tbuckley/cabot-search huggingface dataset:
Group cognitive behavioural courses may reduce fatigue from rheumatoid arthritis
Authors: Rob Cook, Peter Davidson, Rosie Martin
Journal: BMJ (2020)

The study Hewlett S, Almeida C, Ambler N, et al. Reducing arthritis fatigue impact: two-year randomised controlled trial of cognitive behavioural approaches by rheumatology teams (RAFT). Ann Rheum Dis 2019;78:465-72. Hewlett S, Almeida C, Ambler N, et al. Group cognitive behavioural programme to reduce the impact of rheumatoid arthritis fatigue: the RAFT RCT with economic and qualitative evaluations. Health Technol Assess 2019;23:57. This project was funded by the NIHR Health Technology Assessment Programme (project number 11/112/01). To read the full NIHR Signal, go to: https://discover.dc.nihr.ac.uk/content/signal-000860/group-cognitive-behavioural-courses-may-reduce-fatigue-from-rheumatoid-arthritis
Targeted immunotherapy with intentionally mismatched rIL-2 activated donor lymphocytes in an attempt to eliminate minimal residual disease in patients with high-risk metastatic cancer
Authors: S. Slavin, R. Or, L. Dray, S. Samuel, A. Ackerstein, M. Y. Shapira, I. B. Resnick, M. Bitan, S. Morecki
Journal: Journal of Clinical Oncology (2007)

21175 Background: Graft-versus-leukemia and graft-versus-tumor (GVT) effects following stem cell transplantation are well established, however, procedure related toxicity and mortality are unavoidable. In addition to limited efficacy following stem cell transplantation (SCT), graft-versus-host disease (GVHD) is unavoidable. Our protocol was designed to induce more potent anti-cancer immunotherapy by rIL-2 activated intentionally mismatched donor lymphocytes (MDL) at the stage of minimal residual disease (MRD) outpatient procedure with no SCT avoiding GVHD. Methods: Optimizing MDL was accomplished by cyclophosphamide 1,500 mg/m2 and 2 injections of alpha interferon (3x106IU) for more effective immunotherapy, aiming for depletion of regulatory T cells, followed by infusion of haploidentically mismatched lymphocytes activated with rIL-2 (6,000 IU/ml) for 4 days. On the day of cell infusion, patients received rIL-2 6x106 IU subcutaneously outpatient for 5 days. Results: A total of 41 (age 5–73, median 52) high risk patients were included: metastatic breast 13; colorectal 3; gastric 3; pancreatic 3; melanoma 3; head &amp; neck 3; glioblastoma 2; and 6 with other solid tumors. Five patients had resistant hematological malignancies: multiple myeloma 2; non-Hodgkin's lymphoma 2 and Hodgkin's disease 1. 6 patients received lymphocytes with bispecific antibodies for targeted cell-therapy (3 with catumaxomab against CD3 &amp; epithelial cell adhesion molecule (EpCAM); 3 with ertumaxomab directed against CD3 &amp; Her-2/neu WHO toxicity &gt;grade 2 was noted. 14 of evaluable patients are alive. 10/32 with solid tumors are alive, 7 with no evidence of disease &gt; 9–91 (median 17) months (4 breast; 1 squamous cell; 1 head &amp; neck; 1 prostate). Of 5 patients with hematological malignancies 4 are alive and disease free &gt;18–96 (median 46) months. Conclusions: Safe induction of GVT effects may be accomplished by MDL, preferably targeted with bispecific antibodies after cyclophosphamide conditioning lymphocytes are more potent and act faster than matched lymphocytes and GVHD is avoided by rejection of donor lymphocytes. When applied at a stage of MRD, such treatment may result in operational cure. No significant financial relationships to disclose.
Persistence of Drug-Resistant Leukemic Stem Cells and Impaired NK Cell Immunity in CML Patients Depend on <i>MIR300</i> Antiproliferative and PP2A-Activating Functions
Authors: Giovannino Silvestri, Rossana Trotta, Lorenzo Stramucci, Justin J. Ellis, Jason G. Harb, Paolo Neviani, Shuzhen Wang, Ann-Kathrin Eisfeld, Christopher J. Walker, Bin Zhang, Klara Srutova, Carlo Gambacorti-Passerini, Gabriel Pineda, Catriona H. M. Jamieson, Fabio Stagno, Paolo Vigneri, Georgios Nteliopoulos, Philippa C. May, Alistair G. Reid, Ramiro Garzon, Denis-Claude Roy, Moutuaata M. Moutuou, Martin Guimond, Peter Hokland, Michael W. Deininger, Garrett Fitzgerald, Christopher Harman, Francesco Dazzi, Dragana Milojkovic, Jane F. Apperley, Guido Marcucci, Jianfei Qi, Katerina Machova Polakova, Ying Zou, Xiaoxuan Fan, Maria R. Baer, Bruno Calabretta, Danilo Perrotti
Journal: Blood Cancer Discovery (2020)

