tbuckley/cabot-search huggingface dataset:
A first-in-human phase I study of JNJ-26481585, a novel oral histone deacetylase inhibitor (HDACi), in patients with advanced cancer with evidence of target modulation and antitumor activity.
Authors: R. D. Baird, B. Venugopal, R. S. Kristeleit, J. Charlton, M. Blanco-Codesido, E. Saunders, K. J. Shah, D. Crawford, P. Stephens, D. Wilkins, L. Sweeting, A. Forslund, J. W. Smit, P. A. Palmer, N. Fourneau, P. Hellemans, J. S. De Bono, R. Plummer, U. Banerji, T. R. J. Evans
Journal: Journal of Clinical Oncology (2011)

3024 Background: JNJ-26481585 is a potent, hydroxamate, pan-HDACi with broad activity in solid and hematologic tumor models. Methods: JNJ-26481585 was administered orally, once daily (QD) in 3-weekly cycles to advanced cancer patients (pts) using a 2-stage accelerated titration design. As QD dosing was poorly tolerated, three intermittent schedules were explored: 1) 4 days on, 3 days off; 2) every Mon, Wed, Fri (MWF); and 3) every Mon, Thurs (M-Th). Primary objectives were safety, maximum tolerated dose (MTD), and pharmacokinetics (PK). Secondary objectives were pharmacodynamic (PD) effects in normal and tumor tissues (acetylated Histone H3, Ki67), PK food effect and anti-tumor activity. Results: 73 patients (37 M, median age 56 yr) received JNJ-26481585. Number of pts, dose-limiting toxicities (DLTs), and MTD for each cohort and schedule are shown in the Table. Common grade 1-2 toxicities were fatigue, anorexia, and nausea. PK was dose-proportional with high volume of distribution and AUC (range 11-20 h.ng/mL) consistent with the exposure required for activity in xenograft models. There was no food effect. PD data showed increased acetylated Histone H3 in hair follicles, skin biopsies and tumor, confirming proof of mechanism. A partial response lasting 5 months (mo) was seen in one patient with melanoma. Stable disease was seen in 8 pts (duration 4 – 10.5 mo). Conclusions: The adverse event profile of JNJ-26481585 is comparable to other HDACi. Intermittent administration is better tolerated than QD. The recommended dose for phase II trials is 12 mg on the MWF schedule, based on tolerability, anti-tumor activity, PK predictions, and PD activity. Schedule. 2 mg 4 mg 6 mg 8 mg 10 mg 12 mg 15 mg 16 mg 19 mg QD N=2 N=2 N=6 1 DLT (bilirubin↑) N=8 1 DLT (NSVT*) 0 MTD - N=2 2 DLTs (NSVT*, fatigue) - - - 4 days on, 3 days off - - N=3 N=3 N=6 0..DLTs MTD N=7 2 DLTs (NSVT*, infection) - - - MWF - - N=3 N=3 - N=7 1 DLT (hypertension + troponin↑) MTD - N=6 0..DLTs*** - M-Th - - - N=3 - N=3 N=6 0..DLTs MTD - N=3 2 DLTs (T-wave inversion, SVT**) *Nonsustained ventricular tachycardia. **Supraventricular tachycardia. ***Palpitations + ventricular extrasystoles in 2 pts in cycle 2.
The roles of stem cell memory T cells in hematological malignancies
Authors: Ling Xu, Yikai Zhang, Gengxin Luo, Yangqiu Li
Journal: Journal of Hematology & Oncology (2015)

Adoptive cell therapy (ACT) is rapidly migrating from bench to clinical therapy for hematological malignancies. Recently, a new subtype of memory T cells, stem cell memory T (TSCM) cells, was shown to be one of the most favorable subsets for ACT. TSCM has high self-renewal capacity and is associated with superior T cell engraftment, persistence, and antitumor immunity. In this review, we focused on the characteristics of antigen-specific TSCM cells and discussed their potential for immunotherapy targeting hematological malignancies.
Abstract 16196: Impact of Baseline PCSK9 Levels on the Efficacy of Evolocumab, a Monoclonal Antibody Against PCSK9
Authors: Nihar Desai, Robert Giugliano, Scott Wasserman, John Gibbs, Thomas Liu, Robert Scott, Marc Sabatine
Journal: Circulation (2014)

