tbuckley/cabot-search huggingface dataset:
Ethical Framework for Including Research Biopsies in Oncology Clinical Trials: American Society of Clinical Oncology Research Statement
Authors: Laura A. Levit, Jeffrey M. Peppercorn, Alda L. Tam, Jonathan M. Marron, Debra J.H. Mathews, Kathryn Levit, Nancy Roach, Mark J. Ratain
Journal: Journal of Clinical Oncology (2019)

In contrast to clinical biopsies, where tissue is collected to inform patient care, research biopsies are performed for scientific purposes to potentially enhance understanding of the biologic bases of cancer and drug action, thereby improving diagnosis and treatment, but they may offer no direct benefit to participants and have known risks. The widespread use of research biopsies that do not have the potential to directly benefit participants has come under scrutiny, with critics raising ethical concerns related to the adequacy of participant protections, informed consent, and participant understanding of the risks and benefits, as well as the scientific impact of research biopsies on drug development and treatment. This manuscript presents the American Society of Clinical Oncology's (ASCO's) ethical framework for incorporation of research biopsies in trials. The framework provides guidance on the circumstances to include optional and mandatory biopsies, as well as provides recommendations to stakeholders on necessary steps for improving the conduct of research biopsies overall.
Hybrid micelles containing methotrexate-conjugated polymer and co-loaded with microRNA-124 for rheumatoid arthritis therapy
Authors: Fei Hao, Robert J Lee, Lihuang Zhong, Shiyan Dong, Chunmiao Yang, Lirong Teng, Qingfan Meng, Jiahui Lu, Jing Xie, Lesheng Teng
Journal: Theranostics (2019)

Purpose: Methotrexate (MTX) is a first-line drug for rheumatoid arthritis (RA)therapy.However, MTX monotherapy often results in irreversible joint damage due to its slow onset of action and long duration.microRNA-124 (miR-124) has shown direct bone protection activity against RA.A co-delivery system for MTX and microRNA combination may provide therapeutic synergy.Methods: Methotrexate-conjugated polymer hybrid micelles (M-PHMs) were prepared by self-assembly of two functional amphiphilic polymers (MTX-PEI-LA and mPEG-LA) at an optimized weight ratio.Incorporation of microRNA was achieved through electrostatic interactions between microRNA and cationic polymer MTX-PEI-LA.Cellular uptake, endosome escape, biodistribution, and therapeutic efficacy of M-PHMs/miR-124 complexes were investigated and evaluated in RAW264.7 cells and a rat adjuvant-induced arthritis (AIA) model.Results: M-PHMs/miR-124 complexes exhibited folate receptor-mediated uptake in activated RAW264.7 cells.miR-124 was able to escape from the endosome and down-regulate nuclear factor of activated T cells cytoplasmic1 (NFATc1).M-PHMs/miR-124 complexes accumulated in inflamed joints of AIA rats and showed superior therapeutic efficacy through both anti-inflammatory effect and direct bone protective effect.Combination of miR-124 and MTX in these micelles induced disease remission.Conclusions: M-PHMs/miR-124 was highly effective against RA through therapeutic synergy.Additional studies are warranted to further investigate its therapeutic potential and delineate its mechanisms of action.
Focused ultrasound-augmented targeting delivery of nanosonosensitizers from homogenous exosomes for enhanced sonodynamic cancer therapy
Authors: Yichen Liu, Lianmei Bai, Kaili Guo, Yali Jia, Kun Zhang, Quanhong Liu, Pan Wang, Xiaobing Wang
Journal: Theranostics (2019)

