tbuckley/cabot-search huggingface dataset:
Microarray-based tumor ploidy and its association with lymph node involvement in bladder cancer.
Authors: Karla Lindquist, Thomas Sanford, Maxwell V. Meng, Pamela Paris, Sima P. Porten
Journal: Journal of Clinical Oncology (2016)

e16012 Background: Abnormal ploidy (or aneuploidy), defined as more or less than two full sets of chromosomes per cell, is often observed in tumor tissues. Aneuploidy and lymph node involvement (LNI) have both previously been associated with poor outcomes in bladder cancer patients. However, the association between these two markers has not been well studied. Most ploidy studies have also focused on specific regions of the genome using flow cytometry or fluorescence in situ hybridization. In this study, we tested for associations between genome-wide ploidy measured by single nucleotide polymorphism (SNP) arrays and LNI in patients with urothelial carcinoma of the bladder using data from The Cancer Genome Atlas (TCGA). Methods: Patients were selected from the TCGA cohort if they had a cystectomy without neo-adjuvant chemotherapy and a pathology report available for LNI confirmation. Ploidy was estimated using the Affymetrix Genome-Wide Human SNP Array 6.0 (www.affymetrix.com) and ASCAT 2.4 software (Van Loo et al. 2010). Associations between ploidy and LNI were tested using logistic regression models adjusted for other clinical variables, and accuracy and discrimination were compared with and without ploidy. Results: 226 TCGA bladder cancer patients qualified for our study. 86 (38%) were positive for LNI. Aneuploid tumors (ploidy ≥ 3, 53%) had similar LNI rates and were grouped together. Compared to diploid tumors (ploidy = 2, 47%), aneuploid tumors had an increased odds of LNI (unadjusted odds ratio [OR] = 1.75, p = 0.045). After adjusting for age, gender, smoking status and family history, aneuploid tumors had an OR = 1.72 (p = 0.06). Aneuploidy maintained borderline significance even after adding pathologic T stage (OR = 1.75, p = 0.07). Including ploidy in addition to these other variables increased the accuracy of predicting LNI from 68% to 69%, and discrimination from c = 0.709 to c = 0.724 (p = 0.22). Conclusions: Using TCGA SNP microarray data, we detected a modest increase in odds of LNI for aneuploid versus diploid tumors. Based on these findings, patterns of aneuploidy in specific genomic regions will be identified and tested for association with LNI. This may be useful for predicting poor prognosis in bladder cancer patients.
Abstract 3727: Small molecule Mcl-1 inhibitors induce apoptosis and death in multiple cancer subtypes <i>in vitro</i>
Authors: John L. Sensintaffar, Allison Arnold, Craig Goodwin, Leah Hogdal, Subrata Shaw, James C. Tarr, Taekyu Lee, Edward Olejniczak, Stephen W. Fesik
Journal: Cancer Research (2016)

Abstract Mcl-1 is a member of the Bcl-2 family of proteins that play a major role in conferring resistance to apoptosis in cancer cells. Inhibiting Mcl-1 using peptides or RNAi has been shown to induce apoptosis in a broad array of cancer cell lines in numerous studies, making Mcl-1 a compelling target for anticancer therapy. We have discovered potent and selective small molecule Mcl-1 inhibitors that bind to the BH3 binding site of Mcl-1 with sub nanomolar affinities. These agents rapidly induced apoptosis in the Mcl-1 dependent NCI-H929 myeloma cell line, as demonstrated by mitochondrial membrane depolarization, caspase activation, and decreased viability. We measured the anti-proliferative activity of our compounds in cell lines from several cancer subtypes and found a broad spectrum of sensitivity to Mcl-1 inhibition. In cell lines that were resistant to Mcl-1 antagonists, combination with the dual Bcl-2/Bcl-xL inhibitor ABT-263 (navitoclax) greatly enhanced the activity of both compounds. These findings demonstrate that pharmacologic inhibition of Mcl-1 as a single agent or in combination with other cancer therapeutic agents is an effective way to modulate the intrinsic apoptotic pathway and promote cell death in cancer cells. Citation Format: John L. Sensintaffar, Allison Arnold, Craig Goodwin, Leah Hogdal, Subrata Shaw, James C. Tarr, Taekyu Lee, Edward Olejniczak, Stephen W. Fesik. Small molecule Mcl-1 inhibitors induce apoptosis and death in multiple cancer subtypes in vitro. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3727.
Biomarker Levels of Toxic Metals among Asian Populations in the United States: NHANES 2011–2012
Authors: Hiroshi Awata, Stephen Linder, Laura E. Mitchell, George L. Delclos
Journal: Environmental Health Perspectives (2016)

