tbuckley/cabot-search huggingface dataset:
Progression to Stage D Heart Failure Among Outpatients With Stage C Heart Failure and Reduced Ejection Fraction
Authors: Andreas P. Kalogeropoulos, Ayman Samman-Tahhan, Jeffrey S. Hedley, Andrew A. McCue, Jonathan B. Bjork, David W. Markham, Kunal N. Bhatt, Vasiliki V. Georgiopoulou, Andrew L. Smith, Javed Butler
Journal: JACC Heart Failure (2017)
Expert consensus document: The International Scientific Association for Probiotics and Prebiotics (ISAPP) consensus statement on the definition and scope of prebiotics
Authors: Glenn R. Gibson, Robert Hutkins, Mary Ellen Sanders, Susan L. Prescott, Raylene A. Reimer, Seppo J. Salminen, Karen Scott, Catherine Stanton, Kelly S. Swanson, Patrice D. Cani, Kristin Verbeke, Gregor Reid
Journal: Nature Reviews Gastroenterology & Hepatology (2017)
A model for trial level prediction of long term outcome based on pathological complete response (pCR) after neoadjuvant chemotherapy for early-stage breast cancer (EBC).
Authors: Valentina Nekljudova, Sibylle Loibl, Gunter Von Minckwitz, Stefan Gluck, Richard Crane, Huiling Li, Xiaolong Luo
Journal: Journal of Clinical Oncology (2016)

1031 Background: The FDA and EMA have published guidance for industry on the use of pCR as a surrogate endpoint to support accelerated approval in the neoadjuvant treatment of high-risk, EBC. The CTNeoBC consortium (Cortazar 2014), Berruti (2014) and Korn (2015) each used meta analyses to explore the trial level association between pCR odds ratio and the event hazards ratio but did not reach strong association. There are uncertainties raised in both guidances in determining the magnitude of increase in effect size in pCR that is reasonably likely to predict long term clinical benefit. Methods: We introduce a Cox regression model of the relationship among treatment, event hazard, and time dependent effect of pCR as joint co-variates. The trial level association between treatment and event hazard is derived and then shown to be linked with pCR rates. The methodaccounts for the magnitude of the patient level association, which is likely important in predicting clinical benefit. We apply the method to re-analyze the trial level data from CTNeoBC and derive an empirical relationship as an indirect validation between pCR and long term outcome. Results: For the 8 clinical trials included in the CTNeoBC analysis for trial level association, the predictor based on pCR and patient level association served well under the assumption of perfect surrogate endpoint. The difference away from the perfect surrogate prediction was to follow normal distribution based on Kolmogorov-Smirnov test. For event free survival (EFS), the Student's t test p-value of 0.02 suggested non-zero central location with the mean value of -0.161 (s.e. 0.058). For overall survival (OS), the Student's t test p-value of 0.0032 suggested non-zero central location with the mean value of -0.157 (s.e. 0.0393). The observed hazard ratios fit well with the predicted hazard ratios for both EFS and OS and suggest plausible trial level association with the new predictor. Conclusions: Our model predicts well the correlation between pCR and EFS as well as OS. This should serve as a supporting method to help assessment of positive results of clinical studies in the neoadjuvant setting.
Латерально распространяющиеся опухоли толстой кишки при колоноскопии с высокой разрешающей способностью, исследованием в узком спектре света и хромоскопией уксусной кислотой
Authors: V.A. Yakovenko
Journal: GASTROENTEROLOGY (2020)

Рак толстой кишки может развиваться из латерально распространяющихся опухолей. Эффективность колоноскопии для диагностики таких опухолей недостаточно изучена.Цель. Изучить диагностическую ценность колоноскопии с высокой разрешающей способностью, исследованием в узком спектре света и хромоскопией уксусной кислотой для выявления латерально распространяющихся опухолей.Материалы и методы. Были исследованы 1632 протокола колоноскопии: 735 — видеоколоноскопом Olympus CF-HQ190L и 897 — Olympus CF-150. Результаты и обсуждение. В исследовании показатель выявления аденом в опытной группе был достоверно выше, чем в группе контроля: 0,78 (571/735) против 0,47 (422/897), р &lt; 0,00001; χ2 = 157,9. Индекс выявления аденом в опытной группе был в 3,6 раза выше, чем в контрольной: 2,9 (2104/735) против 0,8 (708/897). В опытной группе пациенты с латерально распространяющимиси опухолями были выявлены в 2,2 раза чаще, чем в контрольной: 22 % (187/735) против 10 % (85/897), р &lt; 0,00001; χ2 = 53,6. Выводы. Колоноскопия с высокой разрешающей способностью, исследованием в узком спектре света и хромоскопией уксусной кислотой обладает высокой диагностической ценностью для выявления латерально распространяющихся опухолей толстого кишечника.
The epidemiological profile of hospitalized acquired infections (HAIs) due to multidrug-resistant (MDR) pathogens in patients with hematological malignancies and solid neoplasms: “Real World” experience of a single cancer hospital.
Authors: Maria Kotsopoulou, Dionisios Stoumbos, Stavroula Perlorentzou, Eutihia Kouloukakou, Nikolaos Ziras, Virginia Papaemmanouil
Journal: Journal of Clinical Oncology (2016)

