tbuckley/cabot-search huggingface dataset:
Late Health Outcomes After Contemporary Lymphome Malin de Burkitt Therapy for Mature B-Cell Non-Hodgkin Lymphoma: A Report From the Childhood Cancer Survivor Study
Authors: Matthew J. Ehrhardt, Yan Chen, John T. Sandlund, Elizabeth C. Bluhm, Robert J. Hayashi, Kerri Becktell, Wendy M. Leisenring, Monika L. Metzger, Kirsten K. Ness, Kevin R. Krull, Kevin C. Oeffinger, Todd M. Gibson, Mitchell S. Cairo, Thomas G. Gross, Leslie L. Robison, Gregory T. Armstrong, Yutaka Yasui, Melissa M. Hudson, Daniel A. Mulrooney
Journal: Journal of Clinical Oncology (2019)

The widely used, risk-based Lymphome Malin de Burkitt (LMB) chemotherapy regimen has improved survival rates for children with mature B-cell non-Hodgkin lymphoma (NHL); however, associated late effects remain understudied. We assessed late health outcomes after LMB treatment in the Childhood Cancer Survivor Study.Multivariable regression models compared chronic health conditions, health status, and socioeconomic and neurocognitive outcomes between survivors of NHL treated with the LMB regimen (n = 126), survivors of NHL treated with non-LMB regimens (n = 444), and siblings (n = 1,029).LMB survivors were a median age of 10.2 years (range, 2.5 to 20.5 years) at diagnosis and 24.0 years (range, 10.3 to 35.3 years) at evaluation. Compared with siblings, LMB survivors were at increased risk for adverse health outcomes. However, survivors of NHL treated with LMB and non-LMB regimens did not differ with regard to risk of having any chronic health conditions, impaired health status, neurocognitive deficits, or poorer socioeconomic outcomes. Increased risk for the following specific neurologic conditions was observed in LMB survivors compared with non-LMB survivors: epilepsy (relative risk [RR], 15.2; 95% CI, 3.1 to 73.4); balance problems (RR, 8.9; 95% CI, 2.3 to 34.8); tremors (RR, 7.5; 95% CI, 1.9 to 29.9); weakness in legs (RR, 8.1; 95% CI, 2.5 to 26.4); severe headaches (RR, 3.2; 95% CI, 1.6 to 6.3); and prolonged arm, leg, or back pain (RR, 4.0; 95% CI, 2.2 to 7.1). The survivors from the group C LMB risk group (n = 50) were at the highest risk for these conditions; however, except for worse functional status (odds ratio, 2.7; 95% CI, 1.2 to 5.8), they were not at increased risk for other adverse health status or socioeconomic outcomes compared with non-LMB survivors.Survivors treated with LMB and non-LMB regimens are largely comparable in late health outcomes except for excess neurotoxicity among LMB survivors. These data inform treatment efforts seeking to optimize disease control while minimizing toxicity.
