tbuckley/cabot-search huggingface dataset:
Superior anti-tumor activity of the MDM2 antagonist idasanutlin and the Bcl-2 inhibitor venetoclax in p53 wild-type acute myeloid leukemia models
Authors: Christian Lehmann, Thomas Friess, Fabian Birzele, Anna Kiialainen, Markus Dangl
Journal: Journal of Hematology & Oncology (2016)

Venetoclax, a small molecule BH3 mimetic which inhibits the anti-apoptotic protein Bcl-2, and idasanutlin, a selective MDM2 antagonist, have both shown activity as single-agent treatments in pre-clinical and clinical studies in acute myeloid leukemia (AML). In this study, we deliver the rationale and molecular basis for the combination of idasanutlin and venetoclax for treatment of p53 wild-type AML. The effect of idasanutlin and venetoclax combination on cell viability, apoptosis, and cell cycle progression was investigated in vitro using established AML cell lines. In vivo efficacy was demonstrated in subcutaneous and orthotopic xenograft models generated in female nude or non-obese diabetic/severe combined immunodeficiency (NOD/SCID) mice. Mode-of-action analyses were performed by means of cell cycle kinetic studies, RNA sequencing as well as western blotting experiments. Combination treatment with venetoclax and idasanutlin results in synergistic anti-tumor activity compared with the respective single-agent treatments in vitro, in p53 wild-type AML cell lines, and leads to strongly superior efficacy in vivo, in subcutaneous and orthotopic AML models. The inhibitory effects of idasanutlin were cell-cycle dependent, with cells arresting in G1 in consecutive cycles and the induction of apoptosis only evident after cells had gone through at least two cell cycles. Combination treatment with venetoclax removed this dependency, resulting in an acceleration of cell death kinetics. As expected, gene expression studies using RNA sequencing showed significant alterations to pathways associated with p53 signaling and cell cycle arrest (CCND1 pathway) in response to idasanutlin treatment. Only few gene expression changes were observed for venetoclax treatment and combination treatment, indicating that their effects are mediated mainly at the post-transcriptional level. Protein expression studies demonstrated that inhibition of the anti-apoptotic protein Mcl-1 contributed to the activity of venetoclax and idasanutlin, with earlier inhibition of Mcl-1 in response to combination treatment contributing to the superior combined activity. The role of Mcl-1 was confirmed by small hairpin RNA gene knockdown studies. Our findings provide functional and molecular insight on the superior anti-tumor activity of combined idasanutlin and venetoclax treatment in AML and support its further exploration in clinical studies.
Post-prostatectomy salvage radiation therapy in prostate cancer upon identification of biochemical failure.
Authors: Suneal Gopal Peddada, Craig Oliver, Angela Phelps, Steven H. Stokes, Jarrod Bartlett Adkison
Journal: Journal of Clinical Oncology (2016)

127 Background: Prostate Specific Antigen (PSA) values post-prostatectomy are used as an indication for salvage radiation therapy. It has been suggested that initiation of therapy at lower PSA values lead to better outcomes. This study investigates outcomes of salvage radiation therapy at specific PSA thresholds. Methods: One hundred two prostate cancer patients were treated with salvage radiotherapy at our institution with curative intent, 19 of whom had Gleason score ≤6, 52 of whom had Gleason 7, and 31 with Gleason ≥8. Median follow-up after radiotherapy was 51 months. The median PSA prior to salvage radiotherapy was 0.33 ng/mL, and the median time from prostatectomy to radiotherapy was 24.6 months. Positive margins were identified in 52 patients, and perineural invasion was positive in 83. The median dose delivered was 64.8 Gy. Results: The 5-year actuarial freedom from biochemical failure rates for NCCN low, intermediate, and high risk groups were 100%, 77%, and 62%, p=0.2449. The 5-year actuarial freedom from biochemical failure rates for Gleason score ≤6, Gleason 7, and Gleason ≥8 patients were 87%, 72%, and 49%, p=0.0187. Patients with pre-radiotherapy PSA ≤0.5 ng/mL had better 5-year biochemical control relative to patients with higher pre-radiotherapy PSA, 76% versus 51%, p=0.0211. The pathological margin status did not predict for biochemical control after salvage radiation across the different Gleason grades. Very few interval biochemical failures are observed after the 5-year point of follow-up. The 5-year overall survival for the entire cohort is 92%, with prostate cancer specific survival of 96%. Conclusions: Salvage radiotherapy demonstrated favorable efficacy with durable PSA control and few failures 5 years post radiation. Initiation of salvage radiotherapy for PSA ≤0.5 ng/mL demonstrated improved biochemical control, supporting the adoption of early referral to radiation oncology once post-prostatectomy biochemical failure is identified. [Table: see text]
FDG PET/CT in Monitoring Antituberculosis Therapy in Patient With Widespread Skeletal Tuberculosis
Authors: Na Hu, Yanlin Tan, Zhen Cheng, Zhu Hao, Yunhua Wang
Journal: Clinical Nuclear Medicine (2015)