Sonodynamic therapy (SDT), wherein focused ultrasound is used to guide the site-specific delivery of nano-sonosensitizers and trigger profound sono-damage, has great potential in cancer theranostics. The development of nanosensitizers with high sono-activatable efficiency and good biosafety is however challenging. Methods: In this study, we designed a functionalized smart nanosonosensitizer (EXO-DVDMS) by loading sinoporphyrin sodium (DVDMS), an excellent porphyrin sensitizer with both potential therapeutic and imaging applications, onto homotypic tumor cell-derived exosomes. Because of the high binding-affinity between DVDMS and proteins, coincubation of DVDMS and exosome would result in DVDMS attached on the surface or loaded in the core of exosomes. The prepared EXO-DVDMS was applied for ultrasound-responsive controlled release and enhanced SDT. Results: Tumor cell-derived exosomes exhibited high stability and specificity towards the homotypic tumors, along with highly controlled ultrasound-responsive drug release, and boosted reactive oxygen species (ROS) generation to augment SDT. Intriguingly, EXO-DVDMS was endocytosed by lysosomes, and the low pH in the latter triggered DVDMS relocation synergistically with the ultrasound, thereby initiating multiple cell death-signaling pathways. Furthermore, the exosomal formulation served as a functionalized nanostructure, and facilitated simultaneous imaging and tumor metastasis inhibition, that were respectively 3-folds and 10-folds higher than that of free form. Conclusions: Taken together, our findings suggest that an extracorporeal ultrasound device can non-invasively enhance homogenous tumor targeting and SDT toxicity of EXO-DVDMS, and the developed endogenous nano-sonosensitizer is a promising nanoplatform for activated cancer theranostics.
GM-CSF and CXCR4 define a T helper cell signature in multiple sclerosis
Authors: Edoardo Galli, Felix J. Hartmann, Bettina Schreiner, Florian Ingelfinger, Eirini Arvaniti, Martin Diebold, Dunja Mrdjen, Franziska van der Meer, Carsten Krieg, Faiez Al Nimer, Nicholas Sanderson, Christine Stadelmann, Mohsen Khademi, Fredrik Piehl, Manfred Claassen, Tobias Derfuss, Tomas Olsson, Burkhard Becher
Journal: Nature Medicine (2019)
Breast cancer multifocality-multicentricity and survival outcomes.
Authors: Siobhan P. Lynch, Xiudong Lei, Mariana Chavez-Mac Gregor, Limin Hsu, Funda Meric-Bernstam, Thomas A. Buchholz, Hong Zhang, Gabriel N. Hortobagyi, Vicente Valero, Ana M. Gonzalez-Angulo
Journal: Journal of Clinical Oncology (2012)

1104 Background: Studies have consistently shown a correlation between multifocal (MF) and multicentric (MC) breast cancers and the rate and extent of lymph node metastases, but the literature is divided on whether there is a corresponding impact on survival outcomes. In the absence of compelling evidence to dictate otherwise, the convention according to current TNM staging guidelines has been to stage and treat MF and MC cancers according to the diameter of the largest lesions, without taking other foci of disease into consideration. We evaluated a large single institution cohort of MF and MC breast cancers to determine their frequency, clinico-pathological characteristics and effect on survival outcomes. Methods: MF and MC were defined pathologically as more than one lesion in the same quadrant and more than one lesion in separate quadrants, respectively. Patients were categorized by presence or absence of MF or MC disease. Kaplan-Meier product limit method was used to calculate relapse-free survival (RFS), breast cancer-specific survival (BCSS) and overall survival (OS). Cox proportional hazards models were fit to determine independent associations of MF/MC disease with survival outcomes. Results: Out of 3924 patients, 942 (24%) had MF (n=695) or MC (n=247) disease. MF and MC disease was associated with higher T-stages (T2 26% vs. 21.6%; T3 7.4% vs. 2.3%, P&lt;0.001), higher nuclear grade (grade 3 44% vs. 38.2%, P&lt;0.001), lymphovascular invasion (26.2% vs. 19.3%, P&lt;0.001) and lymph node metastases (43.1% vs. 27.3%, P&lt;0.001). After a median follow up of 51 months, MC but not MF breast cancers were associated with significantly worse 5-year RFS (90% vs. 95%, P=0.02) and BCSS (95% vs. 97%, P=0.01), and a trend towards worse 5-year OS (92% vs. 93%, P=0.08). After controlling for other risk factors, multifocality and multicentricity did not have an independent impact on RFS, BCSS or OS. This was true for the subset of T1N0 breast cancers as well. Conclusions: MF and MC breast cancers occurred in 24% of the cases and were associated with poor prognostic factors, but they were not independent predictors of worse survival outcomes. Our findings support the current TNM staging system of using the diameter of the largest lesion to assign T-stage.
Unilateral Focused Ultrasound-Induced Blood-Brain Barrier Opening Reduces Phosphorylated Tau from The rTg4510 Mouse Model
Authors: Maria Eleni Karakatsani, Tara Kugelman, Robin Ji, Maria Murillo, Shutao Wang, Yusuke Niimi, Scott A. Small, Karen E. Duff, Elisa E. Konofagou
Journal: Theranostics (2019)