Germline TIM-3 Mutations Characterize Sub-Cutaneous Panniculitis T-Cell Lymphomas with Hemophagocytic Lymphohistiocytic Syndrome
Authors: Dong-Anh Khuong-Quang, Tenzin Gayden, Fernando Sepulveda, Jonathan Pratt, Elvis Valera, Alexandrine Garrigue, Susan Kelso, Frank Sicheri, Leonie Mikael, Nancy Hamel, Andrea Bajic, Rola Dali, Dzana Dervovic, Daniel Schramek, Frederic Guerin, Mikko Taipale, Hamid Nikbakht, Jacek Majewski, Despina Moshous, Janie Charlebois, Sharon Abish, Christine Bole-Feysot, Patrick Nitschke, Brigitte Bader-Meunier, David Mitchell, Catherine Thieblemont, Maxime Battistella, Simon Gravel, Van-Hung Nguyen, Rachel Conyers, Jean-Sebastien Diana, Christopher McCormack, H. Miles Prince, Marianne Besnard, Stephane Blanche, Paul G Ekert, Sylvie Fraitag, William D Foulkes, Alain Fischer, Benedicte Neven, David Michonneau, Genevieve de Saint Basile, Nada Jabado
Journal: Blood (2018)
Targets for the reduction of antibiotic use in humans in the Transatlantic Taskforce on Antimicrobial Resistance (TATFAR) partner countries
Authors: Fabio D’Atri, Jacqueline Arthur, Hege Salvesen Blix, Lauri A Hicks, Diamantis Plachouras, Dominique L Monnet
Journal: Eurosurveillance (2019)

Unnecessary and inappropriate use of antibiotics in human healthcare is a major driver for the development and spread of antimicrobial resistance; many countries are implementing measures to limit the overuse and misuse of antibiotics e.g. through the establishment of antimicrobial use reduction targets. We performed a review of antimicrobial use reduction goals in human medicine in Transatlantic Taskforce on Antimicrobial Resistance partner countries. On 31 March 2017, the European Centre for Disease Prevention and Control sent a questionnaire to National Focal Points for Antimicrobial Consumption and the National Focal Points for Antimicrobial Resistance in 28 European Union countries, Iceland and Norway. The same questionnaire was sent to the TATFAR implementers in Canada and the United States. Thirty of 32 countries replied. Only nine countries indicated that they have established targets to reduce antimicrobial use in humans. Twenty-one countries replied that no target had been established. However, 17 of these 21 countries indicated that work to establish such targets is currently underway, often in the context of developing a national action plan against antimicrobial resistance. The reported targets varied greatly between countries and can be a useful resource for countries willing to engage in the reduction of antibiotic use in humans.
Recognizing and Reacting to Microaggressions in Medicine and Surgery
Authors: Madeline B. Torres, Arghavan Salles, Amalia Cochran
Journal: JAMA Surgery (2019)

Diversity and inclusion in medicine, and in surgery in particular, still merit substantial attention in 2019. With each increase in academic rank there are fewer women, with only 24% of full professors in medicine being women. Underrepresented minorities face similar challenges, with only 3% of medical faculty being black and 4% of medical faculty being Hispanic or Latino; only 2% of full professors are Hispanic or Latino and only another 2% are black. Explicit discrimination unfortunately still does exist, but in many environments, more subtle forms of bias are more prevalent. Microaggressions, which are categorized as microassaults, microinsults, microinvalidations, and environmental microaggressions, are indirect expressions of prejudice that contribute to the maintenance of existing power structures and may limit the hiring, promotion, and retention of women and underrepresented minorities. The primary goal of this communication is to help readers understand microaggressions and their effect. We also provide suggestions for how recipients or bystanders may respond to microaggressions.
Abstract P252: The Effects of Sodium Reduction on Metabolism and Thirst
Authors: Stephen P Juraschek, Edgar R Miller, Alexander Chang, Cheryl Anderson, John E Hall, Lawrence J Appel
Journal: Circulation (2018)

Background: Recent studies challenge the traditional understanding of sodium physiology. Some animal studies suggest that high sodium intake may induce catabolism, leading to weight loss. Other studies suggest that high sodium intake might reduce, rather than increase, thirst. Hypothesis: Higher sodium intake increases thirst, fluid intake, and sodium excretion without altering energy intake or lowering weight. Methods: In the DASH-Sodium feeding study, adults with pre- or stage 1 hypertension without antihypertensive medications, were randomly assigned to the DASH diet or a control diet. On their assigned diet, participants consumed each of three sodium levels for 4 weeks (randomized crossover design). Participants were provided all meals, but could drink water freely. Throughout the trial, calorie intake was adjusted to keep weight constant. The three sodium levels (at 2100 kcal/d) were: low (1150 mg), medium (2300 mg), and high (3450 mg). Weight, energy intake, self-reported thirst, urine volume, plasma renin, serum aldosterone, urine osmolality, and urine sodium excretion were assessed at the end of each period. Results: Among 412 participants (57% women, 57% black, mean age 48 yrs), weight increased slightly with higher sodium on the control diet, but not the DASH diet; energy intake did not vary across sodium levels in both diets ( P -trends &gt; 0.34) ( Table ). In contrast, participants reported more thirst with high vs low sodium (both diets P -trends &lt; 0.001) and potentially higher fluid intake (urine volume) during the control diet (1,566 vs 1,491 ml on high vs low sodium; P -trend = 0.07). On both diets, plasma renin and serum aldosterone were lower with higher sodium (each P -trend &lt; 0.001). Likewise, both urine osmolality and sodium excretion were higher with higher sodium intake (all P -trends &lt; 0.001). Conclusions: Higher sodium intake did not alter energy intake, but did increase thirst and sodium excretion. These findings are consistent with the traditional understanding of the physiology of excess dietary sodium intake.
