tbuckley/cabot-search huggingface dataset:
NKTR-102, a novel PEGylated-irinotecan, demonstrates reduced gastrointestinal and hematopoietic toxicity compared to irinotecan with repeat dosing in dogs
Authors: Heather Persson, Tamra Barker, Michael Eldon, Ronald Wolff
Journal: Cancer Research (2008)

5741    Purpose:  NKTR-102, a novel PEGylated-irinotecan, is currently in Phase 2 clinical development as a second-line colorectal cancer therapy. Prior non-clinical studies demonstrate that adding a PEG moiety to irinotecan results in sustained tumor growth inhibition that is associated with an increase in SN38 exposure secondary to extended disposition and metabolism of NKTR-102. The purpose of this study was to evaluate the repeat dose toxicity of NKTR-102 compared to irinotecan in dogs, and to determine the pharmacokinetic profile of the active metabolite SN38 upon repeat dosing.    Methods:  Groups of 6 dogs were administered doses of 20 or 25 mg/kg irinotecan-equivalent doses of either NKTR-102 or irinotecan as 1-hour intravenous infusions on Days 1, 8, 15, and 22. Clinical pathology and histopathology were performed and animals were observed for clinical signs of toxicity. Serial pharmacokinetic blood samples were collected and analyzed for the parent compound and metabolites including SN38. Routine non-compartmental analysis was used to estimate pharmacokinetic parameters.    Results:  At 20 mg/kg NKTR-102, neutropenia was absent. At 25 mg/kg NKTR-102, minimal neutropenia was observed 11 days after dosing in 50% of animals, with spontaneous resolution by Day 22. In both irinotecan dose groups, marked neutropenia was observed as early as 4 days in greater than 50% of animals with no apparent resolution by Day 22. At 20 mg/kg, diarrhea was less frequent in NKTR-102-treated (33%) relative to irinotecan-treated dogs (83%). At 25 mg/kg, the frequency of diarrhea (87.5%) was the same between test articles, but dogs treated with irinotecan exhibited bloody diarrhea (29%) and diarrhea lasting greater than three days (72%) while dogs treated with NKTR-102 did not. Hematopoietic hypocellularity in the bone marrow was minimal in 3/6 dogs treated with 25 mg/kg NKTR-102 but moderate to severe in 4/6 dogs treated with an equivalent dose of irinotecan. The maximum tolerated dose (MTD) for repeated doses of NKTR-102 was 25 mg/kg and less than 20 mg/kg for irinotecan. Pharmacokinetic estimates of SN38 AUC were approximately four fold greater in dogs treated with NKTR-102 when compared to dogs treated with equivalent irinotecan doses at both 20 and 25 mg/kg. Conversely, SN38 Cmax values were approximately one fifth lower in dogs treated with NKTR-102 when compared to dogs treated with equivalent irinotecan doses.   Conclusions:  NKTR-102 exhibits a 25% increase in MTD relative to irinotecan. At 20 mg/kg NKTR-102, no neutropenia and a 60% decrease in incidence of diarrhea were observed relative to the same dose of irinotecan. Compared to similar doses of irinotecan, NKTR-102 achieved a five-fold lower SN38 Cmax, and was associated with lower gastrointestinal and hematopoietic toxicities with a concurrent four-fold increase in exposure (AUC).
Focal TLR4 activation mediates disturbed flow-induced endothelial inflammation
Authors: Dan Qu, Li Wang, Mingyu Huo, Wencong Song, Chi-Wai Lau, Jian Xu, Aimin Xu, Xiaoqiang Yao, Jeng-Jiann Chiu, Xiao Yu Tian, Yu Huang
Journal: Cardiovascular Research (2019)

Disturbed blood flow at arterial branches and curvatures modulates endothelial function and predisposes the region to endothelial inflammation and subsequent development of atherosclerotic lesions. Activation of the endothelial Toll-like receptors (TLRs), in particular TLR4, contributes to vascular inflammation. Therefore, we investigate whether TLR4 can sense disturbed flow (DF) to mediate the subsequent endothelial inflammation.En face staining of endothelium revealed that TLR4 expression, activation, and its downstream inflammatory markers were elevated in mouse aortic arch compared with thoracic aorta, which were absent in Tlr4mut mice. Similar results were observed in the partial carotid ligation model where TLR4 signalling was activated in response to ligation-induced flow disturbance in mouse carotid arteries, and such effect was attenuated in Tlr4mut mice. DF in vitro increased TLR4 expression and activation in human endothelial cells (ECs) and promoted monocyte-EC adhesion, which were inhibited in TLR4-knockdown ECs. Among endogenous TLR4 ligands examined as candidate mediators of DF-induced TLR4 activation, fibronectin containing the extra domain A (FN-EDA) expressed by ECs was increased by DF and was revealed to directly interact with and activate TLR4.Our findings demonstrate the indispensable role of TLR4 in DF-induced endothelial inflammation and pinpoint FN-EDA as the endogenous TLR4 activator in this scenario. This novel mechanism of vascular inflammation under DF condition may serve as a critical initiating step in atherogenesis.
Mouse model of docetaxel neurotoxicity
Authors: William Durham, Robin Ball, Chassidy Hall, George Parker, Cheryl Napier, Beth Hollister, Steadman Harrison
Journal: Cancer Research (2005)