The neuropathological hallmarks of Alzheimer's disease include amyloid plaques and neurofibrillary tangles. Tau pathology correlates well with impaired neuronal activity and dementia. Focused ultrasound coupled with systemic administration of microbubbles has previously been shown to open the blood-brain barrier and induce an immune response, which, in an amyloid AD mouse model, resulted in the reduction of the amyloid brain load. Methods: In this study, we investigated the effect of focused ultrasound at the early stages of tau pathology (pre-tangle) in the rTg4510 mouse model. Results: Reduction of phosphorylated tau from the hippocampal formation processes, and particularly the pyramidal CA1 neurons, was noted in the ultrasound-treated brains without an associated increase in the phosphorylated tau-affected cell somas, typically associated with disease progression. Attenuation of the pathology was found to correlate well with the ultrasound-initiated immune response without compromising neuronal integrity. Unilateral ultrasound application resulted in a bilateral effect indicating a broader reduction of the phosphorylated tau. Conclusion: Findings presented herein reinforce the premise of ultrasound in reducing tau pathology and thus curbing the progression of Alzheimer's disease.
OP0005 Leflunomide reduces transendothelial migration
Authors: J Grisar, GH Stummvoll, D Eselböck, P Pietschmann, JS Smolen
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> The disease modifying drug leflunomide is widely used in the therapy of rheumatoid arthritis (RA). Its active metabolite, A771726, leads to inhibition of dihydroorotate dehydrogenase, an enzyme necessary for pyrimidine de-novo synthesis. Since activated lymphocytes expand their pyrimidine pool, A771726 decreases their proliferation. A771726 also suppresses TNF mediated nuclear factor kappaB activation. We were therefore interested if A771726 also would be capable to influence transendothelial migration (TEM) of peripheral mononuclear cells (PBMC). <h3>Objectives</h3> <h3>Methods</h3> We investigated the TEM of PBMC, which migrated through endothelial cell monolayers in an in-vitro model. Human umbilical vein endothelial cells (EC) were cultured to confluence on collagen gels and then incubated with human PBMC of healthy blood donors. PBMC were recollected in three groups: 1) cells that did not adhere to the endothelium, 2) cells that bound to the endothelium, 3) cells that had migrated through the endothelium, and then counted by microscope. Experiments in which EC and PBMC as well as only EC were treated with A771726 (in the absence or presence of uridine) were compared to simultaneously performed control experiments. No increased toxicity on the PBMC treated with the doses of A771726 used in our experiments, was observed. Paired T Test was used for statistical evaluations. <h3>Results</h3> 24 h incubation of PBMC and EC with A771726 induced a significant decrease in TEM (8 ± 6% vs. 16 ± 12% migrated cells, p = 0.004). Furthermore, 24 h preincubation of solely the EC with A771726 inhibited the TEM of untreated PBMC (11 ± 9% vs. 15 ± 8% migrated cells, p = 0.043), indicating direct effects of A771726 on EC. Uridine significantly reversed the decrease in TEM when incubating PBMC and EC with both uridine and A771726 (15 ± 10% vs 9 ± 7% migrated cells, p = 0.023). <h3>Conclusion</h3> Our results demonstrate that leflunomide may have direct anti-inflammatory effects by inhibiting the extravasation of PBMC, possibly via downregulation of adhesion molecules on EC and mononuclear cells. These data suggest, that leflunomide, besides its influences on lymphocyte proliferation, also reduces recruitement of mononuclear cells to inflammatory sites.
Abstract 16509: Increased Arterial Inflammation by FDG-PET-CT is Associated with an Increased Risk of Cardiovascular Events among Obese Low-Intermediate Risk Individuals
Authors: Amparo L Figueroa, Amr Abdelbaky, Megan H MacNabb, Zachary R Lavender, Meredith A Lawler, Shanmugam Uthamalingam, Quynh A Truong, Thomas J Brady, Udo Hoffmann, Ahmed Tawakol
Journal: Circulation (2012)