Abstract Persistence of drug-resistant quiescent leukemic stem cells (LSC) and impaired natural killer (NK) cell immune response account for relapse of chronic myelogenous leukemia (CML). Inactivation of protein phosphatase 2A (PP2A) is essential for CML-quiescent LSC survival and NK cell antitumor activity. Here we show that MIR300 has antiproliferative and PP2A-activating functions that are dose dependently differentially induced by CCND2/CDK6 and SET inhibition, respectively. MIR300 is upregulated in CML LSCs and NK cells by bone marrow microenvironment (BMM) signals to induce quiescence and impair immune response, respectively. Conversely, BCR-ABL1 downregulates MIR300 in CML progenitors to prevent growth arrest and PP2A-mediated apoptosis. Quiescent LSCs escape apoptosis by upregulating TUG1 long noncoding RNA that uncouples and limits MIR300 function to cytostasis. Genetic and pharmacologic MIR300 modulation and/or PP2A-activating drug treatment restore NK cell activity, inhibit BMM-induced growth arrest, and selectively trigger LSC apoptosis in vitro and in patient-derived xenografts; hence, the importance of MIR300 and PP2A activity for CML development and therapy. Significance: Tumor-naïve microenvironment–induced MIR300 is the only tumor suppressor miRNA that induces CML LSC quiescence while inhibiting NK cell antitumor immune response, and CML LSC/progenitor cell apoptosis through its anti-proliferative and PP2A-activating functions, respectively. Thus, the importance of MIR300 and PP2A-activating drugs for formation/survival and eradication of drug-resistant CML LSCs, respectively. See related commentary by Broxmeyer, p. 13. This article is highlighted in the In This Issue feature, p. 5
Expiratory Resistances Prevent Expiratory Diaphragm Contraction, Flow Limitation, and Lung Collapse
Authors: Mariangela Pellegrini, Magni Gudmundsson, Reka Bencze, Monica Segelsjö, Filip Freden, Christian Rylander, Göran Hedenstierna, Anders S. Larsson, Gaetano Perchiazzi
Journal: American Journal of Respiratory and Critical Care Medicine (2020)

Rationale: Tidal expiratory flow limitation (tidal-EFL) is not completely avoidable by applying positive end-expiratory pressure and may cause respiratory and hemodynamic complications in ventilated patients with lungs prone to collapse. During spontaneous breathing, expiratory diaphragmatic contraction counteracts tidal-EFL. We hypothesized that during both spontaneous breathing and controlled mechanical ventilation, external expiratory resistances reduce tidal-EFL.Objectives: To assess whether external expiratory resistances 1) affect expiratory diaphragmatic contraction during spontaneous breathing, 2) reduce expiratory flow and make lung compartments more homogeneous with more similar expiratory time constants, and 3) reduce tidal atelectasis, preventing hyperinflation.Methods: Three positive end-expiratory pressure levels and four external expiratory resistances were tested in 10 pigs after lung lavage. We analyzed expiratory diaphragmatic electric activity and respiratory mechanics. On the basis of computed tomography scans, four lung compartments-not inflated (atelectasis), poorly inflated, normally inflated, and hyperinflated-were defined.Measurements and Main Results: Consequently to additional external expiratory resistances, and mainly in lungs prone to collapse (at low positive end-expiratory pressure), 1) the expiratory transdiaphragmatic pressure decreased during spontaneous breathing by >10%, 2) expiratory flow was reduced and the expiratory time constants became more homogeneous, and 3) the amount of atelectasis at end-expiration decreased from 24% to 16% during spontaneous breathing and from 32% to 18% during controlled mechanical ventilation, without increasing hyperinflation.Conclusions: The expiratory modulation induced by external expiratory resistances preserves the positive effects of the expiratory brake while minimizing expiratory diaphragmatic contraction. External expiratory resistances optimize lung mechanics and limit tidal-EFL and tidal atelectasis, without increasing hyperinflation.
A randomized phase II trial of PEXG (cisplatin, epirubicin, capecitabine, gemcitabine) or PDXG (docetaxel) regimen in advanced pancreatic adenocarcinoma
Authors: M. Reni, S. Cereda, P. Passoni, A. Rognone, E. Mazza, R. Nicoletti, P. G. Arcidiacono, A. Zerbi, G. Balzano, V. Di Carlo
Journal: Journal of Clinical Oncology (2007)

