tbuckley/cabot-search huggingface dataset:
<scp>CHA<sub>2</sub>DS<sub>2</sub>‐VASc</scp> score and adverse outcomes in patients with heart failure with reduced ejection fraction and sinus rhythm
Authors: Siqin Ye, Min Qian, Bo Zhao, Richard Buchsbaum, Ralph L. Sacco, Bruce Levin, Marco R. Di Tullio, Douglas L. Mann, Patrick M. Pullicino, Ronald S. Freudenberger, John R. Teerlink, J.P. Mohr, Susan Graham, Arthur J. Labovitz, Conrado J. Estol, Dirk J. Lok, Piotr Ponikowski, Stefan D. Anker, Gregory Y.H. Lip, John L.P. Thompson, Shunichi Homma
Journal: European Journal of Heart Failure (2016)
Abstract 1806: TRIM24 is an oncogenic transcriptional activator in prostate cancer
Authors: Anna C. Groner, Laura Cato, Jonas de Tribolet-Hardy, Tiziano Bernasocchi, Qing Zhong, Christian Fankhauser, Christine Fritz, Cédric Poyet, Ulrich Wagner, Levi A. Garraway, Peter J. Wild, Jean-Philippe Theurillat, Myles Brown
Journal: Cancer Research (2016)

Abstract Androgen receptor (AR) signaling is a key driver of prostate cancer (PC). While androgen-deprivation therapy is transiently effective in advanced disease, tumors often progress to a lethal castration-resistant state (CRPC). We show that recurrent PC-driver mutations in SPOP stabilize the TRIM24 protein, which promotes proliferation under low androgen conditions. TRIM24 augments AR signaling, and AR and TRIM24 co-activated genes are significantly up-regulated in CRPC. Expression of TRIM24 protein increases from primary PC to CRPC, and both TRIM24 protein levels and the AR/TRIM24 gene signature predict disease-recurrence. Analyses in CRPC cells reveal that the TRIM24 bromodomain and the AR-interacting motif are essential to support proliferation. These data provide a rationale for therapeutic TRIM24 targeting in SPOP-mutant and CRPC patients. Citation Format: Anna C. Groner, Laura Cato, Jonas de Tribolet-Hardy, Tiziano Bernasocchi, Qing Zhong, Christian Fankhauser, Christine Fritz, Cédric Poyet, Ulrich Wagner, Levi A. Garraway, Peter J. Wild, Jean-Philippe Theurillat, Myles Brown. TRIM24 is an oncogenic transcriptional activator in prostate cancer. [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 1806.
Management of Bleeding With Non–Vitamin K Antagonist Oral Anticoagulants in the Era of Specific Reversal Agents
Authors: Christian T. Ruff, Robert P. Giugliano, Elliott M. Antman
Journal: Circulation (2016)

Vitamin K antagonists are commonly used by clinicians to provide anticoagulation to patients who have or are at risk of having thrombotic events. In addition to familiarity with the dosing and monitoring of vitamin K antagonists, clinicians are accustomed to using vitamin K if there is a need to reverse the anticoagulant effect of vitamin K antagonists. There are now 4 new non–vitamin K antagonist oral anticoagulants (NOACs) that are attractive alternatives to vitamin K antagonists. Despite similar or lower rates of serious bleeding with NOACs in comparison with warfarin, there is a pressing need for strategies to manage bleeding when it does occur with NOACs and to reverse the pharmacological effect of these agents if needed. Important steps in minimizing bleeding risks with NOACs include dose adjustment of the agents in the setting of renal dysfunction and avoidance of the concomitant use of other antithrombotic agents if feasible. Laboratory measurement of the anticoagulant effect of NOACs is best accomplished with specialized assays, although some of the more widely available coagulation tests can provide information that is potentially useful to clinicians. Nonspecific hemostatic agents such as prothrombin complex concentrates and recombinant factor VIIa can be used to reverse the effect of NOACs. More specific reversing agents include the approved humanized monoclonal antibody fragment idarucizumab for reversing the effects of dabigatran, the investigational factor Xa decoy andexanet alfa, and the synthetic small molecule ciraparantag. Both andexanet and ciraparantag have been reported to reverse the effects of the anti-Xa NOACs (rivaroxaban, apixaban, and edoxaban), and a number of other anticoagulant agents in common clinical use, as well.
Abstract 99: Ovarian cancer specific therapeutic vulnerability
Authors: Kosuke Yoshihara, Ryo Tamura, Kazuaki Suda, Tatsuya Ishiguro, Takayuki Enomoto
Journal: Cancer Research (2016)