FDG PET/CT imaging is a useful diagnostic tool in the evaluation of both neoplastic and inflammatory lesions and has a promising role in monitoring therapeutic response. We present a 50-year-old man whose initial PET/CT scan showed multiple foci of intense FDG activity in lytic lesions in the bones. A diagnosis of skeletal tuberculosis was confirmed after bone biopsy. Follow-up FDG PET/CT performed after 12 months of regular antituberculosis treatment demonstrated complete normalization of FDG activity in the bones.
Abstract 1016: Variants in autophagy related genes and clinical characteristics in melanoma: a population-based study
Authors: Kirsten A. m. White, Li Luo, Todd A. Thompson, Salina Torres, Chien-An A. Hu, Nancy E. Thomas, Hoda Anton-Culver, Stephen B. Gruber, Lynn From, Klaus J. Busam, Irene Orlow, Peter A. Kanetsky, Lorraine D. Marrett, Richard P. Gallagher, Roberto Zanetti, Stefano Rosso, Terry Dwyer, Anne E. Cust, Allison Venn, Colin B. Begg, Marianne Berwick, Jenna Lillyquist
Journal: Cancer Research (2016)

Abstract Autophagy has been linked with melanoma, but no polymorphisms in autophagy related (ATG) genes have been investigated for association with melanoma prognostic indicators and survival. We examined 5 ATG gene single nucleotide polymorphisms (SNPs) in a large international multicenter population-based case-control study of melanoma. DNA from 911 melanoma patients was genotyped for five SNPs with a known or suspected impact on autophagic flux. While we did not identify an association with survival, a significant association was identified between the minor allele for an ATG16L polymorphism (rs2241880) and a decrease in Breslow thickness (p = 0.03), earlier tumor stage at diagnosis (OR 0.47, 95% CI 0.27-0.81, p = 0.02) and younger age at diagnosis (p = 0.02). In addition, two SNPs in ATG5 (rs2245214 and rs510432) were found to be significantly associated with increased tumor stage of melanoma (OR 1.84 95% CI 1.12-3.02, p = 0.05; OR 1.47 95% CI 1.11-1.94, p = 0.03). Finally, we identified inverse associations between the minor allele of rs2245214 and melanomas on the scalp or neck (OR 0.20, 95% CI 0.05-0.86, p = 0.03); rs1864182 (OR 0.42, 95% CI 0.21-0.88, p = 0.02) and brisk TILs, and rs510432 (OR 0.55 95% CI 0.34-0.87, p = 0.01) with non-brisk TILs, although they were not globally significant. In summary, our data suggests that ATG SNPs, while not associated with survival, may be associated with Breslow thickness, tumor stage, age at diagnosis, and aggressive histopathological factors. These associations could contribute to our current understanding of the significant role of autophagy in melanoma progression. Citation Format: Kirsten A. m. White, Li Luo, Todd A. Thompson, Salina Torres, Chien-An A. Hu, Nancy E. Thomas, Hoda Anton-Culver, Stephen B. Gruber, Lynn From, Klaus J. Busam, Irene Orlow, Peter A. Kanetsky, Lorraine D. Marrett, Richard P. Gallagher, Roberto Zanetti, Stefano Rosso, Terry Dwyer, Anne E. Cust, Allison Venn, Colin B. Begg, Marianne Berwick, Jenna Lillyquist. Variants in autophagy related genes and clinical characteristics in melanoma: a population-based study. [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 1016.
Abstract 4601: Regulation of Hes1 expression by the Wnt transcription factor T-cell factor-4
Authors: Hironori Koga, Yasuko Imamura, Yu Ikezono, Fumitaka Wada, Toru Nakamura, Hideki Iwamoto, Atsutaka Masuda, Takahiko Sakaue, Hirohisa Yano, Takuji Torimura
Journal: Cancer Research (2016)