4628 Background: Four-drug regimen significantly improved the outcome of patients with advanced pancreatic adenocarcinoma (PA) with respect to standard gemcitabine in a phase III trial (Reni Lancet Oncol 2005). The current study was an attempt to further improve progression-free survival (PFS) by replacing epirubicin with docetaxel. Methods: Patients with stage III or metastatic PA, age 18–75y, Karnofsky performance status (PS) &gt;50 were randomized to receive either D (arm A: 25 mg/m 2 day 1 and 14) or E (arm B: 30 mg/m 2 day 1 and 14) while P (30 mg/m 2 day 1 and 14), G (800 mg/m 2 day 1 and 14) and X (1250 mg/m 2 /day days 1 to 28) remained unmodified in the two arms. Cycles were repeated every 28 days. The primary endpoint of the study was PFS. The sample size was calculated on the probability of being PF at 6 months (PFS6) from treatment start. Assuming P0=25% and P1=45%, with a .05 and b.20, the study was to enroll 32 patients per arm. Results: Between July 2005 and January 2007, 64 patients were enrolled at a single institution, stratified by stage and randomized (32 per arm). Main patient characteristics were balanced (A/B): median age 61/58, PS &gt; 70 93/84%, metastatic disease 69/69%. Treatment is ongoing in 6/7 patients; 16/15 patients concluded at least 6 cycles of chemotherapy while 9/10 interrupted treatment due to progressive disease (PD) and 1/0 due to consent withdrawal. To date, 51 patients are assessable for response and PFS6: 16 of 26 (62%) arm A patients and 12 of 25 (48%) arm B achieved a partial response. PFS6 was 54%/44%. Final results of toxicity, activity, PFS6 and survival will be available at time of meeting. Conclusion: PEXG regimen yielded similar results when compared to historical series treated by PEFG regimen, suggesting that the use of capecitabine instead of 5- fluorouracil did not compromise the outcome. The inclusion of D instead of E seems to be promising. The present trial further confirms the relevant impact on outcome of advanced PA of four-drug regimens. No significant financial relationships to disclose.
A quality-adjusted time without symptoms or toxicity (Q-TWiST) analysis comparing lapatinib plus capecitabine compared to capecitabine for metastatic breast cancer (MBC)
Authors: B. Sherrill, A. Allshouse, M. Amonkar, S. Stein
Journal: Journal of Clinical Oncology (2007)

1026 Background: Data for this analysis is from a Phase III randomized study that was stopped early by the IDMC since a planned interim analysis demonstrated the primary endpoint had been achieved i.e. longer time to disease progression for patients taking lapatinib plus capecitabine (L+C) versus capecitabine (C) alone. The study included women with refractory advanced or ErbB2+ MBC who had received prior therapy which included anthracyclines, taxanes and trastumuzab. The Q-TWiST method was used to compare the trade-off between toxicities and delayed progression. Methods: The area under overall survival curves for each treatment group was partitioned into three health states: toxicity (TOX), time without toxicity or disease progression (TWiST), and the period until death or end of follow-up following disease progression (REL). TOX is time spent with grade ¾ adverse events (AEs) during progression-free survival (PFS) time. TWiST is the remaining time prior to progression in which no serious AEs were experienced. The utility-weighted sum of the mean health state durations was derived and treatment comparisons of Q-TWiST were made at varying combinations of the utility weights using a threshold utility analysis. Results: The ITT population included 399 subjects ages 26–83 [L+C group N=198, C group N=201]. Overall median survival was 67 weeks based on data through 3APR2006. There was not a significant difference between groups in mean duration of serious AEs prior to progression. (L+C 1.7 weeks, C 1.5 weeks). Using utility weights of 0.5 for both TOX and REL, i.e. counting 2 days of TOX or REL as 1 day of TWiST, resulted in a 7-week difference in quality-adjusted survival favoring L+C (p = 0.0013). The Q-TWiST difference was significant across an entire matrix of possible utility weights. Results were robust in sensitivity analyses including all AEs. An observed-utility analysis based on EQ-5D scores is in progress. Conclusions: The longer time to disease progression with L+C versus C was achieved without increased time with serious AEs, resulting in more quality-adjusted survival for patients. No significant financial relationships to disclose.
Abstract P549: The Impact Of Neighborhood Factors On Mortality Among Depressed Patients With Systolic Heart Failure.
Authors: Emily Guhl, Julia P Holber, Kwonho Jeong, Kaleab Z Abebe, Amy Anderson, Jared W Magnani, Bruce L Rollman
Journal: Circulation (2020)