e13104 Background: Isolates of pathogens that are resistant to all, or almost all, commercially available antibiotics are now prevalent worldwide. The increasing frequency of MDR pathogens is concerning as efficacious antimicrobial options are severely limited. Methods: We conducted a descriptive study including all notified cases of HAIs due to MDR organisms in patients with hematological malignancies and solid tumors, that between January 2014 and December 2015. We described case-patients with HAIs in terms of the clinic in which the infection was diagnosed, pathogen which caused the nosocomial infection and the site of infection in relation with the positive cultures obtained to verify it. Results: Overall, 425 case-patients were studied. The most frequently reported multidrug-resistant organisms were: Klebsiella pneumoniae KPC (50%), Clostridium difficile (11%), VRE Enterococcus faecium (10%), Pseudomonas aeruginosa MBL (8%), Klebsiella pneumoniae MBL (6%), Acinetobacter Baumanii (5%), Acinetobacter Baumanii MDR (3%), Providencia stuartii MBL (2%), MRSA Staphylococcus Aureus (2%), Acinetobacter Baumanii KPC (1%). Among all specialties, the most frequently reported wards were in ICU (37%) and Hematology (33%) followed by Oncology (21%), Surgery (7%) and Gastroenterology (1%). The distribution of the positive cultures for multi-drug resistant pathogens by site of infection was as follows: Stool (23%), Bronchial (18%), Rectal (17%), stool for C. Difficile (11%), blood (8%), urine (7%), catheter tip (5%), sputum (5%), trauma/abscess (4%), mouth swab (1%). Conclusions: Our results highlight that the statistical epidemiologic data available up to date, regarding the distribution of patients hospitalized with HAIs differ for patients with hematological malignancies and solid neoplasms. Future preventive strategies, control, and improved understanding of differences in sensitive populations must be addressed. Specialty n % ICU 159 37 Hematology 140 33 Oncology 89 21 Surgery 30 7 Gastroenterology 3 1 Gynecology 2 0 Urology 1 0 Endocrinology 1 0 Grand total 425
Magnetic Oculomotor Prosthetics for Acquired Nystagmus
Authors: Parashkev Nachev, Geoff E. Rose, David H. Verity, Sanjay G. Manohar, Kelly MacKenzie, Gill Adams, Maria Theodorou, Quentin A. Pankhurst, Christopher Kennard
Journal: Ophthalmology (2017)

Acquired nystagmus, a highly symptomatic consequence of damage to the substrates of oculomotor control, often is resistant to pharmacotherapy. Although heterogeneous in its neural cause, its expression is unified at the effector-the eye muscles themselves-where physical damping of the oscillation offers an alternative approach. Because direct surgical fixation would immobilize the globe, action at a distance is required to damp the oscillation at the point of fixation, allowing unhindered gaze shifts at other times. Implementing this idea magnetically, herein we describe the successful implantation of a novel magnetic oculomotor prosthesis in a patient.Case report of a pilot, experimental intervention.A 49-year-old man with longstanding, medication-resistant, upbeat nystagmus resulting from a paraneoplastic syndrome caused by stage 2A, grade I, nodular sclerosing Hodgkin's lymphoma.We designed a 2-part, titanium-encased, rare-earth magnet oculomotor prosthesis, powered to damp nystagmus without interfering with the larger forces involved in saccades. Its damping effects were confirmed when applied externally. We proceeded to implant the device in the patient, comparing visual functions and high-resolution oculography before and after implantation and monitoring the patient for more than 4 years after surgery.We recorded Snellen visual acuity before and after intervention, as well as the amplitude, drift velocity, frequency, and intensity of the nystagmus in each eye.The patient reported a clinically significant improvement of 1 line of Snellen acuity (from 6/9 bilaterally to 6/6 on the left and 6/5-2 on the right), reflecting an objectively measured reduction in the amplitude, drift velocity, frequency, and intensity of the nystagmus. These improvements were maintained throughout a follow-up of 4 years and enabled him to return to paid employment.This work opens a new field of implantable therapeutic devices-oculomotor prosthetics-designed to modify eye movements dynamically by physical means in cases where a purely neural approach is ineffective. Applied to acquired nystagmus refractory to all other interventions, it is shown successfully to damp pathologic eye oscillations while allowing normal saccadic shifts of gaze.
Effect of controlled intratumoral viral delivery of Ad-RTS-hIL-12 + oral veledimex in subjects with recurrent or progressive glioma.
Authors: Francois M. Lebel, John A. Barrett, E. Antonio Chiocca, John Yu, Rimas Vincas Lukas, Seema Nagpal, Priya Kumthekar, Suma Krishnan, Laurence JN Cooper
Journal: Journal of Clinical Oncology (2016)

