tbuckley/cabot-search huggingface dataset:
CMI: how did we do in 2019?
Authors: J. Friedman, L. Leibovici
Journal: Clinical Microbiology and Infection (2020)

The CMI Clarivate impact factor (IF) for 2019 is 7.117, an 11% increase compared to the 2018 figure. CMI is now fourth on the list of infectious diseases journals ranked by IF. Impact factors can be misused [1], but the IF does serve as an indication of the interest our readers show in the CMI content. Another indication of our readers' interest and involvement is the participation of more than 1000 persons in the CMI 2019 readers' survey. We have learned from our readers [2].
P-151 The impact of adjuvant chemotherapy regimens in stage II colon cancer (CC) patients
Authors: S. Lobo-Martins, M. Martins, P. Semedo, C. Alvim, H. Luna Pais, R. Paiva, C. Pinto, L. Ribeiro, I. Fernandes, D. Macedo, A. Mansinho, I. Vendrell, R. Teixeira de Sousa, L. Costa
Journal: Annals of Oncology (2020)
Secukinumab 2‐weekly vs. 4‐weekly dosing in patients with plaque‐type psoriasis: results from the randomized GAIN study*
Authors: K. Reich, A. Körber, U. Mrowietz, M. Sticherling, C. Sieder, J. Früh, T. Bachhuber
Journal: British Journal of Dermatology (2020)

Secukinumab is a fully human monoclonal antibody that selectively neutralizes interleukin‐17A and shows long‐lasting efficacy and safety in plaque psoriasis. More evidence is required to optimize secukinumab dosing according to clinical response. GAIN compared the efficacy and safety of secukinumab 300 mg every 2 weeks (q2w) with 300 mg every 4 weeks (q4w) in patients achieving ≥ 75% improvement in Psoriasis Area and Severity Index (PASI 75) but not PASI 90 after 16 weeks. In total, 772 patients with moderate‐to‐severe plaque psoriasis received secukinumab 300 mg subcutaneously at baseline and weeks 1, 2, 3 and 4, then q4w until week 16. At week 16, patients with PASI ≥ 75 to PASI < 90 were randomized 1: 1 to continue q4w dosing (n = 162) or switch to q2w (n = 163) to week 32. The primary endpoint was superiority of q2w to q4w dosing for PASI 90 response at week 32. PASI 90 response at week 32 was numerically greater with secukinumab 300 mg q2w than with secukinumab 300 mg q4w in suboptimal responders, but this did not reach statistical significance (64·4% vs. 57·4%; odds ratio 0·64, 95% confidence interval 0·39–1·07; P = 0·087). Although the primary endpoint was not met, absolute PASI was significantly lower at week 32 in q2w vs. q4w patients (2·11 vs. 2·84, P = 0·024). Significantly more patients with q2w vs. q4w dosing showed minimal disease activity (Investigator's Global Assessment score 0 or 1: 73·0% vs. 64·1%, P < 0·05) and improved quality of life (Dermatology Life Quality Index score 0 or 1: 58·9% vs. 50·6%, P < 0·05) at week 32. No new or unexpected safety signals arose. Most patients achieved PASI 90 response with secukinumab q4w. There was potential benefit of q2w dosing in some suboptimal responders. Continued q4w treatment can improve response even after 16 weeks.