Background: Obesity is associated with increased cardiovascular event (CVD) risk. We previously demonstrated that obesity is associated with increased vascular inflammation (measured with FDG-PET-C...
New PM promises faster GP appointments and hospital upgrades
Authors: Adrian O’Dowd
Journal: BMJ (2019)

Patients should get quicker access to GP appointments, and hospitals will receive “upgrades,” as part of plans laid out by the new prime minister, Boris Johnson, who took over the post on 24 July.

Leader of doctors’ and NHS organisation have welcomed his promises but said that these must be tempered with an acknowledgment of workforce shortages and pressure on the health service.

Johnson, making his first speech as prime minister outside Number 10 Downing Street, gave broad brush indications of his priorities for the country, alongside his focus on ensuring that the UK leaves the European Union in October, as currently scheduled.

In his speech Johnson said, “My job is to make sure you don’t have to wait …
Corrections to: Checkpoint inhibitor therapy for cancer in solid organ transplantation recipients: an institutional experience and a systematic review of the literature
Authors: Noha Abdel-Wahab, Houssein Safa, Ala Abudayyeh, Daniel H. Johnson, Van Anh Trinh, Chrystia M. Zobniw, Heather Lin, Michael K. Wong, Maen Abdelrahim, A. Osama Gaber, Maria E. Suarez-Almazor, Adi Diab
Journal: Journal for ImmunoTherapy of Cancer (2019)

Following publication of the original article [1], the authors reported an error in the Acknowledgments section. It should be read: 'We are grateful to Mohsin Shah from the Department of Emergency Medicine at The University of Texas MD Anderson Cancer Center for assisting in study selection, and to Gregory F. Pratt from the Research Medical Library and Erica Goodoff, from the Department of Scientific Publications at The University of Texas MD Anderson Cancer Center for their valuable contributions.
Evaluation of Treg and Memory T Cell Profiles, Post-ASCT with Early Combination Nivolumab/Ipilimumab Therapy, in Patients with Multiple Myeloma (MM) and Diffuse Large B Cell Lymphoma (DLBCL)
Authors: Dante B. Descalzi-Montoya, Zheng Yang, Kira Goldgirsh, Rena Feinman, Stacey L. Fanning, David H. Vesole, Pashna N. Munshi, Michael B Atkins, Scott D. Rowley, Noa Biran, David S Siegel, Andre Goy, Tatyana A. Feldman, Lori A. Leslie, Michele L. Donato, Alan P Skarbnik, Andrew L. Pecora, Robert Korngold
Journal: Blood (2018)
Nearly half of cancer patients don’t feel involved in treatment decisions, survey finds
Authors: Elisabeth Mahase
Journal: BMJ (2019)

Almost half (47%) of patients with cancer do not think that they have been sufficiently involved in deciding which treatment option is best for them, a new survey shows.1

The survey of nearly 4000 patients across 10 countries also found that around four in 10 (39%) said that they were never or only sometimes given enough support to deal with symptoms and side effects.