The Centers for Disease Control and Prevention (CDC) recently found that Asians have considerably higher biomarker levels of cadmium, lead, mercury, and arsenic than whites, blacks, Mexican Americans, and other Hispanics in the United States.Our goal was to further evaluate the higher metal biomarker levels among Asians.Biomarker data (blood cadmium, blood lead, blood mercury, urinary total arsenic, and urinary dimethylarsinic acic) from individuals ≥ 6 years of age were obtained from the 2011-2012 National Health and Nutrition Examination Survey (NHANES). We compared geometric mean levels of these five metal biomarkers in Asians with those of four other NHANES race/ethnic groups (white, black, Mexican American, and other Hispanic), and across three Asian subgroups (Chinese, Asian Indian, and other Asian). We also evaluated associations between biomarker levels and sociodemographic, physical, dietary, and behavioral covariates across the Asian subgroups.Asians had significantly higher levels of all five metal biomarkers than other race/ethnic groups (p < 0.05), regardless of sociodemographic, physical, dietary, behavioral, or geographic characteristics. We also found variations in biomarker levels across the Asian subgroups. In general, Asian Indians had lower levels than the other two Asian subgroups, except for blood lead. The following characteristics were found to be significant predictors of several biomarker levels: sex, age, education, birthplace, smoking, and fish consumption.Overall, the Asian group had the highest geometric mean biomarker levels for all of the five metal variables. Furthermore, we provided evidence that significant variations in the biomarker levels are present across the Asian subgroups in the United States. Citation: Awata H, Linder S, Mitchell LE, Delclos GL. 2017. Biomarker levels of toxic metals among Asian populations in the United States: NHANES 2011-2012. Environ Health Perspect 125:306-313; http://dx.doi.org/10.1289/EHP27.
P0850 : Percent of subjects experiencing liver morbidity over a lifetime horizon with abbvie 3D (ABT-450/ritonavir/ombitasvir and dasabuvir) versus no treatment
Authors: S.J. Johnson, H. Parisé, S. Virabhak, D.A. Misurski, T.R. Juday, J.C. Samp, S.E. Marx, S. Saab
Journal: Journal of Hepatology (2015)
Abstract 2190: Isolated cannabidiol from Cannabis sativa plant extracts inhibit growth and induce apoptosis in cervical cancer cells
Authors: Lesetja Raymond Motadi, sindiswa lukhelo.
Journal: Cancer Research (2016)

Abstract Cervical cancer remains a global health related issue among females of Sub-Saharan Africa, with over half a million new cases reported each year. Different therapeutic regimens have been suggested in various regions of Africa, however, over a quarter of a million women die of cervical cancer, annually. Therefore, it is important to search for new drugs through effective screening of medicinal plant extracts to identify lead anti-cervical cancer drugs. The aim of this study was to evaluate for the anti-growth effects of Cannabis sativa extracts and its isolate, cannabidiol on cervical cancer cell lines HeLa, SiHa, and ME-180. To determine for the presence of important constituents and evaluate for the anti-growth effects, phytochemical screening, MTT assay, cell growth analysis, flow cytometry, morphology analysis, Western blot, caspase 3/7 assay, and ATP measurement assay were conducted were conducted. Results obtained indicate that both plant extracts induced cell death at an IC50 of 50 - 100μg/ml and the Inhibition of cell growth was cell line dependent. Flow cytometry confirmed that, with or without cell cycle arrest, the type of induced cell death was apoptosis. Cannabis sativa extracts led to the up-regulation of apoptosis proteins (p53, Bax, caspase-3, and caspase-9) and the down regulation of anti-apoptosis proteins (Bcl-2 and RBBP6), signalling the execution of apoptosis. Apoptosis induction was further confirmed by morphological changes, an increase in Caspase 3/7 and a decrease in the ATP levels. In conclusion, this data implies Cannabis sativa crude extracts has the potential to inhibit growth and induce apoptosis in cervical cancer cell lines, which may be due to the presence of cannabidiol. Citation Format: Lesetja Raymond Motadi, sindiswa lukhelo. Isolated cannabidiol from Cannabis sativa plant extracts inhibit growth and induce apoptosis in cervical cancer cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2190.
P94 Prevalence and clinical significance of heparin induced thrombocytopaenia in patients transplanted for Budd Chiari syndrome
Authors: R Westbrook, D Orr, N Heaton, J Wendon, W Bernal, G Auzinger, J O'Grady, R Patel, A Paglucia, R Arya, G Mufti, M Heneghan
Journal: Gut (2010)