Introduction: Evolocumab (AMG 145), a fully human monoclonal antibody against proprotein convertase subtilisin kexin type 9 (PCSK9), significantly reduces low-density lipoprotein-cholesterol (LDL-C) by ~65%. Whether baseline PCSK9 levels impact the efficacy of evolocumab remains undefined. Methods: The mean placebo-controlled percent change from baseline in LDL-C measured by ultracentrifugation at week 10 &amp; 12 was calculated for evolocumab 140 mg Q2W and 420 mg QM in 2293 patients from the pooled phase 3 trials. Median PCSK9 levels were measured in 138 patients from a substudy of the pooled phase 2 trials. For both analyses, patients were stratified into quartiles based upon baseline PCSK9 levels. Interaction tests were performed to evaluate for heterogeneity across quartiles. Results: At baseline in the pooled phase 3 trials, the median PCSK9 level was 323 ng/mL (25 th %ile 258 ng/mL; 75 th %ile 406 ng/mL). Demographics were similar across quartiles of baseline PCSK9, but, as expected, patients with higher levels of baseline PCSK9 were more likely to be receiving more intensive background statin therapy and had lower levels of LDL-C at baseline. Evolocumab 140 mg Q2W reduced PCSK9 levels by &gt;90% 1 week after dosing and levels remained low (~100 ng/mL), regardless of baseline PCSK9 level (Figure top left). Evolocumab 420 mg QM rendered PCSK9 levels undetectable 1 week after dosing and reduced by &gt;90% 2 weeks after dosing, regardless of baseline PCSK9 levels (Figure top right); 3 weeks after dosing PCSK9 levels remained low (~100 ng/mL) and by 4 weeks levels remained proportionately reduced by nearly half. Evolocumab significantly (P&lt;0.001) reduced LDL-C at week 10 and 12 and to a similar extent regardless of baseline PCSK9 (Figure bottom). Conclusion: Evolocumab, a PCSK9 inhibitor, when administered 140 mg biweekly or 420 mg monthly, consistently and substantially reduces PCSK9 and LDL-C regardless of a patient’s baseline level of PCSK9.
Studies in clinical shock and hypotension
Authors: Jay N. Cohn, Felix E. Tristani, Ibrahim M. Khatri
Journal: Journal of Clinical Investigation (1969)

Left ventricular end diastolic (LVEDP) and mean right atrial (RAP) pressures were recorded simultaneously in 30 patients with shock (14 acute myocardial infarction, 10 acute pulmonary embolism or severe bronchopulmonary disease, and 6 sepsis). Myocardial infarction was characterized by a predominant increase in LVEDP, pulmonary disease by a predominant increase in RAP, and sepsis by a normal relationship between LVEDP and RAP. In all three groups a significant positive correlation was noted between RAP and LVEDP, with the regression line in cor pulmonale deviated significantly toward the RAP axis and the regression line in myocardial infarction exhibiting a zero RAP intercept at an elevated LVEDP.Low cardiac outputs with elevated LVEDP in myocardial infarction indicated severe left ventricular failure. Low outputs with elevated RAP in cor pulmonale were consistent with right ventricular overload. Although cardiac outputs often were normal in sepsis, low outputs with elevated cardiac filling pressures in some patients were consistent with a hemodynamic or humoral-induced generalized depression of cardiac performance.Vasoconstrictor and inotropic drugs often produced a functional disparity between the two ventricles, with the gradient between LVEDP and RAP increasing, apparently because of an increase in left ventricular work or an inadequacy of left ventricular oxygen delivery. Acute plasma volume expansion with dextran in patients with pulmonary vascular disease resulted in a somewhat more rapid rise in RAP than in LVEDP. In septic and myocardial infarction shock, however, LVEDP and RAP usually rose proportionally, with the absolute rise of LVEDP surpassing that of RAP. Although the absolute level of the central venous pressure thus may not be a reliable indicator of left ventricular function in shock, changes in venous pressure during acute plasma volume expansion should serve as a fairly safe guide to changes in LVEDP.
Influence of smoking on respiratory function and status of proteinas-inhibitory system in patients COPD
Authors: Olena Pavlenko, Olena Lykholat, Valeriia Dmytrychenko
Journal: European Respiratory Journal (2014)