The survey report was published by the international All.Can initiative, which works to improve …
Investigating chronic urinary retention
Authors: Jenny Martin, Will Chandler, Mark Speakman
Journal: BMJ (2019)

### What you need to know

A 68 year old man complains of worsening fatigue, nausea, and loss of appetite. He reports minimal urinary symptoms but has described episodes of night time bed-wetting in recent months. On examination, he looks generally unwell. He has no abdominal pain. His lower abdomen is dull to percussion up to the level of the umbilicus. He is still voiding urine. Urgent blood investigations are arranged by the general practitioner, which reveal an acute kidney injury. 

Chronic urinary retention is a common presentation in men in primary care. Women are less commonly affected.1 The condition is frequently not recognised, as symptoms often progress slowly and are not serious. Patients with acute urinary retention are not voiding urine and are in pain.2 In contrast, patients with chronic retention void without pain. Chronic urinary retention has two subtypes: low pressure chronic retention (LPCR) and the more serious, but less common, high pressure chronic retention (HPCR).3 The terms “high” and “low” refer to the bladder pressure at the end of voiding, but pragmatically, HPCR refers to patients with abnormal renal function and/or hydronephrosis, and people with LPCR have normal kidney function and normal kidneys. Acute-on-chronic retention occurs when a patient with chronic retention stops voiding completely.

In this article, we present an approach for non-specialists to investigate chronic urinary retention in men and identify high pressure chronic retention, which warrants immediate specialist referral.

Patients …
Effect of heparin and its derivatives on the progression of tumor growth in mouse Lewis lung carcinoma model.
Authors: Angel Gray, Debra Hoppensteadt, Matthew Hejna, Jawed Fareed
Journal: Journal of Clinical Oncology (2012)

e13115 Background: Preclinical evidence suggests that heparins have an effect on tumor progression independent of their anticoagulant activity. Heparins have also been shown to exhibit interactions with growth factors and other cellular receptors. This study was designed to investigate whether heparin and its derivatives are able to inhibit tumor growth. Methods: Female C57BL/6 mice were obtained at 6-8 weeks of age and were implanted with 5X10 5 LN7 tumor cells by dorsal subcutaneous injection of in the upper back. When tumors were first palpable, after 7-10 days of growth, mice were treated with subcutaneous injections of heparin, a low molecular weight heparin (LMWH), namely enoxaparin, an ultra LMWH, semuloparin or saline, daily for two weeks in a dose range of 1.0 – 0.25 mg/kg. After the treatment period, animals were sacrificed and the spleens and tumors were removed and their weight, volume, spleen weight and size were measured. Results: At the 1.0 and 0.5 mg/kg dosages, both enoxaparin (p&lt;0.01) and semuloparin (p&lt;0.01) showed a decrease in tumor volume compared to the saline control animals. At the 1.0 mg/kg dosage, the mortality was high in the heparin group due to bleeding. At 0.5 mg/kg heparin was not different from the saline control. In addition, at a dosage of 0.25 mg/kg, only semuloparin showed a difference compared to the saline control (p&lt;0.01). Similar results were observed for the tumor weight. There were no significant differences noted in spleen weight or spleen size among these agents. The mortality rates between the mice treated with enoxaparin and semuloparin were comparable. Conclusions: These studies suggest that heparin and its derivatives are capable of inhibiting tumor growth in a dose dependent manner. Enoxaparin and semuloparin are more effective at reducing tumor growth compared to heparin. Clinical studies have shown that semuloparin is safe and effective for the prevention of venous thromboembolism in cancer patients and compares favorably to enoxaparin in terms of antithrombotic effect and safety profile. Therefore, semuloparin may be a better alternate for the prevention of cancer associated thrombosis.
Bi-specific tenascin-C and fibronectin targeted peptide for solid tumor delivery
Authors: Prakash Lingasamy, Allan Tobi, Maarja Haugas, Hedi Hunt, Päärn Paiste, Toomas Asser, Tõnu Rätsep, Venkata Ramana Kotamraju, Rolf Bjerkvig, Tambet Teesalu
Journal: Biomaterials (2019)