Efficacy and Safety of Canakinumab in Patients With Systemic Juvenile Idiopathic Arthritis With and Without Fever at Baseline: Results From an Open‐Label, Active‐Treatment Extension Study
Authors: Hermine I. Brunner, Pierre Quartier, Ekaterina Alexeeva, Tamàs Constantin, Isabelle Koné‐Paut, Katherine Marzan, Rayfel Schneider, Nico M. Wulffraat, Vyacheslav Chasnyk, Irit Tirosh, Tilmann Kallinich, Jasmin Kuemmerle‐Deschner, Carine Wouters, Bernard Lauwerys, Irina Nikishina, Maria Trachana, Olga Vougiouka, Alberto Martini, Daniel J. Lovell, Jeremy Levy, Eleni Vritzali, Nicolino Ruperto
Journal: Arthritis & Rheumatology (2020)

Objective To evaluate the long‐term efficacy and safety of canakinumab and explore prediction of response in patients with systemic juvenile idiopathic arthritis (JIA) with or without fever at treatment initiation. Methods At enrollment, patients with active systemic JIA (ages 2 to &lt;20 years) started open‐label canakinumab (4 mg/kg every 4 weeks subcutaneously). Efficacy measures included the adapted American College of Rheumatology (ACR) Pediatric 50/70/90 criteria, the Juvenile Arthritis Disease Activity Score (JADAS), and clinically inactive disease and clinical remission on medication, evaluated by either the JADAS or ACR criteria. Results Of the 123 patients (70 with fever and 52 without fever [fever status was not reported for 1 patient]), 84 (68.3%) completed the study (median duration 1.8 years). Comparable efficacy (adapted ACR Pediatric 50/70/90/100) was observed by day 15 in both subgroups (60.0%/48.6%/37.1%/24.3% in those with fever and 67.3%/48.1%/34.6%/19.2% in those without fever), and further increased thereafter. By month 6, clinical remission according to the JADAS or the ACR criteria was achieved in 17 (24.3%) and 26 (37.1%), respectively, of patients with fever and 9 (17.3%) and 12 (23.1%), respectively, of patients without fever. Median time to onset of clinical remission according to the JADAS or ACR criteria was 57 and 30 days, respectively, in those with fever, and 58 and 142 days, respectively, in those without fever. An adapted ACR Pediatric 50 response by day 15 was the strongest predictor of achieving clinical remission according to the JADAS (odds ratio [OR] 13 [95% confidence interval (95% CI) 4, 42]; P &lt; 0.0001) or glucocorticoid discontinuation (OR 19 [95% CI 3, 114]; P = 0.002). Of the 71 of 123 patients (57.7%) who received glucocorticoids at study entry, 27 (38.0%) discontinued glucocorticoids and 21 (29.6%) reached a dose of &lt;0.2 mg/kg/day, with no difference between those with and those without fever; 13 patients (10.6%) tolerated a sustained canakinumab dose reduction to 2 mg/kg every 4 weeks. No new safety findings were observed. Conclusion Canakinumab provided rapid and sustained improvement of active systemic JIA irrespective of the presence of fever at treatment initiation.
Human tumor cell sensitivity to pemetrexed decreases as extracellular folate increases: evidence for minimizing the level of folate supplementation in clinical regimens with pemetrexed
Authors: Shrikanta Chattopadhyay, Roni Tamari, I. David Goldman
Journal: Cancer Research (2006)

550  Pemetrexed (PMX) is a new-generation antifolate recently approved for cancer treatment. Current regimens require coadminstration of 350 -1000 μgm of folic acid +vitamin B12 to minimize toxicity. Previous studies have established that 5-methyltetrahydrofolate (5-methylTHF), the major blood folate, increases with oral folate supplementation. The current study evaluates the impact of extracellular (EC) 5-methylTHF or 5-formylTHF levels on the antitumor activity of PMX in vitro and whether the preservation of PMX activity with loss of reduced folate carrier (RFC) function, observed in human carcinoma cell lines grown with 5-formylTHF, also occurs in cells grown with 5-methylTHF. The HCT-15 colon cancer cell line, and its RFC-deficient subline PT1, were adapted for at least one week to either 5-formylTHF or 5-methylTHF. In the latter case 0.1 mM β-mercaptoethanol was present in the growth medium and half the initial concentration of 5-methylTHF was added qd to compensate for oxidative degradation (estimated half -life of 5-methylTHF in growth medium is about 24 hours). The IC50 of trimetrexate (TMQ), a lipophilic antifolate that is very sensitive to levels of intracellular