ENESTop 192-week results: Treatment-free remission (TFR) in patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP) after stopping second-line (2L) nilotinib (NIL).
Authors: Timothy P. Hughes, Carla Boquimpani, Naoto Takahashi, Noam Benyamini, Nelma Cristina D. Clementino, Vasily Shuvaev, Jeffrey Howard Lipton, Anna G. Turkina, Raquel De Paz Arias, Beatriz Moiraghi, Franck E. Nicolini, Jolanta Dengler, Tomasz Sacha, Dong-Wook Kim, Rafik Fellague-Chebra, Sandip Acharya, Catherine Bouard, Francois-Xavier Mahon
Journal: Journal of Clinical Oncology (2019)

7005 Background: In the ENESTop study (NCT01698905) of TFR in pts with CML-CP who achieved a sustained deep molecular response (MR) with 2L NIL, 57.9% remained in TFR 48 wks after stopping NIL (primary endpoint). Analyses at 144 wks showed durability of TFR. Data from longer follow-up (192 wks) evaluating the maintenance of TFR are reported. Methods: Pts treated with ≥2 y NIL after &gt; 4 wks imatinib (≥3 y total) and achieving MR 4.5 ( BCR-ABL1 IS ≤0.0032%) on NIL were eligible. After a 1 y consolidation, pts with no confirmed loss of MR 4.5 could attempt TFR. NIL was resumed upon loss of major MR ( BCR-ABL1 IS ≤0.1%) or confirmed loss of MR 4 ( BCR-ABL1 IS ≤0.01%). At the data cut-off (Sep 24 2018), all pts had completed ≥192 wks of TFR, resumed NIL, or discontinued the study. Results: By the data cut-off, of 126 pts entering TFR, 56 were ongoing, 59 had resumed NIL, and 11 had discontinued. TFR rate at 192 wks was 46.0% (58/126; 95% CI, 37.1–55.1%); all but 1 of the 58 pts were in MR 4.5 . Only 1/61 pts in TFR at 144 wks lost response by 192 wks (confirmed loss of MR 4 ); another 2 pts discontinued due to serious AE (polycythemia vera) and pt/guardian decision, respectively. Of 59 pts who resumed NIL, 56 (94.9%) and 55 (93.2%) regained MR 4 and MR 4.5 , respectively. 40/56 pts (71.4%) who regained MR 4 had stable MR 4 at 96 wks (12 discontinued &lt; 96 wks, and 4 remained on study with &lt; 96 wks, after regaining MR 4 ); 37/55 pts (67.3%) who regained MR 4.5 had stable MR 4.5 at 96 wks (12 discontinued &lt; 96 wks, and 6 remained on study with &lt; 96 wks, after regaining MR 4.5 ). There were no disease progressions, deaths due to CML, or new deaths since the 144-wk analysis. The 192 wk treatment-free survival rate was 50.3% (95% CI, 41.2–58.7%). Of 62 pts who remained in TFR for &gt; 144 wks, 11.3%, 53.2%, 21.0%, 14.5% and 3.2% had musculoskeletal pain AEs during consolidation and each subsequent 48 wk period of TFR. Among 59 pts who resumed NIL, most common AEs were hypertension (20.3%) and arthralgia (13.6%); the majority of AEs were grade 1/2. Conclusions: Results demonstrate long-term durability and safety of TFR following 2L NIL, with no disease progressions or CML-related deaths, and musculoskeletal pain AEs were transient. Clinical trial information: NCT01698905.
Abstract P248: Objectively Measured Physical Activity and Sedentary Behavior Change During a Lifestyle Intervention in Overweight Adults: Does Season Matter?
