tbuckley/cabot-search huggingface dataset:
The Egyptian Goddess
Authors: Jack Coulehan
Journal: Annals of Internal Medicine (2019)

Ad Libitum19 March 2019The Egyptian GoddessJack Coulehan, MD, MPHJack Coulehan, MD, MPHSetauket, New York (J.C.)Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/M18-1489 Audio Reading - “The Egyptian Goddess” Audio. Michael LaCombe, MD, Annals Associate Editor, reads “The Egyptian Goddess” by Jack Coulehan, MD, MPH Your browser does not support the audio element. Audio player progress bar Step backward in current audio track Play current audio trackPause current audio track Step forward in current audio track Mute current audio trackUnmute current audio track 00:00/ SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail the goddess as I eat lunch ... Author, Article, and Disclosure InformationAffiliations: Setauket, New York (J.C.)Current Author Address: Jack Coulehan, MD, MPH; e-mail, [email protected]com. PreviousarticleNextarticle Advertisement Audio Reading - “The Egyptian Goddess” Audio. Michael LaCombe, MD, Annals Associate Editor, reads “The Egyptian Goddess” by Jack Coulehan, MD, MPH Your browser does not support the audio element. Audio player progress bar Step backward in current audio track Play current audio trackPause current audio track Step forward in current audio track Mute current audio trackUnmute current audio track 00:00/ FiguresReferencesRelatedDetails Metrics 19 March 2019Volume 170, Issue 6Page: 422KeywordsIschemiaRiversStroke ePublished: 19 March 2019 Issue Published: 19 March 2019 Copyright & PermissionsCopyright © 2019 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
Machine learning approaches to improve prostate cancer outcome.
Authors: Ronnie Rodrigues Pereira, Crispin Miller, Esther Baena, Robert G. Bristow
Journal: Journal of Clinical Oncology (2019)

82 Background: High-risk Prostate Cancer (PCa) occurs in as much as 37% of PCa cases in England and Wales. This proportion is much higher than in other developed countries. Furthermore, there is an imprecision in the primary treatment of these patients. More specifically, in the administration of systemic therapy. Currently, surgeons prescribe radical prostatectomy and radiation, while radiation oncologists often combine radiation with androgen deprivation therapy (ADT). However, ADT has significant side effects and not all patients develop Biochemical Recurrence/Metastasis. Furthermore, clinical factors have limited ability to identify these patients. Consequently, we turn to biomarker discovery for more accurate disease management. Methods: We applied a machine learning strategy to identify discriminatory DNA Methylation patterns between patients with biochemical recurrence from those with stable disease in high-risk PCa (D’Amico Classification, T-stage ≤ 3a). Training and feature selection occurred in cross-validation (4 Folds, 10 reps) on 102 patients from the TCGA-PRAD dataset (26 BCR). Gene co-expression networks were derived from mRNA expression (|Pearson correlation| &gt; 0.70). Network clustering maximised global modularity (Louvain algorithm) and unsupervised clustering evaluated complete linkage. Functional enrichment employed MiSigDB Hallmarks and g:ProfileR. Results: A linear support vector machine outperformed Naïve Bayes, Random Forest and Artificial Neural Networks with an AUC = 0.91 ± 0.14 (95% CI). This epigenomic test preferentially sub-stratifies high-risk patients, as it shows no improvement over the “No Information Rate” of intermediate- and low-risk patients (p-value &gt; 0.05, t-test). We identified functional clusters from a co-expression network superimposed with the genes most correlated to the epigenomic test. The most enriched cluster reveals disturbances in MYC targets, cell cycle and RNA splicing. Conclusions: Preliminary results indicate that an epigenomic test identifies a sub-group of patients which could benefit from ADT at the stage of primary treatment, however it requires further validation.
Circulating cellular biomarkers associated with delayed time to progression among bladder cancer patients treated with immune checkpoint inhibitors.
Authors: Vadim S Koshkin, Terence W. Friedlander, Patricia Li, Joseph Schonhoft, Rachel Krupa, Robin Richardson, Priscilla Ontiveros, Yipeng Wang, Ryan Dittamore, Pamela Paris
Journal: Journal of Clinical Oncology (2019)