Abstract High-grade serous ovarian cancer comprises approximately 40% of epithelial ovarian cancer cases and is the most aggressive histologic type. Because this type of cancer usually presents as advanced stage disease at the time of diagnosis, the clinical outcome in patients with advanced stage ovarian cancer remains poor. A recent study has identified that homozygous deleted essential-redundant genes generate therapeutic vulnerabilities in glioblastoma multiforme. On the other hand, a pan-cancer analysis of somatic copy number alterations demonstrates that ovarian cancer has high frequent somatic copy number alterations compared to other tumor types including glioblastoma. Therefore, we hypothesized that ovarian cancer has also therapeutic vulnerabilities leading to development of new therapeutic strategies. To discover ovarian cancer specific vulnerability, we used DNA copy number and mRNA expression data submitted to the Cancer Genome Atlas. First, we performed GISTIC 2.0 to detect copy number alterations and found 4107 genes with homozygous deletion in at least 1% of 562 ovarian cancer samples. Of them, 3060 genes had at least one paralogue gene defined by Ensembl. We focused on metabolism pathway to extract 182 metabolism-related genes. By comparing gene expression between homozygous deletion samples and others using unpaired t-test, we identified 73 genes that were significantly down-regulated in homozygous deletion samples (p &amp;lt; 0.05). Next, we used copy number data submitted to Cancer Cell Line Encyclopedia to discover 41 candidate genes that were homozygously deleted in at least one ovarian cancer cell line. These findings suggest that cancer specific vulnerability exists not only glioblastoma multiforme but also other tumor types including ovaryan cancer and that further functional validation of 41 candidate genes might lead to development of new therapeutic strategies in ovarian cancer in the near future. Citation Format: Kosuke Yoshihara, Ryo Tamura, Kazuaki Suda, Tatsuya Ishiguro, Takayuki Enomoto. Ovarian cancer specific therapeutic vulnerability. [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 99.
Intellectual Outcome in Molecular Subgroups of Medulloblastoma
Authors: Iska Moxon-Emre, Michael D. Taylor, Eric Bouffet, Kristina Hardy, Cynthia J. Campen, David Malkin, Cynthia Hawkins, Normand Laperriere, Vijay Ramaswamy, Ute Bartels, Nadia Scantlebury, Laura Janzen, Nicole Law, Karin S. Walsh, Donald J. Mabbott
Journal: Journal of Clinical Oncology (2016)

Purpose To evaluate intellectual functioning and the implications of limiting radiation exposure in the four biologically distinct subgroups of medulloblastoma: wingless (WNT), sonic hedgehog (SHH), Group 3, and Group 4. Patients and Methods A total of 121 patients with medulloblastoma (n = 51, Group 4; n = 25, Group 3; n = 28, SHH; and n = 17, WNT), who were treated between 1991 and 2013 at the Hospital for Sick Children (Toronto, Ontario, Canada), Children's National Health System (Washington, DC), or the Lucile Packard Children's Hospital (Palo Alto, CA), had intellectual assessments. First, we compared intellectual trajectories between subgroups. Next, we evaluated the effect of treatment with reduced-dose craniospinal irradiation (CSI) plus a tumor bed boost versus treatments that deliver higher CSI doses and/or larger boost volumes to the brain (all other treatments) within subgroups. Linear mixed modeling was used to determine the stability or change in intelligence scores over time. Results Intellectual outcomes declined comparably in each subgroup except for processing speed; SHH declined less than Group 3 ( P = .04). SHH had the lowest incidence of cerebellar mutism and motor deficits. Treatment with reduced-dose CSI plus a tumor bed boost was associated with preserved intellectual functioning in WNT and Group 4 patients considered together (ie, subgroups containing patients who are candidates for therapy de-escalation), and not in Group 3 or SHH. Across all subgroups, patients in the all other treatments group declined over time (all P < .05). Conclusion SHH patients appear to have the most distinct functional (ie, motor deficits and mutism) outcomes and a unique processing speed trajectory. Only WNT and Group 4 patients seem to benefit from limiting radiation exposure. Our findings highlight the value of conducting subgroup-specific analyses, and can be used to inform novel biologically based treatment protocols for patients with medulloblastoma.
Abstract LB-162: BRCA2, and not BRCA1, dependent crosstalk between replication stress suppression and nucleotide excision repair - Clinical implications
Authors: Shailja Pathania, Rachel Reed, Haohui Duan, Aedin Culhane, Judy Garber
Journal: Cancer Research (2016)