folate pools, was utilized to estimate changes in cellular folate levels. The IC50s for TMQ were similar when cells were grown in either 5-formylTHF or 5-methylTHF, ∼70 nM and ∼65 nM for HCT-15 and ∼1.2 and ∼1.8 nM for RFC-null PT1 cells, respectively. This supports the equivalence of 5-methylTHF and 5-formylTHF in replenishing intracellular folate pools, whether RFC is present or absent. IC50s for PMX were similar in HCT-15 (∼110 and ∼100 nM), and nearly similar in PT1 cells (∼70 nM and ∼110 nM) with 5-formylTHF or 5-methylTHF, respectively, confirming preservation of PMX activity despite loss of RFC function. Next, EC 5-formylTHF was varied from 1.6 nM to 62.5 nM in 2.5 fold increments and effects on intracellular folate and sensitivity to PMX was assessed in HCT-15 colon and A549 lung cancer cell lines. While TMQ IC50s increased to a similar extent in both cell lines from ∼3 nM to ∼85 nM over this EC folate range, the PMX IC50 increased in A549 cells to a greater extent (from ∼12 nM to ∼300 nM) than in HCT-15 cells (from ∼10 nM to ∼180 nM). Hence, as observed previously in murine leukemia cells, PMX antitumor activity in vitro is markedly decreased as EC and intracellular folates are increased, even over the range of physiological folate concentrations, although different cancer cell-lines are affected to different extents. These observations suggest that (1) excessive folate supplementation in clinical regimens with PMX may decrease chemotherapeutic efficacy, (2) no more than the lowest recommended level of folate supplementation (350-400 μgm) should be utilized and (3) other non-dietary sources of folate should be avoided.
The type 1 repeat peptide ABT510 induces apoptosis of brain microvascular endothelial cells and inhibits glioblastoma tumor growth in vivo
Authors: Roni Mamluk, Michael J. Storek, Jochem Gokemeijer, Janna M. Bates, Brent M. Morse, Jeffrey J. Robinson, Michael L. Gosselin, Alan S. Harris
Journal: Cancer Research (2006)

230  AdNectins are novel protein antagonists based on the 10th Type III domain of human fibronectin. Fibronectin is a protein that is expressed at relatively high levels in the extracellular matrix and plasma (∼300 μg/ml). This domain (∼10 kDa) was chosen due to its structural similarity to the VH domain of antibodies, despite the lack of sequence homology.AdNectins offer important benefits over conventional antibodies including significantly reduced development time, as well as the ability to produce these proteins by economic E. coli-based production methods. CT-322 is an AdNectin that targets vascular endothelial growth factor 2 (VEGFR-2) and inhibits its three ligands VEGF-A, VEGF-C and VEGF-D from binding and activating this receptor. A single 40 kDa polyethylene glycol (PEG) moiety was added to improve AdNectin pharmacokinetics. To characterize the pharmacokinetics and biodistribution, 125I labeled CT-322 was administered intravenously (IV) or intraperitoneal (IP) to rats Following IV administration, CT-322 levels in the plasma declined over time in a bi-phasic manner with terminal half life of 17-24 hours. Following IP administration, CT-322 levels increased to Cmax at 8 to 12 h postdose and then declined. CT-322 exhibited a linear relationship between dose and drug exposure (AUC) at 1, 10 and 50 mg/kg. Similar pharmacokinetic parameters were observed when CT-322levels were directly measured in plasma by ELISA. CT-322 activity was maintained in plasma for at least 24 hours as determined by bioassay analysis. Blocking of VEGFR-2 activity by CT-322 has been found to inhibit angiogenesis and tumor growth in multiple murinemodels. Interestingly a dose schedule of twice a week (3-4 half-lives) was as efficacious as when CT-322 was administered every day (∼1 half-life); indicating that sustained plasma levels are not required for maximal efficacy in murine models. Hence, CT-322 efficacy in relation to treatment schedule might be a result of prolonged down regulation of VEGFR-2 and/or specific accumulation of drug in the tumor. In summary, CT-322 has a half life of 17-24 hours and exhibited linear pharmacokinetics with dose.The inhibition of tumor growth by CT-322 requires a dosing schedule that is less frequent than expected from the plasma levels potentially due to accumulation in tumor tissue or sustained down regulation of the VEGFR-2 receptor.
