tbuckley/cabot-search huggingface dataset:
Reimbursement Rules and Quality Metrics for the Care of Patients With Aortic Stenosis—Are We Missing the Goal?
Authors: Satya Shreenivas, Michael Reardon, Dean Kereiakes
Journal: JAMA Cardiology (2019)

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Abstract LB-016: Radiochemotherapy combined with NK cells followed by a second-line PD-1 inhibition in a patients with NSCLC stage IIIb induces long-term tumor control
Authors: Gabriele Multhoff, Konrad Kokowski, Martin Hildebrandt, Peter Vaupel, Stefan Stangl
Journal: Cancer Research (2019)

Abstract Advanced stage NSCLC is a fatal disease with poor prognosis. Following radiochemotherapy (RCT) tumor progression occurs after 5.6 months in stage III NSCLC patients. We identified membrane heat shock protein 70 (mHsp70) as a biomarker for high-risk NSCLC. Furthermore, mHsp70 serves as a tumor-specific target for NK cells that had been stimulated with Hsp70-peptide (TKD) and IL-2. In this study, a patient with mHsp70 positive inoperable NSCLC (cT4, cN3, cM0, stage IIIb) was treated for the first time with a combined therapy consisting of RCT (64.8 Gy), 4 cycles of mHsp70-targeting, autologous NK cells and PD-1 antibody, as a second-line therapy. Adoptive transfer of ex vivo Hsp70-activated NK cells after RCT combined with PD-1 inhibition was well tolerated and resulted in a superior OS. No viable tumor cells, but a massive immune cell infiltration of T and NK cells in fibrotic tissue were detected after therapy. Neither tumor progression nor distant metastases were detectable by CT-scanning 35 months after diagnosis. Therapy response was associated with significantly increased CD3-/NKG2D+/CD94+ NK cell counts, elevated CD8+ to CD4+ T cell, CD3-/CD56bright to CD3-/CD56dim NK cell ratios, and significantly reduced regulatory T cells (Tregs) in the peripheral blood. In summary, a combined immunotherapy consisting of RCT, mHsp70-targeting NK cells and PD-1 antibody inhibition is well tolerated, induces anti-tumor immune responses and results in long-term tumor control in a patient with advanced NSCLC. Citation Format: Gabriele Multhoff, Konrad Kokowski, Martin Hildebrandt, Peter Vaupel, Stefan Stangl. Radiochemotherapy combined with NK cells followed by a second-line PD-1 inhibition in a patients with NSCLC stage IIIb induces long-term tumor control [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-016.
Micro/Nanomaterials‐Augmented Hydrogen Therapy
Authors: Gaoxin Zhou, Ekta Goshi, Qianjun He
Journal: Advanced Healthcare Materials (2019)

Abstract Hydrogen therapy is an emerging and promising therapy strategy of using molecular hydrogen as a new type of safe and effective therapeutic agent, exhibiting remarkable therapeutic effects on many oxidative stress‐/inflammation‐related diseases owing to its bio‐reductivity and homeostatic regulation ability. Different from other gaseous transmitters such as NO, CO, and H 2 S, hydrogen gas has no blood poisoning risk at high concentration because it does not affect the oxygen‐carrying behavior of blood red cells. Hydrogen molecules also have low aqueous solubility and high but aimless diffusibility, causing limited therapy efficacy in many diseases. To realize the site‐specific hydrogen delivery, controlled hydrogen release and combined therapy is significant but still challenging. Here, a concept of hydrogen nanomedicine to address the issues of hydrogen medicine by using functional micro/nanomaterials for augmented hydrogen therapy is proposed. In this review, various strategies of micro/nanomaterials‐augmented hydrogen therapy, including micro/nanomaterials‐mediated targeted hydrogen delivery, controlled hydrogen release, and nanocatalytic and multimodel enhancement of hydrogen therapy efficacy, are summarized, which can open a new window for treatment of inflammation‐related diseases.
Abstract 1531: The Polycomb repressor complex 1 promotes recruitment of myeloid-derived suppressor cells and immune evasion during bone colonization in castration-resistant prostate cancer
Authors: Wenjing Su, Boyu Zhang, Hyunho Han, Goutam Chakraborty, Bing Zhou, Jie Su, Guangli Yang, Ouathek Ouerfelli, Neal Rosen, Howard I. Scher, Filippo G. Giancotti
Journal: Cancer Research (2019)