Authors: Bonny Rockette-Wagner, Andrea M Kriska, Qianheng Ma, Susan M Sereika, Christopher C Imes, Christopher Kline, Lora Burke
Journal: Circulation (2016)

Introduction: Lifestyle interventions, with physical activity (PA) as a key component, are important to reducing cardiometabolic disease risk. In our work in both efficacy and effectiveness clinical trials, we have shown that season has a significant impact on subjectively determined moderate-vigorous (MV) PA levels, both at baseline and during the intervention. However, the effect of season in these lifestyle interventions has not yet been examined utilizing objective measurements of PA so that time spent in all PA intensities and sedentary behavior(SB) can be quantified. Hypothesis: Our hypothesis is that PA would increase and SB would decrease due to the intervention but that season would have an additional effect on both. Methods: We enrolled 150 overweight/obese adults (51.1±10.2 y; 79% Caucasian; 91% female) in a 12-month lifestyle intervention for weight loss that provided regular feedback to participants on diet and PA goal achievement. Six cohorts were recruited from 2012-2014. The PA goal was to achieve and maintain 150 minutes/week of MVPA. ActiGraph GT3x accelerometers, worn on the waist, were used to assess average daily step counts and time spent in PA and SB. Accelerometer recordings with 10 hours/day of wear time on ≥4 days were considered a valid assessment of typical PA and SB. Changes in activity variables at 6 months and 12 months were examined using linear mixed models. We also examined the season (winter, spring, summer, or autumn) when the intervention was implemented and if this affected changes in PA and SB. Results: Baseline accelerometer data were valid for 149 participants. Mean (SD) baseline values were 6132 (1873) steps counts/day, 11 (11) MVPA min/day, 245 (64) light intensity (L)PA min/day, 635 (85) SB min/day. Season was significantly related to step counts, LPA, MVPA, and SB with significantly lower PA and higher SB in the winter (p&lt;0.05). Changes in LPA and SB were not significant over the entire follow-up (p&gt;0.05). When adjusted (for monitor wear time/day and season) mean (SD) increases in step counts from baseline were 1128 (208) and 742(209) steps/day at 6 and 12 months, respectively (both p&lt;0.0001). For MVPA adjusted mean (SD) increases from baseline were 7(1) and 6(1) min/day at 6 and 12 months, respectively (both p&lt;0.0001). Conclusions: Relevant improvements in steps counts and MVPA were recorded at 6 and 12 months. This was true even after controlling for the effect of differences in the season of implementation. When considering the effect of lifestyle interventions on activity, future studies should consider the effect of seasonal changes on PA levels.
<i>Paulinia cupana</i> (Guaraná) purified dry extract (PC-18) for chemotherapy related fatigue in patients solid tumors.
Authors: Adriana Braz Del Giglio, Tatiana Goberstein Lerner, Andrea Thaumaturgo Lera, Henrique Soares Paiva, Bruno Carelli, Renata Guise Soares Azevedo, Cecilia Goldman, Fernanda Schindler, Luiz F Pianowski, Claudia Grandino Latorre, Patricia Santi, Felipe Melo Cruz, Daniel Iracema Cubero, Auro Del Giglio
Journal: Journal of Clinical Oncology (2012)

e19552 Background: Paulinia cupana (guaraná) is an amazonic plant with stimulant proprieties which was shown previously to be effective for chemotherapy related fatigue in patients with breast cancer in a randomized double blind placebo controlled trial conducted by our group (J Altern Complement Med. 2011;17(6):505-12). Purpose: Extend our study to patients with different tumor types receiving various regimens of chemotherapy, treated with a purified dry extract of Paulinia cupana (PC-18). Methods: We included patients with solid tumors older than 18 years of age who were scheduled to receive systemic chemotherapy. We excluded patients with fibromyalgia and uncontrolled hypothyroidism, depression, anemia, hypertension or cardiac disease. We evaluated basal fatigue with the BFI questionnaire before chemotherapy, and included only patients who had an increase in their BFI score after one week. PC-18 was given at 50 mg PO bid, starting after one week of chemotherapy. We employed the FACIT-F, BFI, Chalder, HADS and PSQI questionnaires to evaluate fatigue, anxiety, depression and sleep quality at one week and after 4 weeks of chemotherapy. Results: 36 patients with a mean age of 54 years, 61 % female, 28% with breast, 22% colorectal, 8.3% lung , 8.3% head/neck, 5.6% ovarian and 27% of other carcinomas were included. Fatigue scores improved significantly when we compared scores of the BFI (mean difference = 19.39; 95%CI 12.4 – 26.37, p &lt; 0.0001), FACIT-F (mean difference = -11.51; 95%CI -19.25 - -3.76, p = 0.0049) and Chalder (mean difference = 4.571; 95% CI 1.86 – 7.28, p = 0.0018) questionnaires. HADS subscales scores of anxiety (p = 0.025) and depression (p = 0.0095) also improved significantly after 3 weeks of PC-18 therapy. PSQI scores did not change significantly (p = 0.26) after 3 weeks of PC-18 treatment. Conclusions: We conclude that Paulinia cupana (Guaraná) PC-18 extract is active for treatment of chemotherapy related fatigue in patients with a variety of solid tumors and also improves their anxiety and depression scores without worsening the quality of their sleep.