Aim: to study the influence of smoking on respiratory function and status of proteinas-inhibitory system (PIS) in COPD patients. Materials and methods: 62 COPD patients were examined and divided into two groups: 1-st 32 smokers with high level of nicotine dependence (male; age 54.1±3.5 yrs.; ill for 15.3±1.2 yrs., smoking history - 36.7±2.9 yrs.) 2nd group included 30 non-smokers (male; age 53.9±2.5 yr.; ill for 15.3±1.2 yrs.) Pulmonary function test (spirometry) was performed in both groups of patients. The state of PIS was assessed by means of evaluating the activity of tripsin (T),α1-antitripsin (AT), α2-macroglobulin (MG) in bronchoalveolar lavage fluid (BALF).  Results: are preformed in the table 1.  In the 1-st group of smokers the activity of AT, MG, T turned out to be higher. In patients of the 1-st group the correlation between the duration of smoking and decrease of FEV1 index was revealed.   Conclusion:  smoking exerts negative effect on the state of proteinas-inhibitory system and pulmonary lung function.
Unifying the service: Creating a COPD action plan to bridge the gap between primary, intermediate, and secondary care
Authors: Claire Lawless, Claire Hodgekiss, Doytchin Dimov
Journal: European Respiratory Journal (2013)

Introduction:Self-management in COPD aims to ensure that timely intervention is provided at exacerbation. Our project aim was to create a plan to use in primary and secondary care to streamline the management of COPD patients.  Methods:20 patients with COPD were asked structured questions about medication use, information presentation, exacerbation recognition and management. A focus group was held to discuss content, structure, and cost of the plan. A draft version was piloted with COPD inpatients. Time taken to explain and complete the plan and patient feedback was recorded.  Results:Structured questionnaires-20 patients, 11 male, Mean age 70 (49-86). 70% did not have an existing medication prompt, 25% prompted by daily tasks, 5% by family. 50% preferred information in text, 20% pictures, 30% both. Exacerbation symptoms in 60% included breathlessness, 30% cough, 20% lethargy, 15% chest tightness, 10% reduced appetite, 5% panic. 25% did not understand the term exacerbation. When managing an exacerbation, 40% rested, 40% took medication, 25% called for help, 10% did breathing exercises. 10% didn’t know what to do. 5% already had a written plan. Contact in an exacerbation in 30% was paramedics, 25% family doctor, 15% community nurse, 15% family, 10% nobody, 5% NHS direct. 25% relied on others to call for help. Pilot: Mean time to explain/complete the plan 6.5 minutes (4.5-9). Feedback was positive overall.  Conclusion:The process of developing the self-management plan has given insight into existing experiences of COPD management and highlighted gaps in knowledge. It is hoped the integrated approach will unify the care pathway for COPD patients locally.
Simple prognostic model to predict survival in patients with undifferentiated carcinoma of unknown primary site.
Authors: A van der Gaast, J Verweij, A S Planting, W C Hop, G Stoter
Journal: Journal of Clinical Oncology (1995)

PURPOSE We performed this study to identify prognostic factors in a subgroup of patients with carcinoma of unknown primary site treated with cisplatin combination chemotherapy. PATIENTS AND METHODS Seventy-nine patients with poorly differentiated adenocarcinoma or undifferentiated carcinoma of unknown primary site were treated on two consecutive phase II chemotherapy protocols. The first protocol consisted of treatment with 3-week courses of cisplatin, etoposide, and bleomycin (BEP). In the second protocol, cisplatin was administered weekly combined with oral administration of etoposide (DDP/VP). To identify prognostic factors, univariate and multivariate analyses were conducted. RESULTS In the univariate analysis, performance status, histology, liver or bone metastases, and serum levels of alkaline phosphatase and AST were significant variables to predict survival. In the multivariate analysis, performance status and alkaline phosphatase were the most important prognostic factors. CONCLUSION Good-prognosis patients had a performance score of 0 (World Health Organization [WHO]) and an alkaline phosphatase serum level less than 1.25 times the upper limit of normal (N). These patients had a median survival duration greater than 4 years. Intermediate-prognosis patients were characterized by either a WHO performance status &lt; or = 1 or an alkaline phosphatase level &gt; or = 1.25 N. These patients had a median survival duration of 10 months and a 4-year survival rate of only 15%. The poor-prognosis group had both a WHO performance status &gt; or = 1 and an alkaline phosphatase level &gt; or = 1.25 N. These patients had a median survival duration of only 4 months and none survived beyond 14 months. Treatment strategies for these three groups are discussed. It is suggested that this prognostic model be validated in other patients series.
Passive properties of canine left ventricle: diastolic stiffness and restoring forces.
Authors: S Nikolić, E L Yellin, K Tamura, H Vetter, T Tamura, J S Meisner, R W Frater
Journal: Circulation Research (1988)