Abstract The mechanisms that enable immune evasion at metastatic sites are poorly understood. We show that the Polycomb Repressor Complex-1 (PRC1) drives colonization of the bones and visceral organs in Double Negative (AR- NE-) Prostate Cancer (DNPC). In vivo genetic screening identifies the cytokine CCL2 as the top pro-metastatic gene induced by PRC1. Mechanistic studies show that CCL2 not only controls self-renewal and metastatic initiation but also governs the recruitment of M2-like TAMs and Tregs, thus creating a profoundly immune suppressive and proangiogenic microenvironment. Inhibition of PRC1 reverses these processes and cooperates with checkpoint immunotherapy to suppress multi-organ site metastasis. These results reveal a link between epigenetic regulation of cancer stem cells and molding of the tumor microenvironment and identify PRC1 as a potential therapeutic target in M-CRPC. Citation Format: Wenjing Su, Boyu Zhang, Hyunho Han, Goutam Chakraborty, Bing Zhou, Jie Su, Guangli Yang, Ouathek Ouerfelli, Neal Rosen, Howard I. Scher, Filippo G. Giancotti. The Polycomb repressor complex 1 promotes recruitment of myeloid-derived suppressor cells and immune evasion during bone colonization in castration-resistant prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1531.
Abstract SY23-02: Actions of the EMT Program in fostering malignant progression
Authors: Robert A. Weinberg
Journal: Cancer Research (2019)

Abstract The cell-biological program commonly termed the epithelial-mesenchymal transition (EMT) confers a variety of distinct traits on epithelial cells that express it, including many that enable primary carcinoma cells to complete most of the steps of the invasion-metastasis cascade. Among other traits, it confers increased resistance to various forms of therapy and a stem-cell phenotype, which appears to be tightly linked to tumor-initiating ability. In addition, mammary carcinoma cells expressing an EMT program show a reduced susceptibility to elimination by anti-CTLA4 checkpoint blockade relative to their more mesenchymal counterparts. Carcinoma cells rarely if ever execute a complete EMT program but instead venture only partway toward the mesenchymal state, resulting in cells that co-express both epithelial and mesenchymal traits. Moreover, tumor-initiating cells appear to co-express both epithelial and mesenchymal traits, indicating that cells that have moved too far into the mesenchymal state actually lose stemness and thus tumor-initiating powers. Citation Format: Robert A. Weinberg. Actions of the EMT Program in fostering malignant progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr SY23-02.
Abstract 3761: Regulation of metastasis by CD8 T lymphocytes
Authors: Robiya Joseph, Rama Soundararajan, Suhas Vasaikar, Fei Yang, Sevinj Isgandarova, Lin Tian, Monika Haemmerle, Barbara Mino, Tieling Zhou, Geraldine Vidhya Raja, Esmeralda Ramirez Pena, Petra Den Hollander, Neeraja Bhangre, Crystal Shin, Melisa Martinez, Jaime Rodriguez Canales, Jeffrey Chang, Anil Sood, Ignacio Ivan Wistuba, Don L. Gibbons, Jeffrey M. Rosen, Ghanashyam Acharya, Navin Varadarajan, Xiang H. Zhang, Sendurai A. Mani
Journal: Cancer Research (2019)