4171  This study documents the development and characterization of neurotoxicity in three strains of mice treated with docetaxel. Docetaxel blocks tubulin depolymerization, which leads to inhibition of microtubule dynamics and cell cycle arrest. Common side effects of docetaxel treatment include bone marrow suppression, hypersensitivity reactions and neurotoxicity, specifically peripheral neuropathy. In this series of studies, three strains of mice, nu/nu, B6D2F1 and C57BL/6, were dosed intravenously once a week for three consecutive weeks at their respective ½ MTD and MTD, which provided equitoxic doses, defined by lethality, for each strain. Docetaxel doses for the nu/nu strain were 15 and 30 mg/kg; for B6D2F1, 20 and 40 mg/kg; and for C57BL/6, 25 and 50 mg/kg. Once treatment started, the mice were evaluated twice weekly for body weight change and any clinical observations of peripheral neuropathy such as impaired gait, hind limb splay, or hind limb paralysis. On days 8, 15, 22, 29, 36 and 60 three mice from each group were euthanized for histologic evaluation of sciatic nerve. For comparison purposes, each study had no-treatment and diluent control groups. Onset of docetaxel-induced neurotoxicity was found to be dose dependent. Day 15 was the earliest indication of toxicity as reflected by impaired gait and histologic evidence of axonal degeneration, microscopically similar to that seen in laboratory rats. At equitoxic ½ MTD doses, the C57BL/6 strain exhibited the highest axonal degeneration scores as a function of time, followed by B6D2F1, then nu/nu. Hind limb splay was observed in all strains by day 22 at docetaxel doses of 30 mg/kg in nu/nu; 20 and 40 mg/kg in B6D2F1; and 50 mg/kg in C57BL/6. Hind limb paralysis was only observed in C57BL/6 mice at the 50 mg/kg dose on day 36. Recovery from peripheral neuropathy was observed to be dose dependent and was evident by day 36 in clinical and histologic endpoints except in the C57BL/6 strain. Docetaxel-induced neurotoxicity in mice offers a model that may prove useful in evaluation of new strategies for chemoprotective drug combinations, permitting assessment of both toxicity and efficacy in a single model that minimizes test article consumption.
Evolutionary Action Score of Missense TP53 Mutations Can Predict Outcome in Patients with Myelodysplastic Syndrome and Acute Myeloid Leukemia
Authors: Rashmi Kanagal-Shamanna, Koji Sasaki, Guillermo Montalban Bravo, Christopher B. Benton, Elias J. Jabbour, Gautam Borthakur, Tapan M. Kadia, Carlos E. Bueso-Ramos, Keyur Patel, Farhad Ravandi, Hagop M. Kantarjian, Guillermo Garcia-Manero
Journal: Blood (2018)
Treatment of higher risk acute lymphoblastic leukemia in young people (CCG-1961), long-term follow-up: a report from the Children’s Oncology Group
Authors: Peter G. Steinherz, Nita L. Seibel, Harland Sather, Lingyun Ji, Xinxin Xu, Meenakshi Devidas, Paul S. Gaynon
Journal: Leukemia (2019)
Update in Lung Cancer 2014
Authors: Avrum Spira, Balazs Halmos, Charles A. Powell
Journal: American Journal of Respiratory and Critical Care Medicine (2015)

In the past 2 years, lung cancer research and clinical care have advanced significantly. Advancements in the field have improved outcomes and promise to lead to further reductions in deaths from lung cancer, the leading cause of cancer death worldwide. These advances include identification of new molecular targets for personalized targeted therapy, validation of molecular signatures of lung cancer risk in smokers, progress in lung tumor immunotherapy, and implementation of population-based lung cancer screening with chest computed tomography in the United States. In this review, we highlight recent research in these areas and challenges for the future.
iNKT Cell Stimulation with Liposomal Alpha/Gal/Cer Amplifies Proliferation of Adoptively Transferred Regulatory T Cells In Vivo and Reduces GvHD
Authors: Toshihito Hirai, Federico Simonetta, Kristina Maas-Bauer, Melissa Mavers, Jeanette Baker, Robert S. Negrin
Journal: Blood (2018)
Update in Cystic Fibrosis 2012
Authors: Christopher H. Goss, Felix Ratjen
Journal: American Journal of Respiratory and Critical Care Medicine (2013)