Oncofetal fibronectin (FN-EDB) and tenascin-C C domain (TNC-C) are nearly absent in extracellular matrix of normal adult tissues but upregulated in malignant tissues. Both FN-EDB and TNC-C are developed as targets of antibody-based therapies. Here we used peptide phage biopanning to identify a novel targeting peptide (PL1, sequence: PPRRGLIKLKTS) that interacts with both FN-EDB and TNC-C. Systemic PL1-functionalized model nanoscale payloads [iron oxide nanoworms (NWs) and metallic silver nanoparticles] homed to glioblastoma (GBM) and prostate carcinoma xenografts, and to non-malignant angiogenic neovessels induced by VEGF-overexpression. Antibody blockage experiments demonstrated that PL1 tumor homing involved interactions with both receptor proteins. Treatment of GBM mice with PL1-targeted model therapeutic nanocarrier (NWs loaded with a proapoptotic peptide) resulted in reduced tumor growth and increased survival, whereas treatment with untargeted particles had no effect. PL1 peptide may have applications as an affinity ligand for delivery of diagnostic and therapeutic compounds to microenvironment of solid tumors.
Atrial Fibrillation (AF) and Ibrutinib, a Monocentric Experience: Should Cardiological Evaluation be a Guide in Clinical Practice?
Authors: Gianluigi Reda, Ramona Cassin, Veronica Mattiello, Tatiana Tonella, Diana Giannarelli, Bruno Fattizzo, Francesco Onida, Ferdinando Maria Massari, Agostino Cortelezzi
Journal: Blood (2017)
Dolutegravir Use at Conception — Additional Surveillance Data from Botswana
Authors: Mmakgomo M Raesima, Chibuike M Ogbuabo, Vasavi Thomas, Sara E Forhan, Gadzikanani Gokatweng, Eldah Dintwa, Chipo Petlo, Catherine Motswere-Chirwa, Elizabeth M Rabold, Sarah C Tinker, Shifawu Odunsi, Sifelani Malima, Omphemetse Mmunyane, Thusoetsile Modise, Kelame Kefitlhile, Kunle Dare, Mpho Letebele, Michelle E Roland, Cynthia A Moore, Surbhi Modi, Dhelia M Williamson
Journal: New England Journal of Medicine (2019)

To the Editor: In May 2018, an unscheduled analysis from the Botswana-Harvard AIDS Institute Partnership Tsepamo birth-outcomes surveillance study showed a higher prevalence of neuraltube defects among infants born to women who were using dolutegravir-based antiretroviral treatment (ART) regimens at the time of conception relative to infants born to women taking other types of ART. 1 In response to this safety signal, the Botswana Ministry of Health and Wellness expanded surveillance for neural-tube defects in selected non-Tsepamo health facilities.The Ministry of Health and Wellness surveillance system followed a protocol that had been approved by the institutional review boards of the Botswana Health Research Development Committee, the Centers for Disease Control and Prevention, and the University of Maryland, Baltimore, and included all pregnancies in which live-born or stillborn infants were delivered at more than 24 weeks of gestation at 22 non-Tsepamo facilities from October 2018 through March 2019.The end date of March 31, 2019, was chosen in light of the anticipated change in practice associated with the 2018 data release from the Tsepamo study, which was expected to result in a decrease in the number of pregnancies with periconceptional exposure to dolutegravir.Midwives conducted systematic surface examinations of all live-born and stillborn infants.Information regarding maternal human immunodeficiency virus (HIV) infection status, ART exposure at conception, and infant examination findings was collected.Data on the use of folate supplements and other medications, including antiepileptic medications, were abstracted only in cases in which a neural-tube defect was found.Data on folate use before pregnancy were not