tbuckley/cabot-search huggingface dataset:
Pilot toxicity study of indenoisoquinoline analogs (NSC-725776 and NSC-724998) in beagle dogs
Authors: Eias Zahalka, Han Seung, Elizabeth Glaze, Joseph Tomaszewski, Mark Cushman, Yves Pommier
Journal: Cancer Research (2007)

1562  The activity of traditional DNA topoisomerase I (Top1) inhibitors, such as camptothecin (CPT) and its derivatives, have been limited due to their chemical instability, rapid cleavage complex reversibility after drug removal, drug resistance and side effects. Through the extensive ongoing work to develop new, novel Top1 inhibitors without these limitations, the indenoisoquinoline analogs, NSC-725776 and NSC-724998, have emerged as potential lead candidates. Both analogs are chemically stable, and exhibit increased resistance to reversal of effects after drug removal, relative to CPT and its derivatives. In order to determine whether NSC-725776 and NSC-724998 would produce similar adverse events as CPT and its derivatives, i.e., neutropenia and diarrhea, and show similar species sensitivity, we conducted a single dose pilot toxicity study in Beagle dogs. NSC-725776 and NSC-724998 were administered via intravenous injection (60 seconds) or infusion (15 minutes) to Beagle dogs at target dose levels of 1.5, 3 and 5 mg/kg or 3.75, 7.5, 10, and 25 mg/kg, respectively. Mortality was observed in dogs treated with NSC-725776 (5 mg/kg) and NSC-724998 (10 or 25 mg/kg). Prior to death, the animals exhibited excessive salivation, emesis, respiratory distress, cyanotic mucous membrane, lethargy, weak pulses, vocalization, mucoid feces and/or soft feces. At necropsy, gelatinous material in bronchial lymph nodes and clear fluid in the trachea and/or foam in the airways were noted in some of the dogs. For surviving animals treated with NSC-725776, a dose of 1.5 mg/kg via injection or 3 mg/kg via infusion produced respiratory distress and prostration, whereas, a dose of 1.5 mg/kg via infusion produced prostration and diarrhea/soft feces. Surviving animals dosed with NSC-724998 via infusion, exhibited signs of breathing difficulty (7.5 mg/kg) or mucoid/soft feces (3.75 mg/kg). Consistent with the signs of respiratory distress in dogs that died prematurely, was a concomitant decrease in serum carbon dioxide CO2 levels just prior to their death. Modest increases in serum total bilirubin concentration (TBILI) and alanine aminotransferase (ALT), aspartate aminotransferase (AST), and creatine kinase (CK) activity were also noted, however because of the small magnitude of these changes, these clinical chemistry effects were probably not biologically relevant. Alterations in hematology parameters consistent with neutropenia, thrombocytopenia and hemoconcentration were noted in animals treated with NSC-725776 (5 mg/kg) or NSC-724998 (10 or 25 mg/kg). No necropsy findings were noted in dogs treated with NSC-725776 ≤ 1.5 mg/kg or NSC-724998 doses ≤10 mg/kg. In conclusion, the maximum tolerated dose level is 3 mg/kg for NSC-725776 and 7.5 mg/kg for NSC-724998 when dosed via a 15 min intravenous infusion and neither compound displays increased sensitivity in dogs. (Supported by NCI Contract N01-CM-42204).
