tbuckley/cabot-search huggingface dataset:
Regression of multifocoal in transit melanoma metastases after palliative resection of dominant masses and 2 years after treatment with ipilimumab
Authors: Raphael B. Moreira, Lana Hamieh, Evisa Gjini, Ana Lako, Katherine M. Krajewski, Charles H. Yoon, Patrick A. Ott
Journal: Journal for ImmunoTherapy of Cancer (2017)

Spontaneous regression of metastatic melanoma and delayed responses more than one year after treatment with ipilimumab are rarely seen.Here, we present the case of a patient with in transit metastases from cutaneous melanoma on his right lower extremity who achieved complete regression of all metastatic lesions 13 months after the first of two consecutive palliative resections of dominant masses and more than two years after treatment with ipilimumab.The exact cause of our patient's sudden onset of tumor regression remains speculative. We hypothesize that the operative trauma followed by the postoperative infections augmented an innate immune response.
THU0724-HPR Self-management exercise program associated to spa therapy increased the physical activity level of people with symptomatic knee osteoarthritis: a quasi-randomized controlled trial
Authors: C Gay, C Auclair, N Boisseau, L Gerbaud, E Coudeyre
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Treating knee osteoarthritis (OA) in the medical phase is today well standardized. Guideline orientated approaches aiming at increasing physical activity (PA), improving pain and disability. <h3>Objectives</h3> To assess effectiveness of self-management exercise program associated to spa therapy at 3 month on the improvement of physical activity (PA) level, disability, pain, anxiety, fears and believes in symptomatic knee osteoarthritis people. <h3>Methods</h3> Prospective, multicentric, quasi-randomized controlled trial with alternate month design method (one month periods). People with symptomatic knee OA people (stage I-IV, Kelgren and Lawrence scale) with low and moderate PA level were included in 3 spa therapy resorts. Intervention group (IG) received 5 self-management exercise sessions (1h30; education, aerobic, strength training, range of motion) + information booklet + 18 sessions (1h) of conventional spa therapy (STC). Control group (CG) received information booklet + 18 sessions of STC. The primary outcome was changes at 3 months in PA level (IPAQ short form score) and secondary outcomes were WOMAC function, pain (VAS), HAD anxiety/depression, KOFBeQ fears and believes changes. <h3>Results</h3> 131 subjects were included. The mean age was 65.6 years [± 6.7]. WOMAC function score was 22.1/68 [±11.3] and pain was 4.6/10 [± 1.9] at inclusion. Both groups significantly increased PA level measured with continuous IPAQ total score (MET-minutes/weeks), with superiority for IG (+77.8%; p=0.0062) than CG (+50.7%; p=0.0099). There was no change in setting time. Disability (-11.3%; p=0.0370) and pain (-15.2%; p=0.0032) also decreased significantly for both groups. Anxiety (-11.6%; p=0.0195) and fears and believes (-18.2%; p=0.0146) decreased significantly only in intervention group. Other data will be presented later. <h3>Conclusions</h3> This study confirms the impact of STC on disability and pain and gives news data9s on physical activity level. Self-management exercise program improve anxiety, fears and believes. Complex educational strategies comprising information booklet with or without self-management exercise program can be proposed and adapted to OA phenotypes. <h3>References</h3> Fernandes, Linda, Kåre B. Hagen, Johannes W. J. Bijlsma, Oyvor Andreassen, Pia Christensen, Philip G. Conaghan, Michael Doherty, et al. EULAR Recommendations for the Non-Pharmacological Core Management of Hip and Knee Osteoarthritis. Annals of the Rheumatic Diseases 72, no. 7 (July 2013): 1125–35. Gay, C., A. Chabaud, E. Guilley, and E. Coudeyre. Educating Patients about the Benefits of Physical Activity and Exercise for Their Hip and Knee Osteoarthritis. Systematic Literature Review. Annals of Physical and Rehabilitation Medicine 59, no. 3 (June 2016): 174–83. <h3>Disclosure of Interest</h3> None declared
Brief Report: Defective Early B Cell Tolerance Checkpoints in Sjögren's Syndrome Patients
Authors: Salomé Glauzy, Joel Sng, Jason M. Bannock, Jacques‐Eric Gottenberg, Anne‐Sophie Korganow, Patrice Cacoub, David Saadoun, Eric Meffre
Journal: Arthritis & Rheumatology (2017)

