison. Further analyses were executed to illustrate possible unmet needs within the field of cancer therapeutics. Of the four immunotherapies, Pembrolizumab was identified with the greatest number of clinical trials overall, with 305 compared to Atezolizumab, 79, Nivolumab, 183, and Ipilimumab, 126. Of these trials the number of trials investigating Pembrolizumab, Atezolizumab, Nivolumab, or Ipilimumab in combination with another therapy was higher than those investigating one of the four immunotherapies as a monotherapy. Phase II trials for both single therapy and combinatorial therapies were greater than both Phase I and Phase III for the same groups, regardless of therapy. On average, 12% ± 3.8% of the combined trials for all four drugs included any advanced solid tumor. Nivolumab combined with Ipilimumab demonstrated the greatest number of trials (61) investigating an immunotherapy in combination with another immunotherapy. Among those, 30 were Phase II trials, 16 were Phase I, and 14 were Phase III. Across five cancer indications (lung, pancreatic, ovarian, prostate, and colon), lung cancer was most commonly indicated in the trials, among all four drugs. Prostate was indicated in the least number of trials, with Ipilimumab ranking the highest (10). The recent success with immunotherapies has garnered significant interest in understanding how these therapies will perform in different tumor types and whether specific combinations will have a greater impact. Interrogation of the clinical trial terrain in the JAX-CKB provides a basis for determining additional investigations that might be warranted. Citation Format: Cara M. Statz, Sara E. Patterson, Taofei Yin, Susan M. Mockus. A comprehensive analysis delineating the immunotherapeutic terrain of cancer-related clinical trials [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 541. doi:10.1158/1538-7445.AM2017-541
Abstract 228: Identification of a novel biomarker to predict castration-resistant prostate cancer (CRPC) by the proteome analysis
Authors: Hiroji Uemura, Noriaki Arakawa, Yusuke Itoh, Takashi Kawahara, Yasuhide Miyoshi, Masahiro Yao, Shouhei Akiba, Norihisa Ohtake
Journal: Cancer Research (2017)

Abstract Prostate specific antigen (PSA) is useful for screening prostate cancer, while it has no reliable correlation with pathological malignancy of prostate cancer and is not a predictor for castration resistant prostate cancer (CRPC). In order to explore novel biomarkers to predict the development of CRPC, we performed proteomics from secreted proteins from human prostate cancer cells and identified the candidates of biomarker for CRPC. Materials and Methods: The proteins secreted from 6 prostate cancers in culture medium were analyzed and compared with 8 other cancer cells including renal and urothelial cancers using LTQ Orbitrap mass spectrometer. With the focus on high tissue specificity, the candidate biomarker proteins were then identified through analysis of gene expressions in proteins common to human prostate cancers by real time qPCR. Next, a system to measure the identified mouse monoclonal antibodies against the focused proteins was established. Finally, serum levels of these proteins from 33 patients with benign prostate hyperplasia (BPH), 31 with untreated prostate cancer (PCa) and 35 with CRPC, were measured. Results: The proteome analysis identified 12 candidates of secreted cell membrane proteins as new biomarkers. The proteome analysis indicated that not only matured GDF15, but pro-peptide as well as fragments (GDPP) are released from prostate cancer cells. Patients’ serum was analyzed for matured and pro-peptide GDF15 using ELISA and immunoprecipitation-MRM mass spectrometry. The results showed that the serum level of GDDP-1, one of the processing forms of GDPP, was significantly higher in CRPC than those in BPH and untreated PCa (P&amp;lt;0.01). ROC analysis also showed that the AUC of GDPP-1(0.86) was higher than that of matured GDF15 (0.76). When the cutoff value of GDPP-1 was set at 4.0 ng/mL, there was a significant difference of overall survival (OS) in CRPC patients between those with more than 4.0 ng/mL compared to less than 4.0 ng/mL of GDPP-1, whereas there was no significant difference of OS measurable by PSA in CRPC patients. These data suggest that GDPP-1 may be a novel biomarker for CRPC. Conclusion: GDPP-1 shows potential as a novel biomarker for CRPC. Citation Format: Hiroji Uemura, Noriaki Arakawa, Yusuke Itoh, Takashi Kawahara, Yasuhide Miyoshi, Masahiro Yao, Shouhei Akiba, Norihisa Ohtake. Identification of a novel biomarker to predict castration-resistant prostate cancer (CRPC) by the proteome analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 228. doi:10.1158/1538-7445.AM2017-228
Abstract 2043: Entinostat in combination with Cladribine synergistically induces apoptosis in multiple myeloma cells
Authors: Bolun Wang, Hui Lyu, Bolin Liu
Journal: Cancer Research (2017)

Abstract Cladribine (2-CDA) is a well-known purine nucleoside analog against lymphoproliferative disorders. Entinostat, a selective class I histone deacetylase (HDAC) inhibitor, exerts anti-tumor activity in various cancers, including multiple myeloma (MM). We sought to determine whether cladribine and entinostat may exhibit synergistic anti-proliferative/anti-survival effects on MM cells. Here we showed that, in cell growth MTS assays, either cladribine or entinostat alone inhibited cell proliferation in a dose-dependent manner. The combinations of cladribine and entinostat significantly induced growth inhibition in MM cells tested. The combination index (CI) curves showed a synergistic effect between cladribine and entinostat. An apoptotic-ELISA and western blot analyses of caspase-3 and PARP revealed that entinostat in combination with cladribine exhibited a much more potent activity than either agent alone to promote the MM cells undergoing apoptosis in a dose and time-dependent manner. Collectively, our data suggest that combinations of entinostat and cladribine possess synergistic anti-proliferative/anti-survival activity in MM cells. Regimens consisting of entinostat and cladribine may represent novel therapeutic strategies against MM. Citation Format: Bolun Wang, Hui Lyu, Bolin Liu. Entinostat in combination with Cladribine synergistically induces apoptosis in multiple myeloma cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2043. doi:10.1158/1538-7445.AM2017-2043
Royal college urges return to traditional structures for safer surgical care
Authors: Bryan Christie
Journal: BMJ (2017)