Abstract Metastatic breast cancer is the most dreadful malignant disease that accounts for the majority of cancer-related deaths worldwide among women. A number of studies have shown that the tumor microenvironment (TME) plays a crucial role in regulating metastasis. It is therefore imperative to understand the dynamic interactions between cancer cells and their microenvironment to examine the molecular interaction and to effectively target cancer cells. TME comprises a variety of cells including immune cells which can influence tumor survival, growth and metastasis. Tumor-infiltrating lymphocytes (TILs), in particular, the CD8 T lymphocytes, has emerged as a promising prognostic marker for immunotherapy in a variety of cancers. However, the key molecular factors that regulate the cross-talk between tumor cells and CD8 T lymphocytes and its impact on metastatic traits in breast cancer is still inconclusive. Platelets are crucial components of the tumor microenvironment that are known to modulate tumor promotion and metastasis. The contribution of platelets and platelet secreted molecules are also carefully examined in metastasis of various cancers. The primary objective of this study is to investigate the role of CD8 T lymphocytes and platelets in breast tumor progression using isogenic tumor lines that form identical primary tumors but differ in their ability to develop metastasis. Citation Format: Robiya Joseph, Rama Soundararajan, Suhas Vasaikar, Fei Yang, Sevinj Isgandarova, Lin Tian, Monika Haemmerle, Barbara Mino, Tieling Zhou, Geraldine Vidhya Raja, Esmeralda Ramirez Pena, Petra Den Hollander, Neeraja Bhangre, Crystal Shin, Melisa Martinez, Jaime Rodriguez Canales, Jeffrey Chang, Anil Sood, Ignacio Ivan Wistuba, Don L. Gibbons, Jeffrey M. Rosen, Ghanashyam Acharya, Navin Varadarajan, Xiang H. Zhang, Sendurai A. Mani. Regulation of metastasis by CD8 T lymphocytes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3761.
High rates of hepatocellular carcinoma within two years of starting treatment for chronic hepatitis C with direct antiviral agents but not with PEG-interferon/ Ribavirin (HORRID Study)
Authors: F. Karbeyaz, B. Müllhaupt, T. Winder, B. Misselwitz, J. Mertens, A. Siebenhuener
Journal: Annals of Oncology (2019)
Abstract 4339: Critical role of Dnmt3b catalytic activity in prevention of oncogene-induced leukemias and lymphomas
Authors: Katarina Lopusna, Pawel Nowialis, Staci L. Haney, Ajay Abraham, Jana Opavska, Rene Opavsky
Journal: Cancer Research (2019)

Abstract Cytosine methylation is involved in a variety of biological processes, including development, X-chromosome inactivation, imprinting, and suppressing unwanted transcription. DNA methylation in mammalian cells is catalyzed by several DNA methyltransferases, including DNMT1, DNMT3A and DNMT3B. In addition to DNA methylation catalysis, these enzymes interact with a number of repressive proteins including HDACs, thereby repressing transcription in methylation-independent manner. The extent to which methylation-dependent and independent activities play roles in biological processes remains poorly understood. Here we examined the role of methyltransferase (MT) activity of Dnmt3b in normal mouse embryogenesis and in prevention of hematologic malignancies. Loss of Dnmt3b in mice is embryonically lethal between 10.5-12.5 dpc. Dnmt3b was also identified as tumor suppressor in murine models of lymphoid and myeloid malignancies. To address whether Dnmt3b’s catalytic activity is important for mouse embryogenesis and prevention of hematologic malignancies, we generated mice bearing a conventional Dnmt3bCI allele using CRISPR/Cas9 system. This catalytically inactive allele of Dnmt3b (Dnmt3bCI) was generated by a double amino acid substitution in enzyme active center (P656V and C657D) abolishing its ability to perform transfer of methyl group onto cytosine. Surprisingly, Dnmt3bCI/CI mice were born at similar ratios as wild-type littermates and lived over 12 months suggesting that Dnmt3b is dispensable for both pre- and post-natal development. Importantly, MYC-induced T-cell lymphomagenesis was accelerated in the absence of Dnmt3b’s methyltransferase activity in MYC;Dnmt3bCI/CI mice. Global gene expression and methylation profiling revealed a number of deregulated events specific for MYC;Dnmt3bCI/CI, resulting in activation of Pak, Fgfr and Igf2 signaling and downregulation of tumor suppressors (e.g. Lrp12, Dusp6 and Marcks). The lack of Dnmt3b catalytic activity also accelerated a development of acute myeloid leukemia induced by MLL-AF9 overexpression in mice. Altogether, our data suggest that Dnmt3b’s MT activity is dispensable for mouse development but critical to prevent hematologic malignancies. Citation Format: Katarina Lopusna, Pawel Nowialis, Staci L. Haney, Ajay Abraham, Jana Opavska, Rene Opavsky. Critical role of Dnmt3b catalytic activity in prevention of oncogene-induced leukemias and lymphomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4339.
Role for DNA polymerase beta in response to ionizing radiation
Authors: C. Vermeulen, M. Verwijs-Janssen, P. Cramers, A.C. Begg, C. Vens
Journal: Cancer Research (2007)