Left ventricular (LV) diastolic pressure-volume (P-V) relations arise from a complex interplay of active decay of force (i.e., relaxation), passive elastic myocardial properties, and time-varying inflow across the mitral orifice. This study was designed to quantify the passive properties of the intact ventricle and the effects of elastic recoil by separating filling from relaxation with a method of LV volume clamping with a remote-controlled mitral valve. Eleven open-chest fentanyl-anesthetized dogs were instrumented with aortic and mitral flow probes, LV and left atrium micromanometers, and a remote-controlled mitral valve. We prevented complete (end-systolic volume clamping) or partial filling at different times in diastole. The ventricle thus relaxed completely at different volumes, and we generated P-V coordinates for the passive ventricle that included negative, as well as positive, values of pressure. We then estimated ventricular volumes from ventricular weight in eight dogs, using regression equations based on data in the literature, to determine the equilibrium volume (V0), that is, volume at zero transmural pressure, in the working ventricle. We abandoned the traditional exponential approach and characterized by the P-V relation with a logarithmic approach that included maximum LV volume (Vm), minimum volume (Vd), and stiffness parameters (Sp and Sn) for the positive (p) and negative (n) phases: Pp = -Sp In[(Vm - V)/(Vm - V0)] and Pn = Sn In[(V - Vd)/(V0 - Vd)]. With this formulation, the chamber compliance, dP/dV, is normalized by the LV operating volume, and Sp and Sn are size-independent chamber stiffness parameters with the units of stress. In eight ventricles with LV weight = 131 +/- 20 g, Vm = 116 +/- 18 ml, V0 = 37 +/- 6 ml, and Vd = 13 +/- 2 ml, stiffness Sp = 14.6 mm Hg and Sn = 5.1 mm Hg were determined from the slopes of the log-linearized equations. Also, the duration of LV relaxation is increased by the process of ventricular filling (161 +/- 31 msec, filling versus 108 +/- 36 msec, nonfilling, measured from dP/dtmin, p less than 0.0001). We conclude that volume clamping is a useful method of studying restoring forces and that the logarithmic approach is conceptually and quantitatively useful in characterizing the passive properties of the intact ventricle.
Metastatic Dissemination of B16 Melanoma: Pattern and Sequence of Metastasis&lt;xref ref-type="fn" rid="FN1"&gt;2&lt;/xref&gt;&lt;xref ref-type="fn" rid="FN2"&gt;3&lt;/xref&gt;
Authors: A L Alterman, D M Fornabaio, C W Stackpole
Journal: JNCI Journal of the National Cancer Institute (1985)

The progressive metastatic spread from subcutaneous transplants of two subpopulations of the mouse B16 melanoma, slow-growing clone G3.5 and fast-growing clone G3.12, was examined during tumor growth in C57BL/6 mice and after surgical excision of tumors of various sizes. In addition to enumeration of visible and lethal or potentially lethal ("clinically relevant") metastases, the occurrence of visibly undetectable proliferating (occult) or nonproliferating (dormant) micrometastases was assessed by implanting lymph nodes and organs subcutaneously into normal mice and monitoring for resulting tumor growth. Occult or dormant metastases were disseminated initially to the lungs from G3.5 tumors of 3-4 mm in mean geometric diameter (MGD) and G3.12 tumors of 6-7 mm in MGD. The ipsilateral axillary lymph node (IALN), the regional draining lymph node for these tumors, received metastases after the lungs, initially from 10 to 12-mm tumors. Subsequently, occult or dormant and visible metastases first appeared in systemic organs and lymph nodes (kidneys, adrenal glands, ovaries, and contralateral axillary lymph node) at tumor sizes of about 26 mm in MGD. Systemic metastases occurred only in mice with large and numerous lung metastases and did not depend on the continuing presence of the subcutaneous tumor or on the presence of IALN metastases, which indicated that established lung metastases were a generalizing site from which systemic metastatic spread initiated. After tumor excision, death generally resulted from extensive lung metastasis. Occasional lethal or clinically relevant metastases were also observed in the IALN, kidneys, adrenal glands, ovaries, brain, eyes, and urinary bladder; liver involvement was evident exclusively as occult or dormant micrometastases. Terminal metastatic patterns of these B16 melanoma transplants were as widespread and indiscriminate as those of malignant melanoma in humans.
Detection of Cellular Immunity to Murine Sarcoma Virus-Induced Tumors by Leukocyte Adherence Inhibition&lt;xref ref-type="fn" rid="FN1"&gt;2&lt;/xref&gt;
Authors: R F Mortensen
Journal: JNCI Journal of the National Cancer Institute (1979)