The Atkins style high fat-low carbohydrate diet inhibits proliferation of prostate cancer in a xenograft model
Authors: Vasundara Venkateswaran, Ahmed Haddad, Laurence H. Klotz, Neil E. Fleshner
Journal: Cancer Research (2005)

5177  Introduction: The mechanism by which high fat diets contribute to cancer progression is likely related to increased levels of insulin and/or related growth factors. High fat, low carbohydrate diets, including Atkins®, are based on maintaining low levels of insulin. Our hypothesis is that a hypoglycemic, low insulin diet would protect against the proliferative effect of high dietary fat. We have studied this experimentally in a prostate cancer xenograft model. Materials and Methods: Athymic male Swiss nu/nu mice, aged 6-8 weeks were inoculated in the hind-limb with (1 x 106) human prostate cancer cells (LNCaP) / 0.2 ml of ice-cold Matrigel. Animals were divided into 2 groups of 20 each. At the end of 2 weeks animals with signs of tumor development were separated and placed either an Atkins style low carbohydrate diet (45% fat, 45% protein and 10% carbohydrate diet) or on a control diet high fat diet (45% fat, 15% protein and 40% carbohydrate diet). Body weight and tumor measurements were carried out every week. Plasma Insulin and PSA measurements were performed biweekly. Plasma insulin was measured using the Medicorp 125I RIA test kit. All animals were on the diet until the end of the treatment period. Results: The diets were well tolerated with no evidence of diet-related toxicity. There was a 10% decrease in body weight of the animals on the Atkins type diet. Animals on the Atkins type diet demonstrated a 18% decrease in tumor volume as compared to the controls. Wet tumors weighed a maximum of 1.2 g in the Atkins type diet compared to 1.6 g in the controls. Plasma insulin levels were decreased three fold in the animals on the Atkins style diet as compared to the controls (350 vs 1060 pmol/l). Conclusion: In this prostate cancer xenograft model, an Atkins type diet (high fat - low carbohydrate) resulted in an 18% reduction in the rate of cancer growth. An Atkins style diet may protect against the proliferative effect on cancer cells on a high fat diet by favorably influencing the levels of insulin and related growth factors.
Chenodeoxycholic acid derivative, HS-1200, induces Egr-1 gene expression and modulates the cell cycle in human hepatoma cells
Authors: Sang Eun Park, Mohammad Akbar Hossain, Min Young Kim, Mi-Na Kim, Eunyoung Ahn, Gi-Young Kim, Yung Hyun Choi, Nam Deuk Kim
Journal: Cancer Research (2008)

2659  We previously reported that HS-1200, a synthetic chenodeoxycholic acid derivative, has apoptosis-inducing activity in various human cancer cells. In this study, we investigated the underlying molecular mechanism for the potent apoptotic effect of HS-1200 on HepG2 (wild-type p53) and Hep3B (p53 deleted, FAS null) human liver cancer cells. Treatment of both cells with HS-1200 resulted in growth inhibition and induction of apoptosis as measured by MTT assay, nuclear staining, DNA electrophoresis and flow cytometry analysis. The increase in apoptosis was associated with the alteration in the ratio of Bcl-2/Bax protein expression. In addition, flow cytometry analysis indicated that HS-1200 induced G1 phase arrest in both cells. When analyzing the expression of cell cycle-related proteins, we found that HS-1200 reduced the expression levels of cyclin D1, cyclin A, and Cdk2. HS-1200 treatment also caused an increase of the expression level of p21WAF1/CIP1 protein in a p53-dependent manner in HepG2 cells. However, Hep3B cells showed no significant induction of p21WAF1/CIP1 and instead, showed significant up-regulation of p27Kip1. We also observed that HS-1200 decreased the levels of cyclooxygenase (COX)-2 mRNA and protein expression. Furthermore, HS-1200 treatment markedly induced the Egr-1 expression at an early time point, and the protein expression of p53, p21WAF1/CIP1, p27 and COX-2 abolished by silencing of Egr-1. Taken together, these findings provide important new insights into the possible molecular mechanisms of the anti-cancer activity of the synthetic bile acid derivative, HS-1200. [This work was supported by the Korea Science and Engineering Foundation (KOSEF) grant funded by the Korea government (MOST) (R01-2006-000-11117-0)].