Although cystic fibrosis (CF) remains a life-limiting disease, we have witnessed major advances in the care and clinical outcome of persons with CF (1).Animal models are shaping our understanding of the early pathophysiological changes in the CF airway (2), but significant challenges persist in understanding key components of airway infection, airway inflammation, as well as how to translate this knowledge into treatment of persons with this lung disease.We highlight some of the important scientific developments in CF during 2012, focusing on infection, airway inflammation, novel treatments, and issues surrounding lung transplantation.
Lenalidomide in Combination with Standard R-CHOP Overcomes the Negative Prognostic Value of Peripheral Blood Absolute Lymphocyte/Monocyte Ratio at Diagnosis and during Treatment in Patients with Diffuse Large B-Cell Lymphoma
Authors: Alessia Castellino, Levy D. Pederson, Kay M. Ristow, Christina Stenzel, Betsy Laplant, Thomas E. Witzig, Thomas M. Habermann, Grzegorz S. Nowakowski, Luis Porrata
Journal: Blood (2018)
Abstract 16710: Network Analysis for Diagnosis and Risk Stratification of Cardiopulmonary Patients With Exercise Dysfunction
Authors: William Oldham, Rudolf Oliveira, Alexander Opotowsky, Bradley Wertheim, George Alba, Calum MacRae, David Rubins, Joseph Loscalzo, Jane Leopold, Aaron Waxman, David Systrom, Bradley A Maron
Journal: Circulation (2017)

Exercise intolerance is a heterogeneous condition associated with increased morbidity and mortality across the spectrum of cardiopulmonary disease. Invasive cardiopulmonary exercise testing (iCPET) measures gas exchange, hemodynamics, and metabolic data to define exercise physiology; however, overlapping clinical diagnoses in iCPET are common. We tested the hypothesis that network modeling of iCPET data in silico identifies distinct exercise pathophenotypes in patients. Data from 757 individual iCPETs (2003-2015; 44% male, age 57±5 yrs) including 73 clinical and exercise variables were analyzed retrospectively. From an exercise network of 39 variables and 98 correlations (
Maintenance Therapies for Hodgkin and Non-Hodgkin Lymphomas After Autologous Transplantation
Authors: Abraham S. Kanate, Ambuj Kumar, Peter Dreger, Martin Dreyling, Steven Le Gouill, Paolo Corradini, Chris Bredeson, Timothy S. Fenske, Sonali M. Smith, Anna Sureda, Alison Moskowitz, Jonathan W. Friedberg, David J. Inwards, Alex F. Herrera, Mohamed A. Kharfan-Dabaja, Nishitha Reddy, Silvia Montoto, Stephen P. Robinson, Syed A. Abutalib, Christian Gisselbrecht, Julie Vose, Ajay Gopal, Mazyar Shadman, Miguel-Angel Perales, Paul Carpenter, Bipin N. Savani, Mehdi Hamadani
Journal: JAMA Oncology (2019)

Maintenance therapies are often considered as a therapeutic strategy in patients with lymphoma following autologous hematopoietic cell transplantation (auto-HCT) to mitigate the risk of disease relapse. With an evolving therapeutic landscape, where novel drugs are moving earlier in therapy lines, evidence relevant to contemporary practice is increasingly limited. The American Society for Blood and Marrow Transplantation (ASBMT), Center for International Blood and Marrow Transplant Research (CIBMTR), and European Society for Blood and Marrow Transplantation (EBMT) jointly convened an expert panel with diverse expertise and geographical representation to formulate consensus recommendations regarding the use of maintenance and/or consolidation therapies after auto-HCT in patients with lymphoma.The RAND-modified Delphi method was used to generate consensus statements where at least 75% vote in favor of a recommendation was considered as consensus. The process included 3 online surveys moderated by an independent methodological expert to ensure anonymity and an in-person meeting. The panel recommended restricting the histologic categories covered in this project to Hodgkin lymphoma (HL), mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL), and follicular lymphoma. On completion of the voting process, the panel generated 22 consensus statements regarding post auto-HCT maintenance and/or consolidation therapies. The grade A recommendations included endorsement of: (1) brentuximab vedotin (BV) maintenance and/or consolidation in BV-naïve high-risk HL, (2) rituximab maintenance in MCL undergoing auto-HCT after first-line therapy, (3) rituximab maintenance in rituximab-naïve FL, and (4) No post auto-HCT maintenance was recommended in DLBCL. The panel also developed consensus statements for important real-world clinical scenarios, where randomized data are lacking to guide clinical practice.In the absence of contemporary evidence-based data, the panel found RAND-modified Delphi methodology effective in providing a rigorous framework for developing consensus recommendations for post auto-HCT maintenance and/or consolidation therapies in lymphoma.
The Best American Science Writing 2009
Authors: Tony Miksanek
Journal: JAMA (2009)