Abstract BRCA2, a breast and ovarian tumor suppressor, is required for replication stress suppression through its role in repair of stalled replication forks. Here we report that inefficient resolution of stalled replication forks in absence of BRCA2 results in persistent accumulation of mostly un-phosphorylated RPA32 (at S33, T21 and S4/S8) at stalled replication forks. Furthermore, this ‘persistent’ accumulation of RPA32 coated ssDNA not only results in fork collapse, as marked by increased accumulation of both 53BP1 and Mre11 at the site of stalling, but also leads to suppression of nucleotide excision repair (NER), especially in S phase population. No such persistent RPA32 coated ssDNA is observed in BRCA1 depleted cells, suggesting that this intermediate is exclusive to BRCA2 deficiency. Furthermore, generation of this intermediate was not dependent on Mre11 implying that persistent accumulation of RPA32 coated ssDNA was not a result of excessive DNA processing by Mre11 exonuclease in absence of BRCA2. This is the first report of differences between BRCA1 and BRCA2 role at stalled replication forks. In this report, we also show that BRCA2 heterozygous primary mammary epithelial cells, and not BRCA1 heterozygous cells, are haploinsufficient for nucleotide excision repair. This would imply higher predisposition to skin lesions, including melanoma in BRCA2 mutation carriers. Risk for melanoma is indeed higher in BRCA2 mutation carriers compared to BRCA1 mutation carriers. We further confirmed that there exists a difference in mutational signature in whole genome sequences derived from BRCA1 and BRCA2 tumors, in line with the kind of differences expected if there is an increased NER defect in BRCA2 mutated cells when compared to BRCA1 mutated cells. Our findings provide first such DNA repair mechanism based evidence that could potentially explain the differences in BRCA1 and BRCA2 mutation driven risk for melanoma. This mechanistic difference between BRCA1 and BRCA2 response at stalled replication forks, and subsequently a crosstalk with nucleotide excision repair, might also contribute towards other clinical differences observed in BRCA1 and BRCA2 mutation driven breast cancer. Citation Format: Shailja Pathania, Rachel Reed, Haohui Duan, Aedin Culhane, Judy Garber. BRCA2, and not BRCA1, dependent crosstalk between replication stress suppression and nucleotide excision repair - Clinical implications. [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 LB-162.
To the American Internist: 1972
Authors: Hugh R. Butt
Journal: Annals of Internal Medicine (1972)