Prostate cancer reactivates developmental epigenomic programs during metastatic progression
Authors: Mark M. Pomerantz, Xintao Qiu, Yanyun Zhu, David Y. Takeda, Wenting Pan, Sylvan C. Baca, Alexander Gusev, Keegan D. Korthauer, Tesa M. Severson, Gavin Ha, Srinivas R. Viswanathan, Ji-Heui Seo, Holly M. Nguyen, Baohui Zhang, Bogdan Pasaniuc, Claudia Giambartolomei, Sarah A. Alaiwi, Connor A. Bell, Edward P. O’Connor, Matthew S. Chabot, David R. Stillman, Rosina Lis, Alba Font-Tello, Lewyn Li, Paloma Cejas, Andries M. Bergman, Joyce Sanders, Henk G. van der Poel, Simon A. Gayther, Kate Lawrenson, Marcos A. S. Fonseca, Jessica Reddy, Rosario I. Corona, Gleb Martovetsky, Brian Egan, Toni Choueiri, Leigh Ellis, Isla P. Garraway, Gwo-Shu Mary Lee, Eva Corey, Henry W. Long, Wilbert Zwart, Matthew L. Freedman
Journal: Nature Genetics (2020)
A stochastic agent-based model of the SARS-CoV-2 epidemic in France
Authors: Nicolas Hoertel, Martin Blachier, Carlos Blanco, Mark Olfson, Marc Massetti, Marina Sánchez Rico, Frédéric Limosin, Henri Leleu
Journal: Nature Medicine (2020)

Many European countries have responded to the COVID-19 pandemic by implementing nationwide protection measures and lockdowns1. However, the epidemic could rebound when such measures are relaxed, possibly leading to a requirement for a second or more, repeated lockdowns2. Here, we present results of a stochastic agent-based microsimulation model of the COVID-19 epidemic in France. We examined the potential impact of post-lockdown measures, including physical distancing, mask-wearing and shielding individuals who are the most vulnerable to severe COVID-19 infection, on cumulative disease incidence and mortality, and on intensive care unit (ICU)-bed occupancy. While lockdown is effective in containing the viral spread, once lifted, regardless of duration, it would be unlikely to prevent a rebound. Both physical distancing and mask-wearing, although effective in slowing the epidemic and in reducing mortality, would also be ineffective in ultimately preventing ICUs from becoming overwhelmed and a subsequent second lockdown. However, these measures coupled with the shielding of vulnerable people would be associated with better outcomes, including lower mortality and maintaining an adequate ICU capacity to prevent a second lockdown. Benefits would nonetheless be markedly reduced if most people do not adhere to these measures, or if they are not maintained for a sufficiently long period. A new study that models the COVID-19 epidemic in France suggests that although a second peak is likely unavoidable, maintaining social distancing and wearing masks when lockdown restrictions are lifted, as well as continuing to shelter vulnerable individuals, will reduce mortality and avoid overwhelming ICU facilities.
Low-intensity pulsed ultrasound ameliorates cardiac diastolic dysfunction in mice: a possible novel therapy for heart failure with preserved left ventricular ejection fraction
Authors: Yuto Monma, Tomohiko Shindo, Kumiko Eguchi, Ryo Kurosawa, Yuta Kagaya, Yosuke Ikumi, Sadamitsu Ichijo, Takashi Nakata, Satoshi Miyata, Ayana Matsumoto, Haruka Sato, Masahito Miura, Hiroshi Kanai, Hiroaki Shimokawa
Journal: Cardiovascular Research (2020)

Heart failure with preserved left ventricular ejection fraction (HFpEF) is a serious health problem worldwide, as no effective therapy is yet available. We have previously demonstrated that our low-intensity pulsed ultrasound (LIPUS) therapy is effective and safe for angina and dementia. In this study, we aimed to examine whether the LIPUS therapy also ameliorates cardiac diastolic dysfunction in mice.
CODEL: phase III study of RT, RT + TMZ, or TMZ for newly diagnosed 1p/19q codeleted oligodendroglioma. Analysis from the initial study design
Authors: Kurt A Jaeckle, Karla V Ballman, Martin van den Bent, Caterina Giannini, Evanthia Galanis, Paul D Brown, Robert B Jenkins, J Gregory Cairncross, Wolfgang Wick, Michael Weller, Kenneth D Aldape, Jesse G Dixon, S Keith Anderson, Jane H Cerhan, Jeffrey S Wefel, Martin Klein, Stuart A Grossman, David Schiff, Jeffrey J Raizer, Frederick Dhermain, Donald G Nordstrom, Patrick J Flynn, Michael A Vogelbaum
Journal: Neuro-Oncology (2020)

Abstract Background We report the analysis involving patients treated on the initial CODEL design. Methods Adults (&amp;gt;18) with newly diagnosed 1p/19q World Health Organization (WHO) grade III oligodendroglioma were randomized to radiotherapy (RT; 5940 centigray ) alone (arm A); RT with concomitant and adjuvant temozolomide (TMZ) (arm B); or TMZ alone (arm C). Primary endpoint was overall survival (OS), arm A versus B. Secondary comparisons were performed for OS and progression-free survival (PFS), comparing pooled RT arms versus TMZ-alone arm. Results Thirty-six patients were randomized equally. At median follow-up of 7.5 years, 83.3% (10/12) TMZ-alone patients progressed, versus 37.5% (9/24) on the RT arms. PFS was significantly shorter in TMZ-alone patients compared with RT patients (hazard ratio [HR] = 3.12; 95% CI: 1.26, 7.69; P = 0.014). Death from disease progression occurred in 3/12 (25%) of TMZ-alone patients and 4/24 (16.7%) on the RT arms. OS did not statistically differ between arms (comparison underpowered). After adjustment for isocitrate dehydrogenase (IDH) status (mutated/wildtype) in a Cox regression model utilizing IDH and RT treatment status as covariables (arm C vs pooled arms A + B), PFS remained shorter for patients not receiving RT (HR = 3.33; 95% CI: 1.31, 8.45; P = 0.011), but not OS ((HR = 2.78; 95% CI: 0.58, 13.22, P = 0.20). Grade 3+ adverse events occurred in 25%, 42%, and 33% of patients (arms A, B, and C). There were no differences between arms in neurocognitive decline comparing baseline to 3 months. Conclusions TMZ-alone patients experienced significantly shorter PFS than patients treated on the RT arms. The ongoing CODEL trial has been redesigned to compare RT + PCV versus RT + TMZ.