Rapid and transient calcium response in acquired granulocytic or monocytic phenotype of promyelocytic human leukemia HL-60 cells
Authors: Kimvan Tran, Dianne Fishwild
Journal: Cancer Research (2008)

3424  Calcium flux is a well established type of signal transduction in cells, elicited by a large number of mediators binding to their respective target receptors. Changes in intracellular calcium levels result in a plethora of effects including changes in gene transcription and post-transcriptional modifications that can lead to cell activation or suppression.  Utilizing the ability of promyelocytic human leukemia HL-60 cells to undergo in vitro differentiation into the granulocytic or monocytic phenotype and the measurement of intracellular response of Fluo-4 loaded cells by a microcapillary flow cytometer, we demonstrated that as expected, A23187 and ionomycin, known pharmacological stimuli, resulted in sharp increases in intracellular calcium response. We then found that FMLP, SDF-1α and ATP elicited a rapid and transient intracellular calcium mobilization in both undifferentiated and granulocytic or monocytic differentiated cells, with ATP being the most efficacious stimulant. In contrast, LPS, known to be potent activator of macrophages, did not cause a rapid and transient increase in intracellular calcium level at the concentration of 1 ug/mL i.e. up to 100-fold the concentration normally required for maximal biological effects.  Thus, the results obtained in this study were consistent with and extended the previous studies of activation of macrophages for tumor cytotoxicity (Johnson & Torres, 1985, Johnston & Kitagawa, 1985 and Wright et al., 1985), suggesting that the importance of intracellular calcium mobilization as a second messenger in macrophages and granulocytes in response to stimuli.
Takayasu arteritis risk locus in <i>IL6</i> represses the anti-inflammatory gene <i>GPNMB</i> through chromatin looping and recruiting MEF2–HDAC complex
Authors: Xiufang Kong, Amr H Sawalha
Journal: Annals of the Rheumatic Diseases (2019)

Objective Previous work has revealed a genetic association between Takayasu arteritis and a non-coding genetic variant in an enhancer region within IL6 (rs2069837 A/G). The risk allele in this variant (allele A) has a protective effect against chronic viral infection and cancer. The goal of this study was to characterise the functional consequences of this disease-associated risk locus. Methods A combination of experimental and bioinformatics tools were used to mechanistically understand the effects of the disease-associated genetic locus in IL6 . These included electrophoretic mobility shift assay, DNA affinity precipitation assays followed by mass spectrometry and western blotting, luciferase reporter assays and chromosome conformation capture (3C) to identify chromatin looping in the IL6 locus. Both cell lines and peripheral blood primary monocyte-derived macrophages were used. Results We identified the monocyte/macrophage anti-inflammatory gene GPNMB ,~520 kb from IL6 , as a target gene regulated by rs2069837. We revealed preferential recruitment of myocyte enhancer factor 2–histone deacetylase (MEF2–HDAC) repressive complex to the Takayasu arteritis risk allele. Further, we demonstrated suppression of GPNMB expression in monocyte-derived macrophages from healthy individuals with AA compared with AG genotype, which was reversed by histone deacetylase inhibition. Our data show that the risk allele in rs2069837 represses the expression of GPNMB by recruiting MEF2–HDAC complex, enabled through a long-range intrachromatin looping. Suppression of this anti-inflammatory gene might mediate increased susceptibility in Takayasu arteritis and enhance protective immune responses in chronic infection and cancer. Conclusions Takayasu arteritis risk locus in IL6 might increase disease susceptibility by suppression of the anti-inflammatory gene GPNMB through chromatin looping and recruitment of MEF2–HDAC epigenetic repressive complex. Our data highlight long-range chromatin interactions in functional genomic and epigenomic studies in autoimmunity.