Introduction Budd Chiari Syndrome (BCS) is associated with an underlying pro-coagulant haematological disorder in up to 87% of cases. Following liver transplantation (LT), anticoagulation with heparin is commonplace in order to prevent thrombotic complications. Heparin induced thrombocytopaenia (HIT) is a rare but life threatening complication of heparin therapy, where the thrombotic risk is 30 times that of control populations. HIT associated thrombosis has a reported incidence of between 0.5 and 3% in patients on un-fractionated heparin. We reviewed all our patients with BCS who underwent LT to assess the incidence and clinical significance of HIT.

Results In total, 36 patients underwent LT for BCS between 1995 and 2008. An underlying pro-coagulant disorder was identified in 22 patients (myeloproliferative disorder (MPD) n=17, Protein C Deficiency n=2, Behcet's n=2 and lupus anti-coagulant n=1). One third of patients were thrombocytopenic (platelets <150 cells/μl) prior to LT. All patients had received un-fractionated heparin prior to and following LT. Thrombocytopaenia occurred in 85% of patients within the first 10 post operative days (median 49 cells/μl, range 7–292 cells/μl). A diagnosis of HIT was made when patients had a platelet count of <150 cells/μl and circulating PF4-heparin antibodies were identified. The overall incidence of HIT was 22% (8/36 patients), however in patients with a MPD the incidence was 41% (7/17). Furthermore a MPD was present in 7/8 (88%) patients who developed HIT vs 10/28 (36%) patients who did not develop HIT (p=0.016). An acute post operative thrombotic complication occurred in 50% (4/8) of patients who developed HIT compared to 4% (1/28) of patients that didn't (p=0.005). Bleeding complications occurred in 38% (3/8) of patients that developed HIT compared to 14% (4/28) who didn't (p=0.16). In hospital mortality was 38% in those patients that developed HIT compared to 7% in those who did not develop HIT (p=0.06). The fall in platelet count was not statistically different between those patients who did and did not develop HIT. In a cohort of patients (n=30) transplanted for hepatic artery thrombosis, who had also received un-fractionated heparin pre and post LT, HIT occurred in 1/30 (3%).

Conclusion We have demonstrated that HIT is a common complication of patients treated with un-fractionated heparin following LT for BCS. Moreover, the presence of an underlying MPD is a strong predisposing factor for its development. In patients that develop HIT the thrombosis rate, bleeding complication rate and pre-hospital discharge mortality are all increased. The diagnosis requires a high index of suspicion due to the frequency of thrombocytopaenia following LT. Due to the exceptionally high incidence of HIT in patients with MPD, these patients may benefit from standardised treatment with lepirudin following LT.
Changes in circulating and intratumoral T cell clonotypes in sipuleucel-T-treated prostate cancer patients.
Authors: Lawrence Fong, Jason Cham, Li Zhang, Todd DeVries, Jeff Pufnock, Debraj GuhaThakurta, Simon Letarte, David Hamm, James B. Trager, Nadeem A. Sheikh
Journal: Journal of Clinical Oncology (2015)