Mortality in US Hemodialysis Patients Following Exposure to Wildfire Smoke
Authors: Yuzhi Xi, Abhijit V. Kshirsagar, Timothy J. Wade, David B. Richardson, M. Alan Brookhart, Lauren Wyatt, Ana G. Rappold
Journal: Journal of the American Society of Nephrology (2020)

Significance Statement Wildfires generate high concentrations of fine particulate matter (PM 2.5 ), which are linked to increased morbidity and mortality. When inhaled, PM 2.5 can travel into the respiratory tract and trigger oxidative stress and systemic inflammation. Because of their frailty, patients with ESKD might be especially susceptible to this environmental stressor, but little is known about the effects of air pollution exposures in this population. In a retrospective cohort analysis, the authors found a 4% increase in daily mortality per 10- μ g/m 3 increase in wildfire PM 2.5 and a 7% increase in mortality over 30 days after exposure. On days with wildfire PM 2.5 &gt;10 μ g/m 3 , fires accounted for 8.4% of daily mortality. The findings highlight an immediate and persistent effect of wildfire smoke on mortality among individuals receiving hemodialysis. Background Wildfires are increasingly a significant source of fine particulate matter (PM 2.5 ), which has been linked to adverse health effects and increased mortality. ESKD patients are potentially susceptible to this environmental stressor. Methods We conducted a retrospective time-series analysis of the association between daily exposure to wildfire PM 2.5 and mortality in 253 counties near a major wildfire between 2008 and 2012. Using quasi-Poisson regression models, we estimated rate ratios (RRs) for all-cause mortality on the day of exposure and up to 30 days following exposure, adjusted for background PM 2.5 , day of week, seasonality, and heat. We stratified the analysis by causes of death (cardiac, vascular, infectious, or other) and place of death (clinical or nonclinical setting) for differential PM 2.5 exposure and outcome classification. Results We found 48,454 deaths matched to the 253 counties. A 10- μ g/m 3 increase in wildfire PM 2.5 associated with a 4% increase in all-cause mortality on the same day (RR, 1.04; 95% confidence interval [95% CI], 1.01 to 1.07) and 7% increase cumulatively over 30 days following exposure (RR, 1.07; 95% CI, 1.01 to 1.12). Risk was elevated following exposure for deaths occurring in nonclinical settings (RR, 1.07; 95% CI, 1.02 to 1.12), suggesting modification of exposure by place of death. “Other” deaths (those not attributed to cardiac, vascular, or infectious causes) accounted for the largest portion of deaths and had a strong same-day effect (RR, 1.08; 95% CI, 1.03 to 1.12) and cumulative effect over the 30-day period. On days with a wildfire PM 2.5 contribution &gt;10 μ g/m 3 , exposure accounted for 8.4% of mortality. Conclusions Wildfire smoke exposure was positively associated with all-cause mortality among patients receiving in-center hemodialysis.