2052 Background: The prognosis of subjects with glioblastoma multiforme (GBM) after first recurrence is extremely poor with a median overall survival (OS) of approximately 90 - 160 days. New therapies are needed, thus we developed an adenoviral vector, Ad-RTS-IL-12 (AD), administered intratumorally under the control of the RheoSwitch Therapeutic System (RTS) expression platform. Gene expression and IL-12 protein production is tightly controlled by activator ligand veledimex (V) and in our mouse model of glioma we have consistently shown a dose-response and survival benefit compared to temozolamide, bevacizumab, and a PD-1 inhibitor. Methods: In a multicenter Phase I dose escalation trial, subjects with recurrent or progressive Grade III or IV glioma undergoing resection were injected intratumorally with AD 2x1011viral particles and daily oral V for 15 doses, beginning on Day 0, prior to surgery. The study primary endpoint is safety and tolerability of AD+V with secondary endpoints including OS. Results: In the first cohort, consisting of 4 males and 3 females (ages 32-58), it was observed that V crossed the blood-brain barrier with 30±6% of the V plasma level in the resected tumor sample (17±6 ng/ml vs. 5±2 ng/ml). Peak serum IL-12 was observed at Day 3 (mean 23 pg/ml) and peak IFNg (mean 32 pg/ml) on Day 7. Peripheral blood samples showed an increase in CD8 T cells and an increase in the ratio of CD8/CD4 and CD8/FoxP3. AD+V was well tolerated with expected toxicities promptly reversing with discontinuance of V. Neurotoxicities were minimal and manageable. To date, 7/7 subjects are alive with 5 subjects having a follow-up of > 90 days and 3 > 160 days posttreatment. Conclusions: Intratumoral regulated IL-12 expression using AD+V in a salvage population with advanced and recurrent glioma has an acceptable and rapidly reversible safety profile. The intracranial administration of AD followed by oral V is clinically feasible and suggests possible benefit vs. historical control and provides a strong rational for dose-escalation as reviewed and approved by the independent Data Safety Monitoring Board. Clinical trial information: NCT02026271.
Diagnostic et surveillance de l'oesophage de Barrett en regard des recommandations de pratiques cliniques
Authors: N Amamra
Journal: Endoscopy (2005)

Depuis la publication en France d'une recommandation nationale en 1998 sur les modalités de diagnostic, de surveillance et de traitement de l'œsophage de Barrett, aucune étude n'a encore évalué la qualité des pratiques. Ce travail avait pour but de décrire les pratiques de prise en charge des patients porteurs d'un œsophage de Barrett en regard de cette recommandation et d'identifier les facteurs associés à leur application.
Frequency of variants of uncertain significance in BRCA1 and BRCA2 in an Irish cohort.
Authors: Michael P. Farrell, Gavin J. Truman, Rosie O Shea, David J. Hughes, David James Gallagher
Journal: Journal of Clinical Oncology (2016)