Afatinib monotherapy in patients with metastatic squamous cell carcinoma of the lung progressing after erlotinib/gefitinib (E/G) and chemotherapy: Interim subset analysis from a phase III trial.
Authors: Joo-Hang Kim, Francesco Grossi, Filippo De Marinis, Manuel Cobo, James Chih-Hsin Yang, Yury Ragulin, Igor N. Bondarenko, Vikram K. Chand, Bushi Wang, Edith Gracien, Martin H. Schuler
Journal: Journal of Clinical Oncology (2012)

7558 Background: Patients with squamous NSCLC have limited treatment options. For those deriving benefit from EGFR TKIs, it is unclear whether sustained ErbB family blockade offers benefit upon progression. We evaluated afatinib, an irreversible blocker of EGFR (ErbB1), HER2 (ErbB2) and ErbB4 receptor tyrosine kinases, in patients with metastatic NSCLC who had failed chemotherapy and E/G. Here we describe a pre-specified analysis of those with squamous histology in Part A. Methods: This randomized Phase III, open-label, multi-center trial enrolled patients with pathologically confirmed metastatic NSCLC after failing ≥1 line of cytotoxic chemotherapy and E/G. In Part A, patients received oral afatinib 50 mg until disease progression. Those with clinical benefit (≥12 wks) who progressed were eligible to receive afatinib plus paclitaxel or investigator’s choice chemotherapy (Part B). Primary endpoint was PFS (RECIST 1.1). Following an amendment, an interim analysis of Part A was performed to assess afatinib monotherapy. Results: Patient enrolment into Part A was from April 2010 to May 2011. Of 1154 afatinib-treated patients, 91 (8%) had squamous histology; 18/91 and 40/91 had CR/PR and SD on prior E/G, respectively (by investigator). Median age was 63 yrs, 71% were male, 76% were current/ex-smokers. Median PFS on afatinib was 3.7 mths in the squamous histology subset. Of 91 patients, 42 had PFS ≥3 mths; 13 had PFS of ≥6 mths. In evaluable patients (n=77), 1 CR and 3 PRs were confirmed; 51 and 22 patients had best overall response of SD and PD, respectively. Of the 31 patients with PD on prior E/G with no intervening chemotherapy, 10 achieved confirmed disease control (2 PR; 8 SD) on afatinib. Most commonly reported grade 3/4 adverse events (AEs) in Part A were diarrhea (13%) and rash/acne (12%). The safety profile in the squamous histology subset was similar to that observed for the whole trial. Conclusions: Afatinib monotherapy demonstrated encouraging activity in treatment-refractory NSCLC patients with squamous histology that merits further evaluation.
Development and Validation of an Rnaseq NGS Assay to Comprehensively Detect Clinically Relevant ALL Gene Fusions
Authors: Parth Sitlani, Maya Panjikaran, Dana Weiner, Claire Orosco Orosco, Durga Cherukuri, Lauryn Keeler, Matthew Dedek, Yu Xia, Armin Graber, Christopher Scott, Jeffrey Falk
Journal: Blood (2017)
Glutamine independence is a selectable feature of pluripotent stem cells
Authors: Santosha A. Vardhana, Paige K. Arnold, Bess P. Rosen, Yanyang Chen, Bryce W. Carey, Danwei Huangfu, Carlos Carmona-Fontaine, Craig B. Thompson, Lydia W. S. Finley
Journal: Nature Metabolism (2019)