Basic changes to hospital structures and systems would help promote safer surgical care, a royal college has advised, after finding failings in the UK surgical workforce.1

A discussion paper published by the Royal College of Surgeons of Edinburgh identifies the re-establishment of the traditional team structure as one suggested improvement, including safe handovers and structured ward rounds. Another is the reintroduction of the …
Abstract 1030: Metabolic reprogramming caused by mutations of the Fbw7 ubiquitin ligase in colorectal cancer
Authors: Ryan J. Davis, Mehmet Gonen, David Hockenbery, Adam Margolin, Bruce E. Clurman
Journal: Cancer Research (2017)

Abstract Fbw7 is an evolutionary conserved F box protein that functions as a substrate adapter for the Skp1-Cullin 1-F box (SCF) E3 ubiquitin ligase complex. Fbw7 is also a tumor suppressor gene that is mutated in diverse human cancers. Many Fbw7 substrates are oncogenic transcription factors, including c-Myc, Notch, and Jun. Cancer-associated Fbw7 mutations diminish its ability to interact with substrates, which results in inappropriate oncoprotein accumulation. One of the significant challenges for understanding the consequences of Fbw7 mutations in tumors is that Fbw7 coordinately regulates approximately two dozen broadly-acting transcription factors. To address this problem, we used novel computational methods to analyze TCGA gene expression datasets to derive transcriptional signatures that could predict a tumor’s Fbw7 mutational status; these signatures were then analyzed for enrichment of genes involved in specific biological processes. We found that genes associated with mitochondrial function were highly predictive of Fbw7 mutations across several tumor types, suggesting that metabolic reprogramming is a crucial oncogenic consequence of Fbw7 mutations. We validated this prediction by creating isogenic colorectal cancer cells with normal or mutant Fbw7 alleles. We found that mitochondrial signature genes are elevated in Fbw7 mutant cells, which also exhibit increased oxidative metabolism. Moreover, metabolomic studies revealed deregulation of other metabolic pathways in Fbw7-mutant cells, including amino acid and nucleotide biosynthesis. These data suggest that metabolic vulnerabilities may represent novel therapeutic targets in Fbw7-associated cancers. Citation Format: Ryan J. Davis, Mehmet Gonen, David Hockenbery, Adam Margolin, Bruce E. Clurman. Metabolic reprogramming caused by mutations of the Fbw7 ubiquitin ligase in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1030. doi:10.1158/1538-7445.AM2017-1030
Abstract 4786: Integrated eoxme and transcriptome sequencing identifies a novel candidate for breast cancer
Authors: Kyung-Min Lee, Dong-Young Noh, Wonshik Han
Journal: Cancer Research (2017)

Abstract Many somatic mutations, structural alterations, and gene expression changes are causally implicated in oncogenesis and tumor progression, and as a result, affect clinical outcome. Although majority of breast cancer patients have benefits from therapeutics targeting tumor biology still many patients suffer from disease recurrence and metastasis. To find novel therapeutic target in breast cancer, here we examine the both whole exome and whole transcriptome of fresh-frozen primary breast cancer tissues from 120 patients whose clinical, pathological, and survival data are available. We identified 11,684 putative somatic mutations in 7,373 genes. We hypothesized that therapeutic target has to have recurrent mutation and gene expression at least more than average expression. With a cut-off of 3 or more mutations in each gene, 1,116 genes were selected. After the filtering of Volume&amp;gt;0.3, 696 genes were selected. Finally, 55 genes were selected which are druggable or potentially druggable using drug database. Interestingly, 18 of the 55 were genes involved in metabolism. Among them we further focused PSMD2 and interrogated their oncogenic roles, a subunit of the 19S regulatory complex of proteasomes, as a constituent of a signature is a candidate driven factor in breast cancer. PSMD2 is required for proliferation both in vitro and in vivo, as shRNA-mediated PSMD2 silencing attenuated tumor growth. Further, PMSD2 is sufficient to induce stem cell characteristics, as forced PSMD2 expression facilitated mammosphere formation and increased the CD44+ breast CSC-like population. Mechanistically, PSMD2 inhibition were associated with changes in epithelial-mesenchymal transition (EMT) phenotype. Knockdown of PSMD2 induced dramatic morphological changes, the typical spindle-like appearance cells were replaced with the round shape, like epithelial morphology. Moreover, treatment of TGF-β1, the main inducer of EMT, lead to increased expression of PSMD2. PSMD2 silencing up-regulated E-cadherin and down-regulated expression of vimentin, N-cadherin and snail, mesenchymal markers. Clinically, PSMD2 expression was elevated in basal-like TNBC (triple negative breast cancer), correlated with poor prognosis, insilico analysis on a dataset comprising over 2413 microarrays of the web application bc-GenExMiner. Altogether, our findings suggest that PSMD2 may be a good molecular target candidate and PSMD2 inhibitor may kills breast cancer stem cells and ameliorates poor prognosis of breast cancer. Citation Format: Kyung-Min Lee, Dong-Young Noh, Wonshik Han. Integrated eoxme and transcriptome sequencing identifies a novel candidate for breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4786. doi:10.1158/1538-7445.AM2017-4786