Abstract Background: The Notch effector Hes1 plays a critical role in stemness of cancer stem cells (CSCs). T-cell factor (TCF)-4 is a key transcription factor in Wnt signaling, which is suggested to be linked with Notch signaling. Among our TCF-4 isoforms cloned previously, the TCF-4J and K pair have been characterized based on the presence (K) or absence (J) of SxxSS motif (Exp Cell Res 2010). TCF-4J was highly expressed in poorly differentiated human hepatocellular carcinoma (HCC) tissues, and the TCF-4J-overexpressing HCC cells (J cells) exhibited high tumor-initiating potential, which is one of the features of CSCs (PLoS One 2013). Thus, the AIM of this study was to investigate whether the SxxSS motif of TCF-4 was involved in the regulation of Hes1 expression in HCC cells. Methods: TCF-4K mutants were prepared by site-directed mutagenesis. Sphere formation assay was used to condense CSC-like cells. Results: Hes1 was strikingly expressed in spheres of J cells and K-mutant cells in both protein and mRNA levels, while its expression level was 70% inhibited in K cells. Consistently, protein expression levels of Jagged1 and Notch1 were highest in J cells under both attached and floating conditions. The Notch inhibitor DAPT, a γ-secretase inhibitor, clearly decreased the expression levels of Hes1, suggesting that the Notch-Hes1 axis was functional. Conclusion: Lack of SxxSS motif in TCF-4 robustly upregulated Hes1 expression in HCC cell spheres. The finding strongly suggests that TCF-4 directly regulates Hes1 in HCC spheres, where CSCs abundantly exist. Citation Format: Hironori Koga, Yasuko Imamura, Yu Ikezono, Fumitaka Wada, Toru Nakamura, Hideki Iwamoto, Atsutaka Masuda, Takahiko Sakaue, Hirohisa Yano, Takuji Torimura. Regulation of Hes1 expression by the Wnt transcription factor T-cell factor-4. [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 4601.
Abstract 2849: RNA-binding protein FXR1 negatively regulates senescence by destabilizing mRNA CDKN1A and stabilizing noncoding RNA telomerase RNA component
Authors: Mrinmoyee Majumder, Nallasivam Palanisamy, Shuo Qie, Terry Day, Alan J. Diehl, Viswanathan Palanisamy
Journal: Cancer Research (2016)

Abstract RNA-binding proteins (RBPs) regulate numerous aspects of co- and post-transcriptional gene expression. RBP fragile X-related protein 1 (FXR1) belongs to a family of RNA-binding proteins that includes functionally similar Fragile X mental retardation 1 (FMR1) and Fragile X-related 2 (FXR2). FMR1 is significantly studied in Fragile X Syndrome (FXS) where the gene is non-functional due to mutation or aberrant methylation. FXR1 protein is highly expressed in multiple cancers including lung and oral cancers. Here, we demonstrate that RBP FXR1 plays an essential role in the growth of head and neck squamous cell carcinomas (HNSCC) by blocking cellular senescence. FXR1 MEF cells were stained positive for senescence associated beta-galactosidase straining. We report a major function of FXR1 as it promotes the stability of Telomerase RNA Component (TERC), a non-coding RNA and simultaneously destabilizes CDKN1A mRNA, and blocks cellular senescence. FXR1-deficient HNSCC cells show an increase in different cyclin dependent kinase inhibitors (p21, p27), a decrease in p-AKT, and these cells also undergo a G0/G1 cell cycle arrest which are the early onsets of cellular senescence. FXR1 binds and stabilizes TERC RNA for telomere maintenance. On the contrary, FXR1 binds and destabilizes CDKN1A mRNA. By an independent assay we also show that the senescence phenomenon was only observed by a combined up and downregulation of CDKN1A and TERC, respectively which was only obtained by FXR1 knockdown. Thus, FXR1 forms a molecular link between CDKN1A and TERC for cell cycle control and telomere length, respectively, to repress cellular senescence in HNSCC. Citation Format: Mrinmoyee Majumder, Nallasivam Palanisamy, Shuo Qie, Terry Day, Alan J. Diehl, Viswanathan Palanisamy. RNA-binding protein FXR1 negatively regulates senescence by destabilizing mRNA CDKN1A and stabilizing noncoding RNA telomerase RNA component. [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 2849.
Acceptability and feasibility of a screen-and-treat programme for hepatitis B virus infection in The Gambia: the Prevention of Liver Fibrosis and Cancer in Africa (PROLIFICA) study
Authors: Maud Lemoine, Yusuke Shimakawa, Ramou Njie, Makie Taal, Gibril Ndow, Isabelle Chemin, Sumantra Ghosh, Harr F Njai, Adam Jeng, Amina Sow, Coumba Toure-Kane, Souleymane Mboup, Penda Suso, Saydiba Tamba, Abdullah Jatta, Louise Sarr, Aboubacar Kambi, William Stanger, Shevanthi Nayagam, Jessica Howell, Liliane Mpabanzi, Ousman Nyan, Tumani Corrah, Hilton Whittle, Simon D Taylor-Robinson, Umberto D'Alessandro, Maimuna Mendy, Mark R Thursz
Journal: The Lancet Global Health (2016)