Introduction: Neighborhood factors have been associated with risk factors for cardiovascular disease.. Among These neighborhood factors also impact physical functioning and access to resources. In individuals with heart failure (HF), who require a significant access to care and physical activity, these neighborhood factors may impact mortality. Data are limited evaluating the association of neighborhood and mortality in HF. Hypothesis: We hypothesized that better walk scores and less deprivation would be associated with a lower mortality in individuals with systolic HF. Methods: We screened hospitalized patients with systolic HF (EF≤45%) and NYHA class II-IV symptoms for depression at 8 Pittsburgh-area hospitals as part of the Hopeful Heart Study (R01 HL114016) and included patients who screened positive for depression and remained depressed when re-contacted by telephone 2 weeks after discharge. We classified neighborhoods using the validated Walk Score®and Area Deprivation Index for each patient’s address at study entry (both 0-100 scales), and assessed all-cause and cardiovascular mortality over a 12 month period post-enrollment. Mortality (top quartile vs. all others) was compared between ADI and Walk Score groups with adjustment for clinical covariates using Kaplan Meier survival analysis. Results: Final analysis included 629 depressed patients with systolic HF (43 % female, 75 % white, 86% HTN, 52% DM). There was no significant difference In mortality when comparing individuals in the top quartile of Walk Score (p = 0.381) or ADI (p = 0.379) to all others (Figure 1). Conclusions: Among depressed patients with systolic HF, there was no significant association between neighborhood factors including Walk Score or ADI and mortality. Further research is warranted to determine how neighborhood factors adversely impact individual with co-morbid depression and systolic HF. Further analyses are ongoing to determine if individual components of the Walk Score and ADI contribute to differences in mortality.
Covid-19: preparedness, decentralisation, and the hunt for patient zero
Authors: Fabrizio Carinci
Journal: BMJ (2020)

The outbreak of covid-19 in Italy officially started on 31 January 2020, after two Chinese visitors staying at a central hotel in Rome tested positive for the new coronavirus SARS-CoV-2.They had landed at Milan Malpensa airport on a flight from Wuhan on 23 January. 1 On 21 February, after a few days of increasing concern, a 38 year old man was admitted to the hospital in Codogno, Lombardy, and was confirmed as the first Italian citizen with covid-19 ("patient 1").After tracing his movements and contacts, the regional authorities found a cluster of other cases, but none of them was identified as the origin of the infection ("patient 0"). 2 In less than one week, the number of cases in Italy increased beyond expectations, putting the Italian health service under considerable strain.Cases were found in several bordering regions and autonomous provinces of northern Italy.
The activity of the synthetic progestin medroxyprogesterone acetate on the invasive phenotype of ovarian cancer cells
Authors: R. Gogoi, M. Kudla, O. Gill, K. Horwitz, D. Fishman
Journal: Journal of Clinical Oncology (2007)

16003 Background: Androgens play an integral role in the physiologic and pathologic processes of the ovary. Yet it has been difficult to study the role of the androgen recptors (AR) separately from the other steroid receptors such as the progesterone receptor (PR) in ovarian cancer. This has been made more complicated because most synthetic progestins such as Medroxyprogesterone acetate (MPA) bind both PR and AR. The objectives of our study were: 1. To create an ovarian cancer cell line constitutively expressing only AR. 2. To compare the role of AR activated by the synthetic progestin MPA vs. the pure androgen dihydrotestosterone (DHT) on the invasiveness of human breast and ovarian cancer cells. 3. To investigate the role of matrix metalloproteases (MMP's) associated with invasion. Methods: ER- and PR- human breast (T47D-Y) and ovarian (OvCa 429) cancer cells were engineered to stably express AR. Immunocytochemistry and western blot analyses confirmed that these breast and ovarian cancer cell lines (called Y-AR and OvCa-AR respectively) are PR-, but AR+. Boyden chamber invasion assays were performed using Y-AR and OvCa-AR cells treated with either vehicle, MPA or DHT. The MMP's associated with invasion were further investigated using zymographic assays. Results: AR activation by either MPA or DHT increased the invasive potential of both breast (p&lt;0.05) and ovarian cancer cells with MPA being significantly more effective than DHT at stimulating invasion. However, regardless of the ligand, activation of AR increases tumor cell invasion. To elucidate the MMP's associated with this activation in OvCa-AR cells, we used zymographic analysis. Interestingly, we found that MPA activation of AR decreases both the total level and activation of MMP-9 compared to DHT and vehicle control. Conclusions: Using our model system we are able to study the role of AR independent of PR on the biology of breast and ovarian cancer cells. Our studies suggest that the use of pharmacological doses of synthetic progestins may actually increase the invasive potential of ovarian cancer cells through AR. We hypothesize that blockade of downstream AR targets or the use of selective AR modulators (SARMS) may be of therapeutic value in the treatment of ovarian cancer. No significant financial relationships to disclose.
Tackling climate change: “plant good, meat bad” is overly simplistic
Authors: George Ramsay, William Ramsay, Robert Ramsay
Journal: BMJ (2020)