e13006 Background: Screening for germline BRCA1/2 mutations predisposing to hereditary breast ovarian cancer (HBOC) syndrome is complicated by the identification of genetic variants of uncertain significance (VUS). These are often rare missense variants, ranging from harmless polymorphisms to deleterious mutations. VUS’s are considered in pre- and post test counseling, and increasingly encountered due to the uptake of panel testing. We determined the frequency of VUS in an Irish HBOC cohort. Methods: The results of consecutive BRCA1/2 genetic analysis performed in the clinical cancer genetics departments of the Mater Private Hospital and the Mater Misericordiae University Hospital were correlated with personal and family history of cancer and age at diagnosis. Results: 519 individuals (501 females and 18 males) underwent formal genetic counseling and diagnostic BRCA1/2 screening between January 2011 and January 2016. Pathogenic mutations were identified in 57 (10.9%) of the individuals tested, 18 (3.4%) mutations in BRCA1 and 39 (7.5%) in BRCA2. Median age of breast cancer (BC) diagnosis in BRCA1 and BRCA2 mutation carriers was 41 years and 40 years respectively. Forty-nine (9.2%) VUS were identified, 11 resided in BRCA1 and 38 in BRCA2. Two women harboured both a deleterious BRCA1 mutation and a BRCA2 VUS and one woman had both a BRCA2 mutation and a BRCA1 VUS. The most frequently detected VUS in 12 individuals, c.9976 A > T, p.Lys3326X in exon 27 of BRCA2 has been reported as a polymorphic stop codon and separately associated with an increased pancreatic cancer risk. p.Lys3326 is considered as a class 2 benign variant. Further molecular work up and co-segregation studies led to provisional reclassifications of a BRCA1 VUS and 7 BRCA2 VUSs as polymorphisms, while one BRCA2 variant was reclassified as suspected deleterious therefore facilitating pre-symptomatic testing for family members. This additional data gives a revised prevalence of 5.6% Conclusions: VUS was detected in 5.6% of Irish BRCA1/2 tests. p.Lys3326X is a common VUS of possible clinical significance in Irish HBOC families.
Outcome after Allogeneic Stem Cell Transplantation for Adult Acute Myeloid Leukaemia Patients Exhibiting Isolated or Associated Trisomy 8 Chromosomal Abnormality: A Survey on Behalf of the Acute Leukemia Working Party (ALWP) of the EBMT.
Authors: Patrice Chevallier, Myriam Labopin, Arnon Nagler, Per T. Ljungman, Leo Verdonck, Liisa Volin, Axel Zander, Jürgen Finke, Gerard Socie, Catherine Cordonnier, Jean-Luc Harousseau, Mohamad Mohty, Vanderson Rocha
Journal: Blood (2008)
Abstract 16165: Cardiac Overexpression of Membrane Type-1 Matrix Metalloproteinase Causes Left Ventricular Remodeling and Pump Dysfunction in Peripartum Cardiomyopathy
Authors: Adam N Franklin, Sarah L Lieser, Risha K Patel, Robert E Stroud, Jeffrey A Jones, Adam W Akerman, Rupak Mukherjee, John S Ikonomidis
Journal: Circulation (2014)

Introduction: Peripartum cardiomyopathy (PPCM) is a rare cause of heart failure (HF) in pregnancy. Like other forms of HF, left ventricular (LV) remodeling (LV dilation and LV pump dysfunction) occur with PPCM. The matrix metalloproteinases (MMPs) are implicated as a cause of adverse left ventricular (LV) remodeling and progression to HF. However, the role of MMPs in PPCM remains unclear. Within the class of membrane type MMPs, the subtype membrane type-1 MMP (MT1-MMP) is expressed in human myocardium and is known to be increased in HF. We tested the hypothesis that a causal relationship exists between myocardial overexpression of MT1-MMP and the development of PPCM. Methods/Results: Pregnant transgenic mice designed to overexpress MT1-MMP (MT1OE; n=8) in cardiomyocytes and littermate wild-type (WT; n=8) and corresponding non-pregnant controls (n=6 each group) were used. MT1-MMP activity was higher in the non-pregnant MT1OE mice than in WT mice and further differentially increased with pregnancy (Fig, pan...
Inhibition of polo-like kinase 1 (PLK1) in endocrine-resistant ER+ breast cancer.
Authors: Valerie Malyvanh Jansen, Neil E Bhola, Sangeeta Bafna, Jennifer Margaret Giltnane, Justin M. Balko, Teresa C Dugger, Carlos L. Arteaga
Journal: Journal of Clinical Oncology (2014)