Five-Year Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma
Authors: James Larkin, Vanna Chiarion-Sileni, Rene Gonzalez, Jean-Jacques Grob, Piotr Rutkowski, Christopher D. Lao, C. Lance Cowey, Dirk Schadendorf, John Wagstaff, Reinhard Dummer, Pier F. Ferrucci, Michael Smylie, David Hogg, Andrew Hill, Ivan Márquez-Rodas, John Haanen, Massimo Guidoboni, Michele Maio, Patrick Schöffski, Matteo S. Carlino, Céleste Lebbé, Grant McArthur, Paolo A. Ascierto, Gregory A. Daniels, Georgina V. Long, Lars Bastholt, Jasmine I. Rizzo, Agnes Balogh, Andriy Moshyk, F. Stephen Hodi, Jedd D. Wolchok
Journal: New England Journal of Medicine (2019)

Nivolumab plus ipilimumab or nivolumab alone resulted in longer progression-free and overall survival than ipilimumab alone in a trial involving patients with advanced melanoma. We now report 5-year outcomes in the trial.
Re: Prajna et al.: Cross-Linking-Assisted Infection Reduction (CLAIR): A randomized clinical trial evaluating the effect of adjuvant cross-linking on outcomes in fungal keratitis (Ophthalmology. 2020;127:159–166)
Authors: Darren Shu Jeng Ting, Christin Henein, Dalia G. Said, Harminder S. Dua
Journal: Ophthalmology (2020)
Vertical Transmission of Severe Acute Respiratory Syndrome Coronavirus 2 From the Mother to the Infant
Authors: David A. Schwartz
Journal: JAMA Pediatrics (2020)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Pediatrics HomeNew OnlineCurrent IssueFor Authors Podcast Journals JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2024 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Pediatrics journal
Vertical Transmission of Severe Acute Respiratory Syndrome Coronavirus 2 From the Mother to the Infant
Authors: Jitendra Meena, Jogender Kumar, Arushi Yadav
Journal: JAMA Pediatrics (2020)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Pediatrics HomeNew OnlineCurrent IssueFor Authors Podcast Journals JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2024 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Pediatrics journal
FRI0045 Development of an evidence-based referral recommendation (err) for the optimum dmard treatment of patients with early stage rheumatoid arthritis (ra)
Authors: P Emery, F Breedveld, M Dougados, J Kalden, M Schiff, J Smolen
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> In patients with active rheumatoid arthritis (RA), early diagnosis and initiation of DMARD therapy can substantially improve the long-term outcome of disease, as well as overall quality of life. However, delay in referral to a rheumatologist for an accurate diagnosis of RA is a major obstacle to early treatment initiation. A clinical guideline that facilitates early referral of the patient with active RA, and thus the early initiation of DMARD therapy, is required so that treatment is initiated at the most appropriate time to positively impact on long-term morbidity and mortality. <h3>Objectives</h3> To develop an ERR for early RA that would serve as a clinical guide for primary care physicians to identify patients with suspected RA during the early inflammatory stages of the disease. <h3>Methods</h3> A literature search targeting early RA, early RA clinics (EACs), DMARD therapy for early RA, prognostic disease progression, early RA clinical trials and quality of life was performed. Published clinical evidence was reviewed and classified into categories I-IV (I = meta-analysis of/or randomised control trial; IV = expert opinion) and graded (A = category I; D = category IV) according to the methodology defined by Shekelle <i>et al</i>. (BMJ 1999;318: 593–6). Key points supported by relevant clinical evidence were developed and critically evaluated. Using an iterative process, participants’ views were incorporated into a final draft, resulting in a consensus statement. <h3>Results</h3> Clinical evidence (Grade C) derived from EACs, prognostic factors for RA, and the consensus of the authors, resulted in the formation of the ERR, which states that rapid referral to a rheumatologist is necessary in the event of clinical suspicion of RA, which may be supported by the presence of any of the following: more than or equal to 3 swollen joints, metacarpophalangeal/metatarsophalangeal involvement and/or morning stiffness of more than or equal to 30 min. This recommendation is strongly supported by graded clinical evidence that structural damage occurs early in RA (Grade B&amp;C) and that early DMARD therapy improves the long-term outcome of the disease (Grade A). <h3>Conclusion</h3> The proposed ERR is a sensitive evidence-based tool that summarises essential diagnostic criteria derived from prospective clinical investigations and should be used to identify patients with early stage, active RA. The use of the EER should result in early referral to a rheumatologist for definitive diagnosis and early DMARD treatment, facilitating an improved long-term outcome in these patients.