398 Background: Circulating tumor cells (CTCs) are an important emerging biomarker in bladder cancer that allow for a minimally invasive assessment of tumor activity and response to treatment. Characterization of CTC and other single cell populations associated with improved clinical outcomes can help guide treatment recommendations for patients with metastatic bladder cancer. Methods: Patients with metastatic bladder cancer who received treatment with anti-PD-1 or anti-PD-L1 agents were enrolled in this study. Patient response to treatment was assessed by treating physicians according to RECIST v1.1. Blood samples were prospectively collected from patients prior to the initiation of therapy and then while on treatment and shipped to Epic Sciences for processing. All nucleated cells were subjected to immunofluorescent (IF) staining and CTC and leukocyte identification by fluorescent scanners using algorithmic analysis. Kaplan-Meier analysis was utilized to compare time to progression of patients whose CTC and leukocyte values were above and below several pre-determined parameters. Results: A total of 27 patients (median age 74 years, 70% male) were enrolled in this study and were treated with anti-PD-1/PD-L1 agents pembrolizumab (n=15), atezolizumab (n=11), or nivolumab (n=1). For 20 patients who had evaluable responses, objective response rate (ORR) was 2/20 (10%), all partial responses; another 5/20 (35%) had stable disease. Increased CD4% (&gt;8% of total leukocytes) was associated with delayed time to progression (TTP) (p=0.002) whereas increased baseline total CTCs (&gt;2) had a statistically non-significant trend towards shorter TTP (p=0.09). Baseline CD8%, CD4/CD8 ratio and CTC PD-L1 status were not associated with TTP. Conclusions: In a preliminary analysis among metastatic bladder cancer patients treated with immune checkpoint inhibitors, patients with an increased baseline CTC count had a statistically non-significant trend towards shorter TTP whereas increased baseline CD4 cells had an association with delayed TTP. This prospective study is ongoing, and the results will be further validated in larger patient cohorts.
Proteomic Landscape of Neutrophils in Sickle Cell Anemia: An Unexpected Autoimmune Profile
Authors: Patricia Hermand-Tournamille, Slim Azouzi, Virginie Salnot, Emilie Fleur Gautier, Patrick Mayeux, Yves Colin, Vincent Bondet, Darragh Duffy, Pierre Louis Tharaux, Caroline Le Va Kim, Bérengère Koehl
Journal: Blood (2018)
Single-cell transcriptomic analysis of the lateral hypothalamic area reveals molecularly distinct populations of inhibitory and excitatory neurons
Authors: Laura E. Mickelsen, Mohan Bolisetty, Brock R. Chimileski, Akie Fujita, Eric J. Beltrami, James T. Costanzo, Jacob R. Naparstek, Paul Robson, Alexander C. Jackson
Journal: Nature Neuroscience (2019)
Induced pluripotent stem cells as a model to test gene augmentation therapy for choroideremia (Conference Abstract)
Authors: Vidyullatha Vasireddy, Jason Mills, Rajashekhar Gaddameedi, Etiena Basner-Tschakarjan, Monika Kohnke, Aaron Black, Kirill Alexandrov, Albert Maguire, Daniel Chung, Helen Mac, Lisa Sullivan, Paul Gadue, Jeannette Bennicelli, Deborah French, Jean Bennett
Journal: Molecular Therapy (2013)
Abstract 1122: The Mammalian Heart Contains Vascular and Myocyte Niches
Authors: Nicole LeCapitaine, Claudia Bearzi, Konrad Urbanek, Federico Mosna, Alessandro Gatti, Marcello Rota, Roberto Bolli, Robert E Michler, David A D’Alessandro, Annarosa Leri, Jan Kajstura, Piero Anversa
Journal: Circulation (2007)

During development the myocyte compartment and the coronary vasculature are generated from distinct progenitor cell classes which are activated at different stages of embryonic life. To determine whether the adult heart is similarly regulated by a coronary vascular progenitor cell (VPC) and a myocyte progenitor cell (MPC), the presence of vascular and myocyte niches was established in the mouse, rat, dog and human heart. Typically, VPCs are c-kit-positive and flk1/KDR positive while MPCs are c-kit-positive but flk1/KDR negative. These phenotypic properties were employed to identify vascular niches within the coronary circulation and myocyte niches in the myocardial interstitium. By definition, vascular and myocyte niches have to be composed of progenitor cells structurally and functionally connected to supporting cells, which modulate growth signals involved in the preservation of stemness and activation of cell differentiation. In the heart of rodents, dogs and humans, flk1/KDR positive VPCs were detecte...
DIABETES IS ASSOCIATED WITH WORSE LONG-TERM OUTCOMES IN YOUNG ADULTS AFTER MYOCARDIAL INFARCTION: THE PARTNERS YOUNG-MI REGISTRY
Authors: Sanjay Divakaran, Avinainder Singh, David Biery, Junjie Yang, Ersilia M. DeFilippis, Bradley Collins, Mattheus Ramsis, Arman Qamar, Jon Hainer, Josh Klein, Christopher Cannon, Donna M. Polk, Jorge Plutzky, Khurram Nasir, Marcelo Di Carli, Deepak L. Bhatt, Ron Blankstein
Journal: Journal of the American College of Cardiology (2019)
A prospective, single-arm, phase I/II trial of RAS peptide vaccine TG01/GM-CSF and gemcitabine as adjuvant therapy for patients with resected pancreatic adenocarcinoma.
Authors: Daniel H. Palmer, Svein Dueland, Juan W. Valle, Tone Otterhaug, Jon Amund Eriksen, Helene Muller, Berit Iversen, Robert M. Miller
Journal: Journal of Clinical Oncology (2015)