515 Background: Estrogen receptor (ER)-positive breast cancers initially respond to antiestrogens but eventually become hormone-independent and recur. ER+ breast cancer cells resistant to long-term estrogen deprivation (LTED) exhibit estrogen-independent ER transcriptional activity and growth. Mechanisms of endocrine resistance remain to be fully characterized. Methods: A siRNA screen was used to identify kinases required for growth of MCF7/LTED cells. PLK1 RNAi oligonucleotides and the small molecule inhibitor volasertib were tested against ER+ LTED cells. Estrogen independent transcription and target genes were assessed with ER reporter assays and qRT-PCR, respectively. Volasertib and fulvestrant were used in ovariectomized athymic mice bearing MCF7 xenografts. Preclinical findings were correlated with RPPA and RNA-seq data from tumor biopsies of patients with ER+/HER2– breast cancer who received letrozole prior to surgery (NCT00651976). Results: A siRNA kinome screen identified Polo-like kinase 1 (PLK1) as one of the top RNAs required for MCF7/LTED cell growth. RNAi-mediated knockdown of PLK1 inhibited LTED cell growth and ligand-independent transcription of the ER-regulated genes PR, TFF1 and GREB1. Treatment with volasertib reduced ER expression, ER transcriptional activity and LTED cell proliferation. Volasertib in combination with fulvestrant reduced ER expression and inhibited growth of MCF7 xenografts more potently than either drug alone. A PCR array of ER regulated genes in MCF7/LTED cells showed that volasertib decreased expression of JUNB, FOS and BCL2L mRNAs. JUNB knockdown decreased ER transcriptional activity and ER expression suggesting that PLK1 affects ER via JUNB. Finally, in ER+/HER2– tumors from newly diagnosed postmenopausal patients, PLK1 protein and transcript levels positively correlated with resistance to letrozole as measured by high Ki67 levels in post-treatment biopsies (p=0.007; p<0.001). Conclusions: These data support a critical role of PLK1 in growth of antiestrogen resistant breast cancer cells. Targeting of PLK1 may abrogate resistance to endocrine therapy in ER+ breast cancer and is worthy of clinical investigation.
Breast cancer mutation frequency between smokers and non-smokers.
Authors: Todd Cory Knepper, Joanna Grabska, B. Nelson Torres, Christine Marie Walko, Jamie K. Teer, Steve Sutton, Howard L. McLeod, Hatem Hussein Soliman
Journal: Journal of Clinical Oncology (2016)

e13015 Background: Molecular profiling of tumor DNA has changed the management of many cancers. Differences in mutations have been observed in lung adenocarcinoma between smokers and non-smokers, with the latter harboring more EGFR mutations. However, there is a paucity of information on differential mutational frequency between smoking groups in other cancers. This is a pilot analysis to determine if there is a difference in mutational profiles between smoking groups in women with breast cancer. Methods: Moffitt’s Clinical Genomic Action Committee (CGAC) database was used to assess 62 patients with breast cancer treated at Moffitt with targeted sequencing of 315 genes as part of clinical care between 4/1/2013 and 12/31/2015. Smoking history was determined by self-report and analyzed for differential mutational burden and differentially altered genes between the groups. The groups were similar with regards to percentage of triple negative (35.3% vs. 33.3%) between active/prior smokers and never smokers respectively. Results: There was no difference in the mutational burden between 17 smokers (mean 14.2 alterations; range 4-24) and 42 never smokers (mean 15.8 alterations; range 6-42). Relative to non-smokers, breast cancers of smokers contained a higher frequency of alterations in APC, BLM, and RAD50 (17.7% vs. 2.4%), BRIP1, EMSY, and FGFR1 (17.7% vs. 4.8%), PIK3CA (58.8% vs. 35.7%), MAP3K1 (23.5% vs. 7.1%), and TP53 (70.6% vs. 50.0%). On the other hand, non-smokers contained increased alterations in MLL2 (5.9% vs. 23.8%), GNAS (0.0% vs. 16.7%), ATM (0.0% vs. 14.3%), FAT1, ATR, AR, and KDM5C (0.0% vs. 11.9%) amongst genes with at least four total alterations. Conclusions: Although there was no difference in the mutational burden between smokers and never smokers in breast cancer, this study demonstrated that there may be an increased frequency of mutations of DNA repair genes in smokers. This supports future studies on the impact of epidemiologic features on breast cancer mutation profiles and treatment outcomes. Smoking Status Mean # of Alterations Range Associated Molecular Alterations Active/ Prior (n = 17) 14.2 4-24 APC, BLM, RAD50, BRIP1, EMSY, FGFR1, PIK3CA, MAP3K1, TP53 Never (n = 42) 15.8 6-42 MLL2, GNAS, ATM, FAT1, ATR, AR, and KDM5C
High-throughput approaches for screening and analysis of cell behaviors
Authors: Jungmok Seo, Jung-Youn Shin, Jeroen Leijten, Oju Jeon, Gulden Camci-Unal, Anna D. Dikina, Katelyn Brinegar, Amir M. Ghaemmaghami, Eben Alsberg, Ali Khademhosseini
Journal: Biomaterials (2017)