Despite the introduction of immunisation for hepatitis B virus (HBV) in the 1990s, HBV-related morbidity and mortality remain high in sub-Saharan Africa. Identification and treatment of asymptomatic people with chronic HBV infection should reduce the disease burden. We therefore assessed the feasibility of a screen-and-treat programme for HBV infection in The Gambia, west Africa, and estimated the proportion of HBV-infected people who had significant liver disease in need of treatment.
Abstract 689: Downregulation of TIMP2 via HIF-1á/miR-210/HIF-3á regulatory feedback circuit enhances cancer metastasis in hepatocellular carcinoma
Authors: Alan KL Kai, Lo Kong Chan, Regina CL Lo, Joyce Lee, Carmen CL Wong, Jack CM Wong, Irene OL Ng.
Journal: Cancer Research (2016)

Abstract Cancer metastasis is a multi-step process that involves a series of tumor-stromal interaction, including extracellular matrix (ECM) remodeling which requires a concerted action of multiple proteolytic enzymes and their endogenous inhibitors. This study investigated the role of tissue inhibitor of metalloproteinases 2 (TIMP2) in the context of hepatocellular carcinoma (HCC) metastasis. We found that TIMP2 was the most significantly downregulated member among the TIMP family in human HCCs. Moreover, TIMP2 underexpression was frequent (41.1%; 23/56) in human HCCs as compared to the corresponding non-tumorous livers and was significantly associated with direct liver invasion into the adjacent liver parenchyma and poorer survival outcomes of the HCC patients. Furthermore, stable silencing of TIMP2 in HCC cell lines enhanced the cell invasive ability and ECM degradation associated with formation of invadopodia-like feature, suggesting that TIMP2 is a negative regulator of HCC metastasis. Furthermore, using orthotopic tumor xenograft model, we demonstrated that ectopic expression of TIMP2 open reading frame in the highly metastatic HCC cell line MHCC-97L not only significantly reduced the incidence of tumor microsatellite formation and venous invasion in the primary hepatic tumor xenografts, but also pulmonary metastasis, suggesting that both extrahepatic and intrahepatic metastasis in HCC was suppressed by TIMP2 expression. Mechanistically, TIMP2 suppression in a hypoxic environment was induced through a regulatory feedback circuit consisting of HIF-1á, miR-210 and HIF-3á. Taken altogether, our findings established that TIMP2 was frequently downregulated in human HCCs and its downregulation was associated with aggressive behavior and poorer patients’ outcome. Its suppression was under the regulation of a novel feedback circuit consisting of HIF-1á/ miR-210/ HIF-3á. Overall, our study has provided solid in vitro and in vivo evidence that TIMP2 is an important regulator of ECM degradation and HCC metastasis. These findings demonstrated that perturbation of the dynamic HIF-1a signaling circuit by miR-210 inhibitor abolished TIMP2 downregulation and suppressed HCC cell invasion. They also support the notion that targeting against HIF-1á signaling is a promising direction to tackle the hypoxic responses in HCC elicited by transarterial chemo-embolization (TACE) treatment to HCC patients. Citation Format: Alan KL Kai, Lo Kong Chan, Regina CL Lo, Joyce Lee, Carmen CL Wong, Jack CM Wong, Irene OL Ng. Downregulation of TIMP2 via HIF-1á/miR-210/HIF-3á regulatory feedback circuit enhances cancer metastasis in hepatocellular 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 689.
Abstract 4447: EZH2 contributes to breast cancer metastasis
Authors: Shira Yomtoubian, Seongho Ryu, Sharrell Lee, Lauren Havel, Dingcheng Gao, Vivek Mittal
Journal: Cancer Research (2016)