4121 Background: TG01 targets oncogenic mutations in RAS genes that are present in 80-90% of pancreatic cancers. TG01 is a mixture of 7 RAS peptides and previously, as monotherapy in patients with pancreatic cancer, induced specific cellular immune responses in 100% of patients. This study evaluated safety and whether induced immune responses are maintained with standard adjuvant chemotherapy. Methods: Patients were eligible after an R0 or R1 pancreatic adenocarcinoma resection and expected to receive gemcitabine (1000 mg/m2 for 3/4 weeks x 6 cycles) started within 12 weeks of surgery. For gemcitabine toxicity 5-FU/leucovorin could be substituted. TG01 0.7 mg id was given on days 1, 3, 5, 8, 15, 22 and 2-weekly until end of chemotherapy, 4-weekly up to 1 year and 12-weekly thereafter. GM-CSF 0.03 mg id was given 15 minutes prior to TG01. TG01 was used for the DTH test. Results: 18 patients were included from 3 sites (Norway and UK). 6 patients are ongoing 3 to 50 weeks from the start of vaccinations. 5 patients were withdrawn due to recurrent disease, 1 for an unrelated death, 3 for related AEs and 2 for other reasons. 10 SAEs in 6 patients occurred; 3 related to gemcitabine (pulmonary infection and fever) and 2 related to TG01 (anaphylaxis) the others were unrelated to gemcitabine or GM-CSF/TG01. The main AEs related to GM-CSF/TG01 were local reactions in 4/18 patients (8 events), allergic reactions in 4/18 patients (6 events); one occurring before gemcitabine (Grade 1). Anaphylaxis only occurred after gemcitabine completion. Other adverse events were flu-like symptoms and single cases of fatigue, arthralgia, fever, nausea and vomiting. 14/16 patients (87.5%) had a positive DTH by week 11 persisting after gemcitabine and to date 7/8 patients (87.5%) generated positive T cell responses. Conclusions: TG01/GM-CSF generated immune responses in 87.5% of patients with resected pancreatic cancer, these responses were maintained with chemotherapy and persisted with booster injections. The regimen was generally well tolerated although some late allergic reactions were seen. Clinical trial information: NCT02261714.
Abstract P224: Chili Pepper Intake and Risk of Total and Cardiovascular Mortality in Italian Adults: Prospective Findings From the Moli-Sani Study
Authors: Marialaura Bonaccio, Augusto Di Castelnuovo, Simona Costanzo, Emilia Ruggiero, Amalia De Curtis, Mariarosaria Persichillo, Chiara Cerletti, Maria Benedetta Donati, Giovanni de Gaetano, Licia Iacoviello
Journal: Circulation (2019)