The leukocyte adherence inhibition (LAI) response of C57BL/6 mice inoculated with a regressing strain of Moloney murine sarcoma virus (M-MuSV) was measured in a microassay with 3 M KCI extracts of either the RBL-5 or FBL-3 leukemia cell line. The LAI reactivity of spleen and peritoneal cells of mice bearing M-MuSV-induced tumors was antigen-specific, reached its highest level when the tumors began to regress (12–14 days), and developed more rapidly in M-MuSV-immune mice following a secondary challenge with RBL-5 or FBL-3 cells. The kinetics of the LAI response was monophasic, and the development and magnitude of the reactivity correlated with the size of the MMuSV-induced tumor. Extensive cross-reactive LAI activity was observed with extracts from RBL-5 and FBL-3 cells. Extracts from normal syngeneic tissues, allogeneic tumor cells, and syngeneic tumor cells induced by nonviral agents did not elicit an LAI response with lymphoid cells from mice with M-MuSV-induced tumors. Indirect assays detected the production of a mediator(s) of LAI in response to both intact cells and extracts of RBL-5 and FBL-3. LAI reactivity was both lower in magnitude and rapidly lost in unsensitized C57BL/6 mice bearing progressively growing, as opposed to regressing, FBL-3 tumors. These results showed that LAI reactivity is a good indicator of host responsiveness to M-MuSV-induced tumors.
Favorable Biology and Outcome of Stage IV-S Neuroblastoma With Supportive Care or Minimal Therapy: A Children’s Cancer Group Study
Authors: H. James Nickerson, Katherine K. Matthay, Robert C. Seeger, Garret M. Brodeur, Hiroyuki Shimada, Carlos Perez, James B. Atkinson, Michael Selch, Robert B. Gerbing, Daniel O. Stram, John Lukens
Journal: Journal of Clinical Oncology (2000)

PURPOSE: Stage IV-S neuroblastoma is a metastatic disease associated with spontaneous regression and good survival, but 10% to 20% of infants die from early complications. The purpose of this study was to evaluate outcome and prognostic factors in infants with stage IV-S neuroblastoma treated prospectively with supportive care only or, in symptomatic patients, with low-dose cytotoxic therapy. PATIENTS AND METHODS: Eighty eligible infants were studied for response and survival with supportive care or, for symptomatic patients, cyclophosphamide 5 mg/kg/d for 5 days with or without hepatic radiation of 4.5 Gy over 3 days. Staging was reviewed centrally, and MYCN gene copy number, Shimada histopathologic classification, serum ferritin levels, and bone marrow immunocytology were determined. RESULTS: Stage IV-S and International Neuroblastoma Staging System stage 4S were 98% concordant. MYCN was not amplified in any of the tumors tested (n = 58), and Shimada histopathologic classification was favorable in 96% (n = 68/71). The 5-year event-free survival (EFS) rate for all infants was 86% and the survival rate was 92%. Supportive care was the only treatment provided for 44 (55%) of 80 infants, and their 5-year survival rate was 100%, compared with 81% survival for those requiring cytotoxic therapy for symptoms (P = .005). Five of six deaths were in infants younger than 2 months of age at diagnosis and were due to complications of extensive abdominal involvement with respiratory compromise or disseminated intravascular coagulation. Although age ≤ 3 months at diagnosis was significant for EFS (P = .043), it was less significant for survival (P = .077). The only other significant factor predictive for improved survival was favorable Shimada histopathologic classification. Sites of metastatic involvement (liver, skin, or bone marrow) and surgical resection of the primary tumor were not significant for survival. CONCLUSION: This study confirms the favorable biologic features and excellent survival of infants with stage IV-S neuroblastoma with minimal therapy. Infants younger than 2 months old at diagnosis with rapidly progressive abdominal disease may benefit from earlier and more intensive treatment.
Identification of a plant isoflavonoid that causes biliary atresia
Authors: Kristin Lorent, Weilong Gong, Kyung A. Koo, Orith Waisbourd-Zinman, Sara Karjoo, Xiao Zhao, Ian Sealy, Ross N. Kettleborough, Derek L. Stemple, Peter A. Windsor, Stephen J. Whittaker, John R. Porter, Rebecca G. Wells, Michael Pack
Journal: Science Translational Medicine (2015)

A plant toxin with a previously uncharacterized chemical structure causes biliary atresia in zebrafish and mammals.
Impact of Baseline Covariates and Prior Therapy on the Efficacy of Second-Line Panitumumab (Pmab) + Folfiri Vs Folfiri Treatment
Authors: M. Peeters, T. Price, A. Cervantes, A. Sobrero, M.P. Ducreux, T. André, F. Lordick, C. Punt, R. Koukakis, J. Terwey, E. Van Cutsem
Journal: Annals of Oncology (2014)