Objective Central and peripheral B cell tolerance checkpoints are defective in many patients with autoimmune diseases, but the functionality of each discrete checkpoint has not been assessed in patients with Sjögren's syndrome ( SS ). We undertook this study to assess this functionality in SS patients. Methods Using a polymerase chain reaction–based approach that allows us to clone and express, in vitro, recombinant antibodies produced by single B cells, we tested the reactivity of recombinant antibodies cloned from single CD 19+ CD 21 low CD 10+IgM high CD 27– newly emigrant/transitional B cells and CD 19+ CD 21+ CD 10–IgM+ CD 27– mature naive B cells from 5 SS patients. Results We found that the frequencies of newly emigrant/transitional B cells expressing polyreactive antibodies were significantly increased in SS patients compared to those in healthy donors, revealing defective central B cell tolerance in SS patients. Frequencies of mature naive B cells expressing autoreactive antibodies were also significantly increased in SS patients, thereby illustrating an impaired peripheral B cell tolerance checkpoint in these patients. Conclusion Defective counterselection of developing autoreactive B cells observed in SS patients is a feature common to many other autoimmune diseases and may favor the development of autoimmunity by allowing autoreactive B cells to present self antigens to T cells.
Abstract 107: The Innate Immune NALP3 Receptor Mediates Cardiac Ischemic Preconditioning in the Isolated Heart
Authors: Coert J Zuurbier, Willeke Jong, Otto Eerbeek, Anneke Koeman, Wilco P Pulskens, Jaklien C Leemans, Markus W Hollmann
Journal: Circulation Research (2012)

Objective: Recent studies indicate that the innate immune system is not only activated by exogenous pathogens and pollutants, but also by endogenous danger signals released during ischemia and necrosis. As activation triggers (cellular K+ extrusion, ROS production) for the innate immune NALP3 inflammasome protein complex overlap with those for cardiac ischemia-reperfusion (I/R) and ischemic preconditioning (IPC), we explored the possibility that the NALP3 inflammasome is involved in IPC and acute I/R injury of the heart. Methods &amp; Results: Baseline performance and I/R injury was investigated in isolated, Langendorff-perfused hearts from wild-type, ASC-/- and NALP3-/- mice. Baseline cardiac performance was unaffected by genetic deletion of NALP3 inflammasome components. Deletion of the ASC and NALP3 component exacerbated IR injury on mechanical parameters of the heart. However, deficiency in ASC or NALP3 was without effect on cell death (LDH release during reperfusion). In a separate series we subjected these same hearts to IPC, consisting of 3 x 5 min I/R preceding the 35 min I. IPC protected WT and ASC-/- hearts against IR injury (improved function and less cell death). However, no IPC effects on function or cell death were observed in NALP3-/- hearts. NALP3-/- hearts had significantly decreased cardiac IL-6 levels with a trend towards lower Il-1β levels at end reperfusion, suggesting abrogating of IPC through diminished IL-6 and/or Il-1β signalling. However, subsequent experiments showed that inhibition of the IL-1r receptor with the IL-1 receptor inhibitor Anakinra (100 mg/L) was without effect on IPC in WT hearts. In contrast, neutralising IL-6 using an antibody against IL-6 in WT hearts abrogated IPC in NALP3-/- hearts. Conclusions: The data suggest that the innate immune NALP3 protein, in an NALP3-inflammasome-independent fashion, is an integral component of IPC in the isolated heart, possibly through an IL-6 dependent mechanism
Single domain antibody (SBT-100) crosses the blood brain barrier (BBB) and inhibits human glioblastoma by selectively targeting KRAS and P-STAT3.
Authors: Sunanda Singh, Genoveva Murillo, Avani Singh, Samara Singh, Meenakshi S Parihar, Anjali H Singh, Rajendra Mehta, Ashutosh S Parihar
Journal: Journal of Clinical Oncology (2017)