3903  Evidence for a role of DNA polymerase beta in determining radiosensitivity is conflicting. In vitro assays show an involvement of DNA polymerase beta in single strand break repair and base excision repair of oxidative damage, both products of ionizing radiation. Nevertheless the lack of DNA polymerase beta has been shown to have no effect on radiosensitivity. Here we show that mouse embryonic fibroblasts deficient in DNA polymerase beta are considerably more sensitive to ionizing radiation than wild-type cells, but only when confluent. The data indicates that replication associated repair is independent of DNA polymerase beta, and when replication is low, repair of DNA damage induced by ionizing radiation depends on DNA polymerase beta. To further strengthen our hypothesis, we synchronized wild-type and polymerase beta deficient cells with ‘mitotic shake off’ and found that DNA polymerase beta deficient cells are more sensitive to ionizing radiation than wild-type cells in G1 phase of the cell cycle, but radiosensitivity of DNA polymerase beta deficient cells decreased when cells progressed from G1 to S phase. No difference in radiosensitivity between wild-type and polymerase beta deficient cells was observed in S phase, showing that redundant pathways are active in replicating cells only. To characterize these pathways further, we used the inhibitor methoxyamine that renders abasic sites refractory to the dRP lyase activity of DNA polymerase beta. Methoxyamine did not significantly change radiosensitivity of wild-type fibroblasts in log phase. However, DNA polymerase beta deficient cells in log phase were radiosensitized by methoxyamine. Alkaline comet assays confirmed repair inhibition of ionizing radiation induced damage by methoxyamine in these cells, indicating both the existence of a polymerase beta-dependent long patch pathway and the involvement of another methoxyamine sensitive process, implying the participation of a second short patch polymerase(s) other than DNA polymerase beta. This is the first evidence of a role for DNA polymerase beta in radiosensitivity in vivo.  To further investigate the possibility of a second short patch pathway, we are currently studying DNA polymerases iota and lambda, both translesion synthesis polymerases which have enzymatic and structural similarities to DNA polymerase beta. Knockdown and overexpression experiments are being performed to reveal the possible contribution of DNA polymerase iota and lambda to single strand break repair and base excision repair after ionizing radiation.
A New Immunohistochemical Algorithm Using Four Antibodies Has a High Concordance with Gene Expression Profiling Defined ABC and GCB Diffuse Large B-Cell Lymphoma
Authors: Henry Theophraste, Julie Bruneau, Christiane Copie, Philippe Ruminy, Petrella Tony, Josette Briere, Richard Delarue, Marie Parrens, Corinne Haioun, Danielle Canioni, Olivier Casasnovas, Bettina Fabiani, Franck Morschhauser, Jean-François Emile, Herve Tilly, Martin Figeac, Philippe Gaulard, Gilles Andre Salles, Fabrice Jardin, Karen Leroy, Jean-Philippe Jais, Thierry Jo Molina
Journal: Blood (2017)
Abstract 4306: JunD-induced cell proliferation requires MYC signaling in prostate cancer cells
Authors: Bethtrice Thompson (Elliott), Ana Cecilia Millena, Lilya Matyunina, Mengnan Zhang, Jin Zou, Guangdi Wang, Qiang Zhang, Nathan Bowen, Vanessa Eaton, Gabrielle Webb, Shadyra Thompson, John McDonald, Shafiq Khan
Journal: Cancer Research (2019)