Introduction: Chili pepper, along with other spices, is an integral part of a traditional Mediterranean diet (MD). Yet there is paucity of epidemiological data on the association between chili pepper intake and mortality risk, with lack of studies from Mediterranean populations. Hypothesis: We assessed the hypothesis of an association between chili pepper consumption and total and cardiovascular (CVD) risk of death in a large sample of the Italian general population, and tested different biological mediators of the association. Methods: Longitudinal analysis on 22,811 men and women aged≥35 years enrolled in the Moli-sani Study cohort, Italy (2005-2010). Chili pepper intake was estimated by the EPIC food frequency questionnaire and categorized as none/rare consumption, up to 2 times/week, 2-4 and &gt; 4 times/week. Multivariable hazard ratios (HR) with 95% confidence intervals (95%CI) were calculated by multivariable Cox regression and competing risk models. Results: Over a median follow up of 8.2 years, a total of 1,236 deaths were ascertained, of which 444 from CVD. Multivariable risk estimates for all-cause and CVD mortality among participants in the regular (&gt;4 times/week) relative to the none-rare intake were, respectively, 0.77 (0.66-0.90) and 0.66 (0.50-0.86). Regular intake also lowered ischemic heart disease (0.55;0.35-0.87) and cerebrovascular death risks (0.39;0.20-0.76). Traditional CVD risk factors (e.g. blood cholesterol, triglycerides) only marginally account for such associations (Table). Conclusions: In a large Mediterranean population, regular consumption of chili pepper is associated with lower risk of total and CVD death independent of adherence to MD. Known biomarkers only marginally accounted for the association of chili pepper intake with total mortality.
Genomic features of metastatic testicular sex cord stromal tumors.
Authors: Andrea Necchi, Gennady Bratslavsky, Rubin Pinkhasov, Oleg Shapiro, Laurie M. Gay, Julia Andrea Elvin, Jo-Anne Vergilio, Jonathan Keith Killian, Nhu Thi Nho, Shakti Ramkissoon, Eric Allan Severson, Amanda Hemmerich, Siraj Mahamed Ali, Jon Chung, Venkataprasanth P. Reddy, Vincent A. Miller, Alexa Betzig Schrock, Jeffrey S. Ross, Nick Liu, Joseph Jacob
Journal: Journal of Clinical Oncology (2019)

532 Background: Metastatic testicular sex cord stromal tumors of the testis (MSCST) comprise an extremely uncommon form of genitourinary malignancy. In a comparative genomic study, we performed comprehensive genomic profiling (CGP) to characterize the genomic alterations (GA) in MSCST and to enable the search for potential therapy targets. Methods: The MSCST were classified as metastatic Leydig Cell Tumors (LCT), Sertoli Cell Tumors (SCT) and Undifferentiated (USCST). In this study, 10 cases of LCT, 6 cases of SCT and 3 cases of USCST underwent hybrid-capture based CGP to evaluate all classes of genomic alterations. Tumor mutational burden (TMB) was determined on 1.1 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on 114 loci. Results: All patients had clinically advanced recurrent and/or metastatic disease. The primary testis tumor was used for sequencing in 6 MSCST (32%) and a metastatic site in 9 (68%) of the MSCST. In 10 (91%) of 11 MSCST positively stained by IHC for inhibin expression. The overall frequencies of GA were similar in all LCT, SCT and UTST ranging from 3.0 to 3.5 GA/tumor. The most frequent untargetable GA found in all MSCST cases included CTNNB1 and CDKN2A/B, both ranging from 20-33% of cases. Targetable GA were uncommon in all MSCST sub-groups but several tumors featured potential for cell cycle inhibitors ( CDK4 in LCT), MTOR inhibitors ( RICTOR, NF2 and PTEN in all 3 tumor types), hedgehog inhibitors ( PTCH1 in LCT) and PARP inhibitors ( BAP1 in SCT). No MSI-High status was identified in any MSCST. The TMB was also low in all MSCST groups. Conclusions: Although the 3 subgroups of testicular MSCST feature defining histopathologic features, these tumors have similar genomic signatures on CGP. The low levels of GA per tumor, infrequent tumor aneuploidy, absence of MSI-High status and low TMB all indicate that testicular MSCST are genetically stable. However, rare cases of testicular MSCST reveal GA linked to potential targeted therapy benefits on CGP linked to dysregulation of multiple biologic pathways. In contrast, the lack of MSI-High status and overall low TMB in testicular MSCST indicates a likely lack of benefit for immunotherapies for these rare forms of malignancy.
Abstract 17791: Association of Enhanced Adventitial Vasa Vasorum Formation With Atherosclerotic Changes in the Human Coronary Arteries Adjacent to Myocardial Bridging -An Optical Frequency Domain Imaging Study
Authors: Hongxin Wang, Yasuharu Matsumoto, Kensuke Nishimiya, Jun Takahashi, Hironori Uzuka, Kiyotaka Hao, Ryuji Tsuburaya, Hirokazu Amamizu, Kazuma Ohyama, Masayasu Komatsu, Yuji Odaka, Kenta Ito, Hiroaki Shimokawa
Journal: Circulation (2015)