e13547 Background: Glioblastoma is difficult to treat malignancy that has a high incidence of KRAS mutations ( &gt; 90%) and hyper-expression of P-STAT3 ( &gt; 90%). Most chemotherapeutic agents and large biologics (four chain heterotetrameric IgG) cannot cross the BBB. Therefore Singh Biotechnology’s (SBT) propriety technology has developed a novel targeted therapy and engineered SBT-100 a 15 kD single domain antibody (sdAb) that is bispecific for KRAS and STAT3, which can cross the BBB to target gliablastomas. Methods: Human glioblastoma (U87MG) cell line was used and obtained from ATCC. Biacore affinity assay was used to demonstrate SBT-100 binding to KRAS, KRAS (G12D), and STAT3. The glioblastoma cells were incubated with 0µg/ml to 200µg/ml of SBT-100. MTT assay was performed after 3 days of treatment with SBT-100 and the growth inhibition was calculated. Xenograft (athymic nude mouse) with a well established tumor growing for 6 weeks was injected with SBT-100 intraperitoneally (IP). After 15 minutes the brain of this animal was harvested for immunohistochemical staining. Results: Biacore studies showed SBT-100 binds KRAS with affinity constant of 10 -9 M, KRAS (G12D) at 10 -8 M, and STAT3 at 10 -8 M. MTT assay reveals 62% (p &lt; 0.01) growth inhibition of U87MG within 3 days. A xenograft mouse with a well established tumor ( &gt; 150mm3), when injected IP with 5mg/kg of SBT-100 showed localization in the brain within 15 minutes. Therefore SBT-100 (sdAb) crosses the BBB, and shows intracellular localization in the animal’s neurons and glial cells. Conclusions: SBT-100 significantly inhibits the growth of glioblastoma. KRAS mutations and/or over expression of P-STAT3 in glioblastomas are promising targets for sdAbs like SBT-100, which is bispecific for KRAS and STAT3. SBT-100 crosses the BBB and localizes within the neurons and glial cells of the brain. SBT’s proprietary single domain antibody technology platform used to engineer SBT-100 holds promise for targeting primary brain malignancies, metastatic cancers that go to the brain, and for neurologic disease amenable to targeted therapy. Many chemo-resistant and radiation-resistant cancers use STAT3 as an escape mechanism.
Antitumor activity of lurbinectedin (PM01183) and doxorubicin in relapsed small-cell lung cancer: results from a phase I study
Authors: E. Calvo, V. Moreno, M. Flynn, E. Holgado, M.E. Olmedo, M.P. Lopez Criado, C. Kahatt, J.A. Lopez-Vilariño, M. Siguero, C. Fernandez-Teruel, M. Cullell-Young, A. Soto Matos-Pita, M. Forster
Journal: Annals of Oncology (2017)

Lurbinectedin (PM01183) has synergistic antitumor activity when combined with doxorubicin in mice with xenografted tumors. This phase I trial determined the recommended dose (RD) of doxorubicin (bolus) and PM01183 (1-h intravenous infusion) on day 1 every 3 weeks (q3wk), and obtained preliminary evidence of antitumor activity for this combination in small-cell lung cancer (SCLC).
Wnt5a Induces ROR1 to Complex with HS1, Which Undergoes Tyrosine Phosphorylation and Contributes to Planar-Cell-Polarity Migration in Chronic Lymphocytic Leukemia
Authors: Md Kamrul Hasan, Jian Yu, Liguang Chen, Bing Cui, Zhouxin Shen, George F. Widhopf, Laura Z. Rassenti, Steven P. Briggs, Thomas J. Kipps
Journal: Blood (2016)
Acute Myeloid Leukemia (AML) Blasts Influence the Gene Expression Signature and Co-Signaling Receptor Expression of CD8+ T Cells
Authors: Hanna A. Knaus, Sofia Berglund, Hubert Hackl, Raúl Montiel-Esparza, Mark J. Levis, Judith E Karp, Ivana Gojo, Leo Luznik
Journal: Blood (2016)
Oxaliplatin toxicity: preliminary evaluation in inbred mouse
Authors: Shi-Rong Cai, Wanghai Zhang, Howard L McLeod
Journal: Cancer Research (2006)