Editorials1 November 1972To the American Internist: 1972HUGH R. BUTT, M.D.HUGH R. BUTT, M.D.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-77-5-807 SectionsAboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail ExcerptThe medical profession, like all special units of society, sees criticism or intervention from without as a threat to its purposes; but certainly the public have a right to demand that their physicians maintain their professional excellence at all times.We are internists because we have achieved a degree of excellence in professional skills. To continue to meet the justifiable expectations of the public, we must have within our professional lives a system of continuing education with potential for solid improvement of our skills. In support of excellence throughout our profession we must actively lead and participate in peer review... This content is PDF only. To continue reading please click on the PDF icon. Author, Article, and Disclosure InformationAffiliations: Department of Gastroenterology and Internal Medicine Mayo Clinic Rochester, Minn.*Based on "Remarks by the President," given by Dr. Butt on 17 April 1972 at the Convocation, Fifty-Third Annual Session, American College of Physicians, Atlantic City, NJ. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics Cited byOutlook for Treating Patients with Self-Destructive HabitsJOHN F. BURNUM, M.D., F.A.C.P. 1 November 1972Volume 77, Issue 5Page: 807-808KeywordsMotivationPeer review ePublished: 1 December 2008 Issue Published: 1 November 1972 PDF downloadLoading ...
Abstract 4758: Benzaldehyde suppresses multiple signal pathways in cancer cells by regulating 14-3-3ζ-mediated protein-protein interactions
Authors: Jun Saitoh, Hideyuki Saya
Journal: Cancer Research (2016)

Abstract Benzaldehyde is the simplest aromatic aldehyde constituent of almonds and many fruits. Anticancer effect of Benzaldehyde was first reported in 1980, and multi-institutional clinical trials were performed in those days in Japan. However trial was over without determination of effectiveness, only its safety was confirmed. The underlying mechanism why Benzaldehyde specifically suppresses growth of some particular cancer cells but not that of normal cells has not been elucidated. Therefore, we attempted to clarify the mechanism of anticancer effect of Benzaldehyde. In pancreatic cancer cell BxPC3 and in non-small cell lung cancer cell A549, we found that Benzaldehyde inhibits PI3K/AKT/mTOR, STAT3, NFκB and ERK pathways, those are major signaling pathways activated in cancer cells. Effects of Benzaldehyde on multiple signaling pathways are found to be derived from regulation of 14-3-3 family proteins which interact with phosphorylation sites of various proteins of multiple signals. In BxPC3 cells, Benzaldehyde treatment reduced the phosphorylation levels of 14-3-3-binding sites. Furthermore, we ectopically expressed seven isoforms of 14-3-3 in HEK293T cells and found that Benzaldehyde treatment significantly suppressed association of 14-3-3ζ with client proteins such as mTOR, Rictor, cRaf, STAT3 and FOXOs. The interaction of other isoforms of 14-3-3 with their client proteins was also partially reduced. But, the expression levels of those seven 14-3-3 isoforms were not significantly changed. Those data indicate that Benzaldehyde suppresses the interaction of 14-3-3ζ with its client proteins. Recent reports have shown that 14-3-3ζ is overexpressed in many cancers and acts as a signaling hub controlling the network of oncogenic pathways, suggesting that 14-3-3ζ associates with carcinogenesis, metastasis and resistance for chemotherapy and radiation. Hence, Benzaldehyde is considered to be a new class of anti-cancer agent inhibiting 14-3-3ζ-mediated tumor promoting and/or maintaining signals. Citation Format: Jun Saitoh, Hideyuki Saya. Benzaldehyde suppresses multiple signal pathways in cancer cells by regulating 14-3-3ζ-mediated protein-protein interactions. [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 4758.
Abstract 149: Integrated analysis of intratumor heterogeneity with genetic and epigenetic aberrations during colorectal cancer evolution
Authors: Shinya Kidogami, Atsushi Niida, Ryutaro Uchi, Yusuke Takahashi, Masaki Mori, Satoru Miyano, Koshi Mimori
Journal: Cancer Research (2016)