Background: Although myocardial bridge (MB) has been implicated as a cause of adverse cardiac events, its pathological significance remains to be fully elucidated. Recent advance in imaging with optical frequency domain imaging (OFDI) has enabled us to precisely evaluate the coronary arterial wall in humans, including adventitial vasa vasorum (VV). In the present study, we thus examined with OFDI whether coronary adventitial VV formation is enhanced in the MB segments in humans and if so, whether there is any correlation between adventitial VV formation and atherosclerotic changes. Methods and Results: We examined 15 consecutive patients (age 67±2, M/F 7/8) who were diagnosed as having MB in the left anterior descending coronary arteries without significant organic stenosis in the present OFDI study. MB was diagnosed by CAG when systolic compression was noted, as previously reported. The cross-sectional OFDI showed diffuse enhancement of VV formation at the proximal and distal segments compared with the MB site ( Figure A ). Quantitative analysis at every 1-2 mm length showed that adventitial VV area density on OFDI was significantly greater at both the proximal and the distal segments compared with the MB site (0.122±0.005 vs. 0.075±0.003 vs. 0.108±0.005 mm 2 /mm 2 , P&lt;0.001) ( Figure B ). In addition, intimal (I) + medial (M) area was significantly greater at the proximal segments compared with the MB site and the distal segments. (2.70±0.12 vs. 1.66±0.07 vs. 1.83±0.11 mm 2 , P&lt;0.001) ( Figure C ). Importantly, there was a significant positive correlation between the extent of VV formation and that of I+M area in the coronary artery (R=0.582, P&lt;0.0001) ( Figure D ). Conclusions: These results suggest an important role of adventitial VV formation in the pathogenesis of human coronary atherosclerosis adjacent to the MB, for which altered blood turbulence may be involved.
A phase I study of intratumoral injection of ipilimumab and interleukin-2 in patients with unresectable stage III-IV melanoma.
Authors: Randy Christopher Bowen, Stephanie Meek, Matthew Williams, Kenneth F. Grossmann, Robert Hans Ingemar Andtbacka, Tawnya Lynn Bowles, John Robert Hyngstrom, Sancy Ann Leachman, Douglas Grossman, Sheri L Holmen, Matthew W VanBrocklin, Hung T. Khong
Journal: Journal of Clinical Oncology (2015)

3018 Background: Intratumoral (IT) IL-2 is highly effective and well tolerated, but does not generate systemic immunity or response in untreated lesions. Intravenous (IV) ipilimumab (Ipi) lowers the threshold for T cell activation leading to a durable clinical response in a minority of melanoma patients, but is associated with potentially severe toxicities. Since IV Ipi doesn’t have tissue distribution, circulating anti-tumor T cells activated by this drug may differ greatly from tumor-infiltrating lymphocytes (TILs) activated by IT Ipi in terms of quantity and quality. Therefore, we hypothesized that a combination of IT IL-2 and IT Ipi would effectively hyperactivate and expand TILs to engender systemic immunity with minimal toxicity. Methods: This was a phase I dose escalation study for Ipi with fixed dose IL-2 in patients with unresectable stage III/IV melanoma and at least one injectable lesion. A single lesion (0.5-2.0 cm) in each patient was treated with IL-2 (3 mIU) IT TIW x 2 weeks, then BIW x 6 weeks, with escalating doses of Ipi IT weekly x 8 wks. A minimum of 3 patients were enrolled at each dose level. Endpoints included safety, tumor responses, and changes in systemic T cells. Results: 12 patients were treated at 3 Ipi dose levels (0.5, 1, 2 mg). Treatments were well tolerated. The only grade 3 toxicity observed was injection/tumor site ulceration/necrosis, not a DLT per protocol. Other toxicities were grade 1 in nature. An abscopal effect (response in at least 1 non-injected lesion) was seen in 9/12 patients (75%). 10 patients were evaluable for response by immune-related response criteria: 4 PR (40%) and 6 PD. 1 PD was later found to be a CR by resection. The 2 nonevaluable patients had regression of multiple skin lesions. An increase in the frequency of total peripheral IFN-γ-producing CD8+ T cells was detected in 6/8 abscopal responders. Tbet+ and granzyme-B + CD8+ T cells were observed in 4/5 and 3/5 responders tested, respectively. Conclusions: IT injection with the combination of Ipi/IL-2 is well tolerated and generates responses in both injected and non-injected lesions in the majority of patients. We plan to conduct a phase II trial using IT Ipi/IL-2 in conjunction with systemic immunotherapy. Clinical trial information: NCT01672450.