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Management of Cardiovascular Disease in Women With Breast Cancer
Authors: Rachel Barish, Filipa Lynce, Keith Unger, Ana Barac
Journal: Circulation (2019)

Cardio-oncology is a rapidly developing field which seeks to improve patient outcomes through enhanced clinical and research collaboration across the disciplines of oncology and cardiology. Breast cancer (BC) is the most common cancer diagnosis among women in the United States and, as decades of research have resulted in decreased mortality rates, there has been an increasing focus on reducing short- and long-term treatment toxicity and improving morbidity among survivors. Preexisting or emergent cardiovascular disease in a patient with BC requires a multidisciplinary, team-based approach to balance the need for curative cancer treatment while preventing increased cardiovascular disease morbidity and mortality. Given the overlap in risk factors for BC and cardiovascular disease, such as smoking, sedentary lifestyle, and obesity, there are opportunities for cardiovascular disease prevention and detection before, during, and after BC treatment. Cardiology providers also play an important role in preventing, diagnosing, and treating cardiac dysfunction and other cardiovascular complications that may develop as a result of BC treatment. A number of recent clinical practice guidelines address approaches to cardiotoxicity, however, they focus on specific agents or treatment modality, rather than on collaborative disease management. In this review we present cardiovascular concerns associated with contemporary, multimodality BC treatment and illustrate how current guideline recommendations apply to clinical cardiology and oncology questions. We provide a cardio-oncology team-based approach to cardiovascular assessment and management of patients with BC from diagnosis through treatment and in survivorship.
RESPIRE 2: a phase III placebo-controlled randomised trial of ciprofloxacin dry powder for inhalation in non-cystic fibrosis bronchiectasis
Authors: Timothy Aksamit, Anthony De Soyza, Tiemo-Joerg Bandel, Margarita Criollo, J. Stuart Elborn, Elisabeth Operschall, Eva Polverino, Katrin Roth, Kevin L. Winthrop, Robert Wilson
Journal: European Respiratory Journal (2018)

We evaluated the efficacy and safety of ciprofloxacin dry powder for inhalation (DPI) in patients with non-cystic fibrosis bronchiectasis, two or more exacerbations in the previous year and predefined sputum bacteria. Patients were randomised 2:1 to twice-daily ciprofloxacin DPI 32.5 mg or placebo in 14- or 28-day on/off treatment cycles for 48 weeks. Primary end-points were time to first exacerbation and frequency of exacerbations. Enrolling countries and α level split (0.049 and 0.001 for 14- and 28-day cycles, respectively) differed from RESPIRE 1. Patients were randomised to ciprofloxacin DPI (14 days on/off (n=176) or 28 days on/off (n=171)) or placebo (14 days on/off (n=88) or 28 days on/off (n=86)). The exacerbation rate was low across treatment arms (mean± sd 0.6±0.9). Active treatment showed trends to prolonged time to first exacerbation (ciprofloxacin DPI 14 days on/off: hazard ratio 0.87, 95.1% CI 0.62–1.21; p=0.3965; ciprofloxacin DPI 28 days on/off: hazard ratio 0.71, 99.9% CI 0.39–1.27; p=0.0511) and reduced frequency of exacerbations (ciprofloxacin DPI 14 days on/off: incidence rate ratio 0.83, 95.1% CI 0.59–1.17; p=0.2862; ciprofloxacin DPI 28 days on/off: incidence rate ratio 0.55, 99.9% CI 0.30–1.02; p=0.0014), although neither achieved statistical significance. Ciprofloxacin DPI was well tolerated. Trends towards clinical benefit were seen with ciprofloxacin DPI, but primary end-points were not met.
Analysis of Readmissions Following Hospitalization for Cellulitis in the United States
Authors: Jonathan M. Fisher, Jeremy Y. Feng, Sally Y. Tan, Arash Mostaghimi
Journal: JAMA Dermatology (2019)