LBA-3 CheckMate 459: Long-term (minimum follow-up 33.6 months) survival outcomes with nivolumab versus sorafenib as first-line treatment in patients with advanced hepatocellular carcinoma
Authors: B. Sangro, J. Park, R. Finn, A. Cheng, P. Mathurin, J. Edeline, M. Kudo, K. Han, J. Harding, P. Merle, O. Rosmorduc, L. Wyrwicz, E. Schott, S. Choo, R. Kelley, D. Begic, G. Chen, J. Neely, M. Tschaika, T. Yau
Journal: Annals of Oncology (2020)
Increase in Incidence of Neonatal Abstinence Syndrome Among In-Hospital Birth in the United States—Reply
Authors: Andrea E. Strahan, Gery P. Guy, Jean Y. Ko
Journal: JAMA Pediatrics (2020)

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Abstract NT-117: INHIBITION OF PARG, SENSITIZES OVARIAN CANCER CELLS TO PARP INHIBITORS AND DNA DAMAGING AGENTS
Authors: Emad Matanes, Tahira Baloch, David Octeau, Roy Kessous, Liron Kogan, Ido Laskov, Walter Gotlieb, Amber Yasmeen
Journal: Clinical Cancer Research (2019)

Abstract BACKGROUND: Poly(ADP-ribose) glycohydrolase (PARG) is responsible poly(ADP-ribose) (PAR) catabolism, which is synthesized by poly(ADP-ribose) polymerases (PARPs) at the site of DNA single-strand breaks (SSB). Faulty PAR formation or disintegration inhibits SSB repair. PARP inhibitors (PARPi) exploit the synthetic lethality between SSB repair and homologous recombination (HR) double strand break (DSB) repair. The most effective PARPi traps PARP at the SSB site, causing a double strand break during DNA synthesis that the cell cannot repair. The trapping of PARP can also be achieved through PARG inhibition. Due to the high rate of HR defects in epithelial ovarian cancer, the aim of this study is to evaluate the effect of a PARG inhibitor (PARGi) on epithelial ovarian cancer cell lines, alone and in combination with PARPi or cisplatin. METHODS: PARG protein levels were assessed in 74, unselected, snap-frozen, tumors kept in our bio-bank by western blotting and immuno-histochemistry (IHC), as well as in the TCGA database. PARG was knocked down in two cell lines resistant to PARP inhibition, OVCAR3 and SKOV3. The knockdowns were subjected to cell migration and cell proliferation assays, as well as single cell analysis. BRCA1 mutated and BRCA1 wild-type cell lines were exposed to clinically relevant doses of PARGi, PARPi, or cisplatin, separately or in various combination. Therapeutic efficacy was assessed using colony formation assay. Western Blotting was used to detect the levels of PARG and PARP proteins in the cell lines. RESULTS: PARG mRNA was expressed in 30% of tumors in TCGA. PARG protein was also detected in 30% of the biobank tumors analyzed. PARG knockdowns exhibited reduced rates of cellular proliferation and significant G2/M cell cycle arrest. In PARG over expressed ovarian cancer cell lines, PARG inhibitor similarly reduced cell migration (OVCAR3 and SKOV3: 75% reduction, SNU-251: 48% reduction). CONCLUSION: PARG inhibition appears to be a viable, complementary strategy to PARP inhibition in HR-deficient cancers. The effect of BRCA1 on the efficacy of PARG inhibition, as well as various treatment combinations, are currently under investigation. Citation Format: Emad Matanes, Tahira Baloch , David Octeau, Roy Kessous, Liron Kogan, Ido Laskov, Walter Gotlieb, Amber Yasmeen. INHIBITION OF PARG, SENSITIZES OVARIAN CANCER CELLS TO PARP INHIBITORS AND DNA DAMAGING AGENTS [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr NT-117.