Abstract [background] Intratumor heterogeneity (ITH) is presumably generated by branching clonal evolution of cancer cells. Recently, a multiregional sequencing approach, which sequences DNA sampled from geographically separated regions of a single tumor, has revealed branched evolution and ITH. In this study, we present genetic and epigenetic analysis of ITH in a series of nine colorectal cancers [material and method] We conducted analysis of samples from geographically separated regions from nine colorectal tumors. From each of the nine tumor, we obtained 5-21 multiregional samples, which were 75 samples in total, together with 9 paired normal mucosa samples. For two cases, samples from liver metastases were obtained. We performed exome sequencing and copy number (CN), methylation, and mRNA expression array profiling. [Result] Each of the multiregional mutation profiles harbored founder and progressor mutations; founder mutations are shared by all regions while progressor mutations are not. We found that mutations in well-known driver genes such as APC, KRAS, and FBWX7 were acquired as founder mutations, while mutations in PIK3CA recurrently occurred as progressor mutations, suggesting that PIK3CA mutations are a late event in the evolution of colorectal cancer. We counted each category of mutation and then identified a correlation between the number of founder mutations and the age of the patients. Our analysis showed that C &amp;gt; T transitions at CpG sites are more prominent in founder mutations than in progressor mutations. Then, the multiregional CN profiles showed that amplifications of 7p, 13q, 10q, 20p, and 20q frequently occurred across all samples in multiple tumors, namely as founder CN alterations. Finally, our data showed that hypermethylations in CpG islands were more prominent in founder methylations than in progressor methylations, suggesting that CpG island hypermethylations mainly occur in the early phase of colorectal cancer evolution. [Conclusion] In this study, our integrated analysis revealed not only extensive ITH, but also the evolutionary histories of the nine tumors. In particular, by focusing on founder and progressor mutations, we identified clues for decoding the life history of the tumors. Citation Format: Shinya Kidogami, Atsushi Niida, Ryutaro Uchi, Yusuke Takahashi, Masaki Mori, Satoru Miyano, Koshi Mimori. Integrated analysis of intratumor heterogeneity with genetic and epigenetic aberrations during colorectal cancer evolution. [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 149.
Chemokine (C‐C motif) receptor 2–positive monocytes aggravate the early phase of acetaminophen‐induced acute liver injury
Authors: Jana C. Mossanen, Oliver Krenkel, Can Ergen, Olivier Govaere, Anke Liepelt, Tobias Puengel, Felix Heymann, Sandra Kalthoff, Eric Lefebvre, Dirk Eulberg, Tom Luedde, Gernot Marx, Christian P. Strassburg, Tania Roskams, Christian Trautwein, Frank Tacke
Journal: Hepatology (2016)

Acetaminophen (APAP, paracetamol) poisoning is a leading cause of acute liver failure (ALF) in humans and induces hepatocyte necrosis, followed by activation of the innate immune system, further aggravating liver injury. The role of infiltrating monocytes during the early phase of ALF is still ambiguous. Upon experimental APAP overdose in mice, monocyte-derived macrophages (MoMFs) massively accumulated in injured liver within 12-24 hours, whereas the number of tissue-resident macrophages (Kupffer cells) decreased. Influx of MoMFs is dependent on the chemokine receptor, chemokine (C-C motif) receptor 2 (CCR2), given that Ccr2-/- mice display reduced infiltration of monocytes and attenuated liver injury post-APAP overdose at early time points. As evidenced by intravital multiphoton microscopy of Ccr2 reporter mice, CCR2+ monocytes infiltrate liver as early as 8-12 hours post-APAP overdose and form dense cellular clusters around necrotic areas. CCR2+ MoMFs express a distinct pattern of inflammatory, but also repair-associated, genes in injured livers. Adoptive transfer experiments revealed that MoMFs primarily exert proinflammatory functions early post-APAP, thereby aggravating liver injury. Consequently, early pharmacological inhibition of either chemokine (C-C motif) ligand (CCL2; by the inhibitor, mNOX-E36) or CCR2 (by the orally available dual CCR2/CCR5 inhibitor, cenicriviroc) reduces monocyte infiltration and APAP-induced liver injury (AILI) in mice. Importantly, neither the early nor continuous inhibition of CCR2 hinder repair processes during resolution from injury. In line with this, human livers of ALF patients requiring liver transplantation reveal increased CD68+ hepatic macrophage numbers with massive infiltrates of periportal CCR2+ macrophages that display a proinflammatory polarization.Infiltrating monocyte-derived macrophages aggravate APAP hepatotoxicity, and the pharmacological inhibition of either CCL2 or CCR2 might bear therapeutic potential by reducing the inflammatory reaction during the early phase of AILI. (Hepatology 2016;64:1667-1682).