Abstract JunD, a member of the AP-1 transcription factor family, is involved in a variety of biological processes including cell proliferation, inflammation, differentiation, apoptosis, and carcinogenesis. We previously showed that JunD is essential for cell proliferation and demonstrated that the knock-down (KD) of JunD in PCa cells resulted in cell cycle arrest in G1-phase concomitant with a decrease in the levels of Id1, c-MYC, and Ki67, but an increased in p21 protein levels. Furthermore, the over-expression of JunD significantly increased proliferation in these cells suggesting that JunD regulates the expression of genes which are required for cell cycle progression. In this present study, employing gene expression profiling, quantitative proteomics, and validation approaches, we demonstrated that JunD KD is associated with distinct gene and protein expression patterns. Comparison integrative analysis by Ingenuity Pathway Analysis (IPA) identified 1) cell cycle control/regulation as the top canonical pathway whose members exhibited a significant decrease in their expression following JunD KD including PRDX3, PEA15, KIF2C, and CDK2, and 2) JunD target genes are involved in cell proliferation, with MYC as the key downstream regulator. Conversely, JunD over-expression induced cell proliferation and the expression of the above JunD target genes including c-MYC. When treated with JQ1, a c-MYC inhibitor, these cells exhibited a significant reduction in cell proliferation and a decrease in JunD target genes. Our data suggest that JunD-mediated cell proliferation involves MYC signaling and inhibiting its target genes may be an effective approach to blocking prostate carcinogenesis Citation Format: Bethtrice Thompson (Elliott), Ana Cecilia Millena, Lilya Matyunina, Mengnan Zhang, Jin Zou, Guangdi Wang, Qiang Zhang, Nathan Bowen, Vanessa Eaton, Gabrielle Webb, Shadyra Thompson, John McDonald, Shafiq Khan. JunD-induced cell proliferation requires MYC signaling in prostate cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4306.
Abstract 19713: Decreased Astrocytes via Central Angiotensin II Receptor and Dysfunction of Nrf2 is Associated With Sympathoexcitation in Heart Failure
Authors: Takuya Kishi, Keita Saku, Kenji Sunagawa, Hiroyuki Tsutsui
Journal: Circulation (2017)

Introduction: We have determined that central angiotensin II receptor (AT1R)-induced oxidative stress causes sympathoexcitation heart failure. Interestingly, our recent study showed that astrocyte,...
The incidence and survival of melanoma and nonmelanoma skin cancer in patients with vitiligo: a nationwide population‐based matched cohort study in Korea
Authors: H.S. Kim, H.J. Kim, E.S. Hong, K.B. Kim, J.D. Lee, T.U. Kang, H.S. Ahn
Journal: British Journal of Dermatology (2019)

While studies report a lower incidence of skin cancer in white patients with vitiligo compared with controls, the skin cancer incidence in Asian patients with vitiligo is unknown. To quantify the incidence of melanoma and nonmelanoma skin cancer (NMSC) in Korean patients with vitiligo and compare it with matched nonvitiligo controls. A retrospective matched cohort study was performed with 131 245 incident vitiligo cases and 2 624 900 age‐ and sex‐matched (1 : 20) controls at index date, who were selected from the Korean National Health Insurance database between January 2005 and December 2017. Stratified Cox proportional hazards regression (stratified by sex, birth year and index year) was used to calculate the hazard ratio (HR) of skin cancer in patients with vitiligo. Patients with vitiligo were followed up for a mean duration of 6·34 years compared with a follow‐up period of 6·27 years for matched controls. Ultraviolet (UV) treatment‐adjusted HR for melanoma in patients with vitiligo was 3·32 [95% confidence interval (CI) 2·29–4·81] and 1·29 (95% CI 1·06–1·56) for NMSC. The HRs for melanoma and NMSC in the vitiligo population without a history of UV treatment were 3·37 (95% CI 2·32–4·90) and 1·35 (95% CI 1·11–1·64), respectively. In contrast to white patients with vitiligo, the risk of skin cancer was increased in the Korean vitiligo population. However, it is noteworthy that the skin cancer incidence in Korean patients with vitiligo was lower than that of their white counterparts. Owing to possible ethnic differences in the susceptibility to skin cancer, skin cancer surveillance in the vitiligo population may be adjusted for race. What's already known about this topic? Prior studies have reported a lower incidence of melanoma and nonmelanoma skin cancer (NMSC) in white patients with vitiligo compared with nonvitiligo controls. The skin cancer incidence in Asian patients with vitiligo is unknown. What does this study add? In contrast to white patients, the risk of both melanoma and NMSC was increased in Korean patients with vitiligo compared with controls. Owing to possible ethnic differences in susceptibility to skin cancer, skin cancer surveillance in the vitiligo population should be adjusted for race.