HIV antiretroviral therapy and prevention use in US blood donors: a new blood safety concern
Authors: Brian Custer, Claire Quiner, Richard Haaland, Amy Martin, Mars Stone, Rita Reik, Whitney R. Steele, Debra Kessler, Phillip C. Williamson, Steven A. Anderson, Alan E. Williams, Henry F. Raymond, Willi McFarland, William T. Robinson, Sara Glick, Kwa Sey, C. David Melton, Simone A. Glynn, Susan L. Stramer, Michael P. Busch
Journal: Blood (2020)
Influence of Surgical Excision on the Survival of Patients With Stage 4 High-Risk Neuroblastoma: A Report From the HR-NBL1/SIOPEN Study
Authors: Keith Holmes, Ulrike Pötschger, Andrew D. J. Pearson, Sabine Sarnacki, Giovanni Cecchetto, Javier Gomez-Chacon, Roly Squire, Enrique Freud, Adam Bysiek, Lucas E. Matthyssens, Martin Metzelder, Tom Monclair, Jakob Stenman, Michal Rygl, Lars Rasmussen, Jean-Marc Joseph, Sabine Irtan, Stefano Avanzini, Jan Godzinski, Kristin Björnland, Martin Elliott, Roberto Luksch, Victoria Castel, Shifra Ash, Walentyna Balwierz, Geneviève Laureys, Ellen Ruud, Vassilios Papadakis, Josef Malis, Cormac Owens, Henrik Schroeder, Maja Beck-Popovic, Toby Trahair, Ana Forjaz de Lacerda, Peter F. Ambros, Mark N. Gaze, Kieran McHugh, Dominique Valteau-Couanet, Ruth Lydia Ladenstein
Journal: Journal of Clinical Oncology (2020)

To evaluate the impact of surgeon-assessed extent of primary tumor resection on local progression and survival in patients in the International Society of Pediatric Oncology Europe Neuroblastoma Group High-Risk Neuroblastoma 1 trial.Patients recruited between 2002 and 2015 with stage 4 disease > 1 year or stage 4/4S with MYCN amplification < 1 year who had completed induction without progression, achieved response criteria for high-dose therapy (HDT), and had no resection before induction were included. Data were collected on the extent of primary tumor excision, severe operative complications, and outcome.A total of 1,531 patients were included (median observation time, 6.1 years). Surgeon-assessed extent of resection included complete macroscopic excision (CME) in 1,172 patients (77%) and incomplete macroscopic resection (IME) in 359 (23%). Surgical mortality was 7 (0.46%) of 1,531. Severe operative complications occurred in 142 patients (9.7%), and nephrectomy was performed in 124 (8.8%). Five-year event-free survival (EFS) ± SE (0.40 ± 0.01) and overall survival (OS; 0.45 ± 0.02) were significantly higher with CME compared with IME (5-year EFS, 0.33 ± 0.03; 5-year OS, 0.37 ± 0.03; P < .001 and P = .004). The cumulative incidence of local progression (CILP) was significantly lower after CME (0.17 ± 0.01) compared with IME (0.30 ± 0.02; P < .001). With immunotherapy, outcomes were still superior with CME versus IME (5-year EFS, 0.47 ± 0.02 v 0.39 ± 0.04; P = .038); CILP was 0.14 ± 0.01 after CME and 0.27 ± 0.03 after IME (P < .002). A hazard ratio of 1.3 for EFS associated with IME compared with CME was observed before and after the introduction of immunotherapy (P = .030 and P = .038).In patients with stage 4 high-risk neuroblastoma who have responded to induction therapy, CME of the primary tumor is associated with improved survival and local control after HDT, local radiotherapy (21 Gy), and immunotherapy.