Cellulitis commonly results in hospitalization. Limited data on the proportion of cellulitis admissions associated with readmission are available.To characterize the US national readmission rate associated with hospitalization for treatment of cellulitis.This retrospective cohort analysis of cellulitis admissions from the nationally representative 2014 Nationwide Readmissions Database calculated readmission rates for all cellulitis admissions and subsets of admissions. The multicenter population-based cohort included adult patients admitted for conditions other than obstetrical or newborn care. Data were collected from January 1 through November 30, 2014, and analyzed from February 1 through September 18, 2018. Bivariate logistic regression models were used to assess differences in readmission rates by patient characteristics. Costs were calculated for all readmissions after discharge from hospitalization for cellulitis (hereinafter referred to as cellulitis discharge) and by readmission diagnosis.Admission with a primary diagnosis of cellulitis.Proportion of cellulitis admissions associated with nonelective readmission within 30 days, characteristics of patients readmitted after cellulitis discharge, and costs associated with cellulitis readmission.A total of 447 080 (95% CI, 429 927-464 233) index admissions with a primary diagnosis of cellulitis (53.8% male [95% CI, 53.5%-54.2%]; mean [SD] age, 56.1 [18.9] years) were included. Overall 30-day all-cause nonelective readmission rate after cellulitis discharge was 9.8% (95% CI, 9.6%-10.0%). Among patients with cellulitis, age (odds ratio for 45-64 years, 0.78; 95% CI, 0.75-0.81; P = .001) and insurance status (odds ratio for Medicare, 2.45; 95% CI, 2.33-2.58; P < .001) were associated with increased readmission rates. The most common diagnosis of readmissions included skin and subcutaneous tissue infections. The total cost associated with nonelective readmissions attributed to skin and subcutaneous infections within 30 days of a cellulitis discharge during the study period was $114.4 million (95% CI, $106.8-$122.0 million).Readmission after hospitalization for cellulitis is common and costly and may be preventable with improved diagnostics, therapeutics, and discharge care coordination.
GENE-42. THE GENOMIC LANDSCAPE OF TRIPLE-NEGATIVE GLIOBLASTOMA
Authors: Bill Diplas, Matthew Waitkus, Xujun He, Jackie Brosnan-Cashman, Heng Liu, Lee Chen, Zhaohui Wang, Casey Moure, Patrick Killela, Eric Lipp, Fausto Rodriguez, Yuchen Jiao, Roger McLendon, Darell Bigner, Alan Meeker, Hai Yan
Journal: Neuro-Oncology (2018)

Glioblastoma (GBM) is the most common and deadly primary malignant brain tumor in adults. Mutations in the TERT promoter (TERTp) and isocitrate dehydrogenase 1 or 2 (IDH1/2) can classify ~80% of GBMs into molecular subgroups with distinct clinical courses. These molecular subgroups utilize distinct genetic mechanisms of telomere maintenance, either TERTp mutation leading to telomerase activation or ATRX-mutation leading to an alternative lengthening of telomeres phenotype (ALT). However, approximately 20% of GBMs lack alterations in TERTp and IDH1/2. These tumors, designated TERTpWT-IDHWT or triple-negative glioblastomas (as they also lack 1p19q co-deletion) do not have well-established genetic biomarkers or defined mechanisms of telomere maintenance. Here we performed whole-exome, whole-genome, and RNA-sequencing on a cohort of triple-negative GBMs to define their genetic landscape. We discovered recurrent inactivating mutations in SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily A-like 1 (SMARCAL1) in 21% (8/39) of triple-negative GBMs. Using telomere maintenance characterization assays, we show that SMARCAL1-mutant cases exhibited the ALT phenotype. Using CRISPR/Cas9 gene editing in GBM cell lines, we found that inducing loss of SMARCAL1 generates features of ALT. Rescue of expression of SMARCAL1 in SMARCAL1-null cell lines markedly suppressed ALT features and was dependent on the enzyme helicase activity. Furthermore, using break-apart FISH and whole genome sequencing, we identified recurrent rearrangements upstream of TERT in ~50% of triple-negative GBMs. These TERT-rearranged tumors exhibited elevated levels of TERT mRNA expression. This represents a novel mechanism of telomerase activation in GBMs lacking the well-known TERT promoter hotspot mutations. Finally, we identify recurrent BRAF V600E mutations in younger patients with GBM. Collectively, our findings define novel molecular subgroups of glioblastoma, including a telomerase-positive subgroup driven by TERT-structural rearrangements (IDHWT-TERTSV, ~50%), and an ALT-positive subgroup (IDHWT-ALT, ~40%) with mutations in ATRX or SMARCAL1. We also establish SMARCAL1 inactivating