e16008 Background: Sipuleucel-T (sip-T) is an autologous cellular immunotherapy approved by the FDA and EMA for treatment of certain patients with asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer and is generated by culturing autologous peripheral blood mononuclear cells (PBMCs) with a fusion protein of prostatic acid phosphatase and granulocyte macrophage colony stimulating factor. We have shown that sip-T induces T cell infiltration into prostate tumor tissue. Methods: We used next-generation sequencing to examine changes in the T cell receptor (TCR) β-chain repertoire from PBMCs and post-treatment radical prostatectomy (RP) tissues from localized prostate cancer subjects (PCS, n = 5) participating in a neoadjuvant sip-T trial (NeoACT; NCT00715104). PBMCs were evaluated in PCS at week (wk) 0 (before sip-T treatment) and during treatment at wks 2 and 4. RP tissues from the same patients were also evaluated. Serial PBMCs from healthy subjects (HS, n = 3) as well as PBMCs and RP tissue from PCS not treated with sip-T (n = 5) were used as comparators. Sequence reads quantitated the absolute TCR frequencies using standardized clonotype determination algorithms. TCR sequence diversity and commonality across blood timepoints and RP tissue were assessed. Results: At baseline, the TCR repertoire in PBMCs from sip-T subjects was more diverse compared with HS PBMCs. With sip-T treatment, the TCR repertoire diversity, as measured by the number of unique TCR sequences, decreased over time (P < 0.001). In contrast, HS TCR diversity remained unchanged over the same time period. Sip-T increased TCR diversity in prostate tissue compared with untreated PCS tissue (P = 0.04). Moreover, T cell clonotypes present in both RP tissue and PBMCs increased after sip-T (wks 2 and 4) compared with baseline (wk 0) PBMCs (P = 0.01). Conclusions: Changes in TCR sequence frequency and diversity demonstrate that sip-T treatment narrows the TCR repertoire in the blood while increasing the TCR diversity in prostate tissue. The increase in common TCR sequences between RP tissue and blood after sip-T treatment supports a treatment-induced T cell migration into the prostate tissue. Clinical trial information: NCT00715104.
Abstract 2019: SOX2 silencing upregulates CDKN1A and suppresses growth of lung squamous cell carcinoma
Authors: Takuya Fukazawa, Tomokoki Yamatsuji, Munenori Takaoka, Etsuko Yokota, Minoru Haisa, Naomasa Ishida, Masakazu Yoshida, Noriko Miyake, Nagio Takigawa, Yutaka Maeda, Yoshio Naomoto
Journal: Cancer Research (2016)

Abstract SOX2 is a master pluripotency controller that was recently identified as a novel major oncogene, recurrently amplified and activated in lung squamous cell carcinoma (lung SCC). Then, transcriptional downstream targets of SOX2 have been actively investigated; however, such targets are often cell line specific. Here, in order to identify highly consensus SOX2 downstream genes in lung SCC cells, we used RNA-seq data from 178 lung SCC specimens (containing tumor and tumor-associated cells) and analyzed the correlation between SOX2 and previously-reported SOX2-controlled genes in lung SCC. In addition, we used another RNA-seq dataset from 105 non-small cell lung cancer cell lines (NSCLC; including lung SCC cells) and again analyzed the correlation between SOX2 and the reported SOX2-controlled genes in the NSCLC cell lines (no tumor-associated cells). We combined the two analyses and identified genes commonly correlated with SOX2 in both datasets. Among the 99 genes reported as SOX2 downstream and/or correlated genes, we found 4 negatively-correlated (e.g., CDKN1A) and 11 positively-correlated genes with SOX2. We used biological studies to demonstrate that CDKN1A was suppressed by SOX2 in lung SCC cells. G1 cell cycle arrest induced by SOX2 siRNA was rescued by CDKN1A siRNA. These results indicate that the tumorigenic effect of SOX2 in lung SCC cells is mediated in part by suppression of CDKN1A. Citation Format: Takuya Fukazawa, Tomokoki Yamatsuji, Munenori Takaoka, Etsuko Yokota, Minoru Haisa, Naomasa Ishida, Masakazu Yoshida, Noriko Miyake, Nagio Takigawa, Yutaka Maeda, Yoshio Naomoto. SOX2 silencing upregulates CDKN1A and suppresses growth of lung squamous cell carcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2019.
Abstract SY18-02: Immunogenomics and precision cancer medicine
Authors: Eliezer Van Allen
Journal: Cancer Research (2016)