We agree that climate change is a reality and is related to human activity, but a meat-free conference, as suggested by Morgan, is unlikely to help.1 The impact of meat production on the climate is multifactorial. Destruction of the Amazon for grazing livestock systems is clearly detrimental to the environment. In Scotland, however, farmers have made substantial progress in reducing emissions, …
Socioeconomic and Health Characteristics of Families at Risk for Losing Supplemental Nutrition Assistance Program Benefits
Authors: Alon Peltz, Alison A. Galbraith, Stephen Rogers, Ryan Walsh, Arvin Garg
Journal: JAMA Internal Medicine (2020)

This cross-sectional study compares the health, nutritional, and financial vulnerabilities of families at risk for losing extended categorical eligibility for the Supplemental Nutrition Assistance Program (SNAP) with those of families meeting federal eligibility standards.
Polycomb group protein Bmi1 regulates proliferation and senescence of breast cancer cells and is transcriptionally repressed by TP53.
Authors: Xunyi Luo, Jacqueline Mason, Vincent Nadeem, Yury Bukhman, Nancy Ng, James Pan
Journal: Cancer Research (2008)

2798  The Polycomb group (PcG) gene Bmi1 was first identified as a collaborating oncogene in the induction of mouse pre-B-cell lymphoma, and was subsequently reported overexpressed in various human malignancies including breast cancer. Bmi1 regulates cellular proliferation and senescence, and self-renewal of specific normal and malignant stem cell types via its repressive effect on the Ink4a/Arf tumor suppressor locus. Here we show that Bmi1 is overexpressed in a number of human breast cancer cell lines and breast tumors. Moreover, published and in-house microarray data suggest that Bmi1 expression negatively correlates with that of Ink4a/p16, and positively correlates with that of PTEN in human breast tumors; these correlations are statistically significant and consistent across multiple datasets. To determine the biological importance of deregulated Bmi1 expression in breast carcinogenesis, we repressed expression of the protein using a RNA interference (RNAi) strategy. Knockdown of Bmi1 led to induction of cell death and senescence in a number of breast cancer cell lines as determined by annexin V/propidium iodide (PI) and senescence-associated beta-galactosidase (SA-β-gal) staining, respectively. Consistent with this, overexpression of Bmi1 led to increased cell proliferation of MCF-7 breast cancer cells. Additionally, depletion of Bmi1 inhibited anchorage-independent growth of T-47D breast cancer cells, indicating a decrease in transformed phenotype of these cells. Interestingly, we observed that Bmi1 expression positively correlates with TP53 mutation status in a number of breast cancer cell lines, and was significantly higher in the colon cancer cell line, HCT116 compared to its isogenic TP53-/- subcell line. Knockdown of TP53 in HCT116 cells resulted in a decrease in Bmi1 expression, suggesting that TP53 might regulate Bmi1 levels. To further examine this possibility, we utilized tetracycline-repressible DLD-1 colon cancer cell lines carrying either wild-type TP53 or a tumor-derived mutant form of TP53 (R175H), which is incapable of activating gene transcription. Quantitative real-time PCR and Western blot analysis demonstrated that overexpression of wild-type, but not mutant, TP53 results in repression of Bmi1. These data suggest that Bmi1 and TP53 might act in an antagonistic manner. Future studies will be aimed at determining whether an imbalance between these proliferation-regulating signals contributes to oncogenesis.