AMG 479, a fully human anti-IGF-1R monoclonal antibody, Inhibits IGF-1 induced phospho-Akt and enhances the antineoplastic activity of cyclophosphamide in vivo
Authors: Pedro Beltran, Elaina Cajulis, Gordon Moody, Young-Ah Chung, Petia Mitchell, Mei Mei Tsai, Robert Radinsky, Calzone Frank
Journal: Cancer Research (2008)

4001  AMG 479 is a fully human monoclonal antibody raised against the type I IGF-1 receptor (IGF-1R). AMG 479 exerts its anti-tumor effects by inhibiting IGF-1R signaling through ligand blocking and receptor internalization and degradation. Currently, a single agent phase II clinical trial is underway to test the activity of AMG 479 against Ewing’s sarcoma. In the present study, we tested the ability of AMG 479 to inhibit IGF-1 driven PI3K/Akt pathway activation in sarcoma cell lines as well as its ability to enhance responsiveness to cyclophosphamide.AMG 479 was able to inhibit more than 80% of IGF-1 induced phospho-Akt (pAkt) and phospho-p70S6K (pp70S6K) in the sarcoma cell lines SK-ES-1, SJSA-1 and A673. To test whether this inhibitory effect can also be achieved in vivo, we dosed xenograft bearing mice (SK-ES-1, SJSA-1 or A673) with 1 mg of AMG 479 or hIgG1 6 hrs prior to challenge with an intraperitoneal injection of IGF-1 (15 μg). Tumor lysates generated from xenograft samples demonstrated that AMG 479 effectively inhibited IGF-1 induced Akt and p70S6K phosphorylation. Interestingly, in SJSA-1 xenografts, AMG 479 was also able to inhibit all basal pAkt activity. Treatment of SK-ES-1 and SJSA-1 xenografts with AMG 479 (300 μg/dose, 2x/week) resulted in highly significant (p 70% vs. hIgG1). In contrast, AMG 479 failed to inhibit the growth of A673 xenografts when used as single agent. In this resistant model, the addition of the DNA alkylating agent cyclophosphamide (25 mg/kg, 3x/week) to AMG 479 therapy resulted in significant (p=0.0020 vs. AMG 479, p=0.0002 vs. cyclophosphamide) tumor growth inhibition compared to either therapy alone, suggesting that these two agents can be combined clinically for the treatment of sarcoma. Together, the data suggest that AMG 479 has therapeutic potential in sarcoma patients both as monotherapy and in combination with approved chemotherapeutic agents.
A vulnerability index for the management of and response to the COVID-19 epidemic in India: an ecological study
Authors: Rajib Acharya, Akash Porwal
Journal: The Lancet Global Health (2020)

BackgroundCOVID-19 is spreading rapidly in India and other parts of the world. Despite the Indian Government's efforts to contain the disease in the affected districts, cases have been reported in 627 (98%) of 640 districts. There is a need to devise a tool for district-level planning and prioritisation and effective allocation of resources. Based on publicly available data, this study reports a vulnerability index for identification of vulnerable regions in India on the basis of population and infrastructural characteristics.MethodsWe computed a composite index of vulnerability at the state and district levels based on 15 indicators across the following five domains: socioeconomic, demographic, housing and hygiene, epidemiological, and health system. We used a percentile ranking method to compute both domain-specific and overall vulnerability and presented results spatially with number of positive COVID-19 cases in districts.FindingsA number of districts in nine large states—Bihar, Madhya Pradesh, Telangana, Jharkhand, Uttar Pradesh, Maharashtra, West Bengal, Odisha, and Gujarat—located in every region of the country except the northeast, were found to have high overall vulnerability (index value more than 0·75). These states also had high vulnerability according to most of the five domains. Although our intention was not to predict the risk of infection for a district or a state, we observed similarities between vulnerability and the current concentration of COVID-19 cases at the state level. However, this relationship was not clear at the district level.InterpretationThe vulnerability index presented in this paper identified a number of vulnerable districts in India, which currently do not have large numbers of COVID-19 cases but could be strongly impacted by the epidemic. Our index aims to help planners and policy makers effectively prioritise regions for resource allocation and adopt risk mitigation strategies for better preparedness and responses to the COVID-19 epidemic.FundingNone.