Abstract The expansion of precision cancer medicine through robust interrogation of cancer genomes at the point of care has enhanced patient stratification and treatment selection strategies in numerous cancer types. In parallel, the rise of multiple immunotherapies, such as immune checkpoint blockade, has significantly improved clinical outcomes for multiple patient populations. The intersection of clinical cancer genomics and immuno-oncology has created an opportunity to learn how the tumor and germline genomes impact immune checkpoint blockade response, and how the immune system can be leveraged with knowledge of the cancer genome to more effectively stratify patients and tailor immune-specific therapies. Here, we describe the landscape of genomic correlates of immune checkpoint blockade, and examine how emerging genomic studies of immunotherapy responders and non-responders may inform patient selection strategies for clinical trial design. Furthermore, we explore how knowledge of the cancer genome and prioritization of neoantigens that arise from somatic mutations may impact personalized cancer vaccine development. Finally, we examine emerging data on genomic resistance to immunotherapies and the implications for combination treatment strategies. Broadly, the convergence of comprehensive clinical genomics and immuno-oncology treatment strategies may inform precision medicine for immunotherapies across cancer types. Citation Format: Eliezer Van Allen. Immunogenomics and precision cancer medicine. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr SY18-02.
Abstract 4569: Use of ACPD and ICA-1 as inhibitors of atypical proteinkinase C-zeta (ζ) and iota (ι) in metastasized melanoma cells
Authors: Wishrawana S. Ratnayake, Mildred Acevedo-Duncan
Journal: Cancer Research (2016)

Abstract The number of melanoma cases report is increased every year. Malignant melanoma is very common among all Caucasian populations worldwide. New cases in these populations are expected to be doubled every 10-20 years. According to the NIH Surveillance, Epidemiology and End Results (SEER) program, 73,870 new cases and 9,940 deaths were reported in 2015 in USA [http://seer.cancer.gov/statfacts/html/melan.html (11/10/2015)]. It is not totally understood which intracellular chemicals are involved in certain signaling pathways and which governs the metastasis of melanoma cancer cells. Even though PKC- iota (ι) was not reported in normal melanocytes, it was detected in high amounts in both transformed melanocytes and melanoma metastases. PKC- zeta (ζ) was also reported in both normal melanocytes and melanoma metastases [Melanoma Res. 12:201-209 (2002)]. We believe these atypical PKCs play an important role in cell motility of melanoma therefore we tested two inhibitors for them. The objective of this study was to test the inhibition effectiveness of ACPD [Diabetes. 63:2690-2701 (2014)] on both PKC-ι and PKC-ζ and ICA-1 [Int. J. Biochem. Cell Biol.43:784-794(2011)] as an inhibitor of PKC-ι. SK-MEL-2 metastasis melanoma cells and PCS-200-013 normal melanocyte cells were cultivated and treated with ACPD and ICA-1 in separate sets of flasks for three consecutive days while taking the cell count for every 24 hrs. Preliminary results of this experiment shows statistically significant decrease in cell number in SK-MEL-2 cells while no change in PCS-200-013. Future investigations will involve examining the effects of ACPD and ICA-1 on cell motility. Our preliminary results confirms the cell population of melanoma cells have an inversely proportional relationship with the drug concentrations. In conclusion, ACPD and ICA-1 are capable of decreasing the cell proliferation of melanoma cancer cells. Citation Format: Wishrawana S. Ratnayake, Mildred Acevedo-Duncan. Use of ACPD and ICA-1 as inhibitors of atypical proteinkinase C-zeta (ζ) and iota (ι) in metastasized melanoma cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4569.
GSK and Google form partnership to develop bioelectronic medicines
Authors: Gareth Iacobucci
Journal: BMJ (2016)

GlaxoSmithKline (GSK) has announced a new partnership with Google’s parent company, Alphabet, to carry out research into bioelectronic medicines.

GSK, the United Kingdom’s biggest drug company, will form a joint venture with Verily Life Sciences (formerly Google Life Sciences), a division of Alphabet. The joint venture, Galvani Bioelectronics, will focus on the research, development, and commercialisation of bioelectronic medicines. It will be 55% owned by GSK, and Verily will hold the remaining 45%.

The new company’s headquarters will be at GSK’s global research and development centre in Stevenage, UK. It will also operate a …