Abstract While the 5-year relative survival rate of localized stage breast cancer is 99%, once the cancer spreads to distant lymph nodes and organs the survival rate falls to 25%. In order to develop strategies to combat metastasis, we have been studying epigenetic factors that contribute to the aggressive nature of breast cancer. We have focused on enhancer of zeste homolog 2 (EZH2), a histone methyl transferase, because breast cancer patients expressing increased EZH2 exhibit highest metastatic recurrence. We have found through in vivo studies that blocking EZH2 activity not only prevents metastasis formation, but also targets established metastases. Genome wide ChIP-seq analysis revealed that EZH2 may impact breast cancer metastasis through regulating the expression of EMT marker, E-cadherin, and stem cell markers, GATA3 and DKK2. Mammosphere assays from tumors treated with pharmacological blockade of EZH2 and limiting dilution analysis validates that EZH2 inhibition impacts the tumor-initiating cell population. Our data suggests that inhibition of EZH2 activity may have anti-metastatic therapeutic potential and may complement current standards of breast cancer therapy. Citation Format: Shira Yomtoubian, Seongho Ryu, Sharrell Lee, Lauren Havel, Dingcheng Gao, Vivek Mittal. EZH2 contributes to breast cancer metastasis. [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 4447.
Incidence élevée de la coqueluche aux Pays-Bas depuis l'épidémie de 1996
Authors: S E Neppelenbroek, H de Melker, J. F.P Schellekens, M A E Conyn-Van Spaendonck
Journal: Eurosurveillance (1999)

L'incidence de la coqueluche aux Pays-Bas, mesuree a partir des declarations de cas, a brutalement augmente en 1996 pour atteindre 27,2 cas pour 100 000 habitants, alors que la moyenne entre 1989 et 1995 etait de 2,3 pour 100 000. Si les augmentations anterieures enregistrees en 1989-1990 et en 1994 correspondaient au schema classique observe dans d'autres pays, a savoir des cycles epidemiques de coqueluche tous les trois a cinq ans, l'epidemie de 1996 etait imprevue. Elle ne pouvait etre expliquee par un changement dans la qualite du vaccin, par une interference avec la vaccination contre Haemophilus influenzae type b mise en place en 1993, ni par une baisse de la couverture vaccinale (96% a l’âge de 12 mois) (1,2,3).
Abstract 4168: Mig-6 ablation cooperates with oncogenic Kras in promoting mouse lung tumorigenesis
Authors: Jian Liu, Sung-Nam Cho, Nili Jin, Seyed Javad Moghaddam, Jennifer Gilbert, Ignacio Wistuba, Francesco J. DeMayo
Journal: Cancer Research (2016)

Abstract Lung tumorigenesis is a stochastic multistep process, during which different gene mutations accumulate, and Kras is an oncogene with the most frequent mutation in the Caucasian lung adenocarcinoma. Although Mig-6 (mitogen-inducible gene 6) has been shown to be a tumor suppressor gene in lung, skin and uterus, the interplay between Mig-6 and Kras in lung tumorigenesis remains elusive. Here, we found Mig-6 expression was down-regulated in oncogenic KrasG12D-induced lung tumors and Mig-6d/dKrasG12D mice showed an earlier onset of pulmonary tumor development and a significantly reduced life span as compared to KrasG12D mice though no obvious lung phenotype was observed in Mig-6d/d mice. Meanwhile, ablation of Mig-6 can change the lung epithelial cell fate in KrasG12D mice. Furthermore, lung tumor tissues of Mig-6d/dKrasG12D mice showed decreased cellular apoptosis, elevated EGF/Akt signaling and increased severity of inflammation as compared to those of KrasG12D mice. Thus, ablation of Mig-6 cooperated with oncogenic Kras in promoting lung tumorigenesis and this novel murine model of lung cancer can be applied for future study. Citation Format: Jian Liu, Sung-Nam Cho, Nili Jin, Seyed Javad Moghaddam, Jennifer Gilbert, Ignacio Wistuba, Francesco J. DeMayo. Mig-6 ablation cooperates with oncogenic Kras in promoting mouse lung tumorigenesis. [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 4168.