1315  Oxaliplatin is an antineoplastic platinum and has become an integral part of various chemotherapy protocols. However, acute neutropenia and a cumulative, sensory neurotoxicity affect its clinical use. There are no current evidence-based recommendations for oxaliplatin-induced toxicity. If the toxicity could be predicted, various strategies could be proposed to prevent or reduce oxaliplatin’s toxicity. The laboratory inbred mouse provides an ideal model system for the study of oxaliplatin toxicity. In this study, oxaliplatin was administered to 26 DBA/2J female mice at 10mg/kg by I.P followed by analysis of neutropenia, and neurotoxicity. Individual animals (control, n=2; treated, n=5) were bled on day 0, 3, 7, 10, 14 from lateral saphenous vein. Creatinine/Bilirubin levels were also determined to assess liver and renal toxicity. Neutrophil toxicity (control, n=2; treated, n=5) was determined on days 0, 1, 3, 4, 5, 6, 7, 8, 11, and 14 after treatment. For neurotoxicity study, oxaliplatin, and vehicle were administered on day 1, 14 (two doses) or on day 1, 14, and 28 (three doses), sciatic nerve was obtained on day 28, 42 or 56. Sciatic nerve studies were performed using toluidine blue staining. The results showed that oxaliplatin-induced neutropenia nadir was 35% of baseline (Grade=3) on day 6 after treatment, then returned to baseline on day 11 after treatment. Creatinine and bilirubin levels did not increase during the study. Toluidine blue staining that showed sciatic nerve pathological change varied intensity of axonal atrophy and axonal loss in fascicles (all grade 1 or 2 neurotoxicity) in mice received three doses group but not two dose group. Neurotoxicity was observed in 40% or 60% of mice on day 42 or 56 in the three dose treatment group, respectively. No neurotoxicity was found on day 28, 42 in the two dose group. Our data demonstrated that oxaliplatin can induce neutropenia, and cumulate neurotoxicity, in the absence of liver and renal toxicity. We are now expanding the studies to use multiple inbred mice strains to facilitate genomic analysis for both neutropenia and neurotoxicity. These data may provide a model for evaluating oxaliplatin-based therapy to develop strategies to prevent or reduce the neurotoxicity side-effect for clinical chemotherapy.
CD38 Expression in B-Lineage Acute Lymphoblastic Leukemia, a Possible Target for Immunotherapy
Authors: Marion Eveillard, Victor Floc'h, Nelly Robillard, Camille Debord, Soraya Wuilleme, Richard Garand, Fanny Rialland, Caroline Thomas, Pierre Peterlin, Thierry Guillaume, Philippe Moreau, Patrice Chevallier, Marie C Bene
Journal: Blood (2016)
Locum pay bill has fallen 20% from last year
Authors: Abi Rimmer
Journal: BMJ (2017)

The amount paid by NHS trusts in England for locum staff fell by 20% between 2015 and 16 and 2016-17, data have shown.

Liaison, a company that manages staff payment systems, gathered data on locums’ pay and agency commission rates paid by 61 NHS trusts between April 2016 and April 2017.1 It found that the total bill for agency staff in NHS trusts in England decreased by £700m (€790m; …
Spatial heterogeneity of MRI response to first-line hormonal therapy to predict progression-free survival in metastatic breast cancer.
Authors: Michael Kosmin, Andreas Makris, Heminder Sokhi, Toon Thijssen, Anwar R. Padhani
Journal: Journal of Clinical Oncology (2017)

e12544 Background: Whole-body magnetic resonance imaging (WB-MRI) can positively identify response to systemic therapy in metastatic breast cancer (MBC) by the analysis of water diffusivity, cellularity and cell variability. We adapted a novel methodology that captures patient-level, spatial response heterogeneity using the METastasis Response Assessment Diagnostic System (MET-RADS) using WB-MRI. This study evaluated whether spatial heterogeneity seen at the first response assessment is predictive of duration of treatment (i.e. progression-free survival, PFS) in patients on first line hormonal therapy for MBC. Methods: Patients on first line hormonal therapy for MBC had baseline and on-treatment response assessment WB-MRI scans. All patients had a primary breast mass in situ. Patients showing unequivocal disease progression at their first response assessment scans were excluded from further analysis. Criteria for response assessment utilised the methodology described by MET-RADS. A Likert five-point response assessment category (RAC) score (1 = response highly likely, 5 = progression highly likely) was applied to 14 anatomic regions (7 bone &amp; 7 soft tissue). Two scores reflecting the dominant and next most common response per region were recorded, capturing inter- and intra-region response heterogeneity. A novel Response Heterogeneity Index (RHI) summarised the response heterogeneity at the patient level. RHI and depth of response (mean RAC score for all involved regions) and therapy duration were analysed. Results: Twenty-one patients with primary breast mass in situ were analysed. Patients with higher levels of response heterogeneity (defined as RHI &gt; 5; n = 11) had significantly shorter PFS than those with RHI ≤5 (n = 10; median PFS: 11 vs 27 months; log rank test p = 0.011). The depth of response and PFS were unrelated (mean RAC ≤2.5 vs mean RAC &gt; 2.5; median PFS: 21 vs 18 months; log rank test p = 0.46). There were no correlations between RHI score and mean RAC (r 2 = 0.007). Conclusions: A low spatial heterogeneity of response is predictive of improved PFS in patients receiving first line hormonal therapy for MBC.
Reversal of Low Donor Chimerism Following Hematopoietic Cell Transplantation Using Pentostatin and Donor Lymphocyte Infusion
Authors: Merav Bar, Mary Flowers, Barry E. Storer, Thomas R. Chauncey, Michael A Pulsipher, Monica S Thakar, Wolfgang Bethge, Rainer F. Storb, David G Maloney, Brenda M. Sandmaier
Journal: Blood (2016)
Focused Ultrasound Hyperthermia Mediated Drug Delivery Using Thermosensitive Liposomes and Visualized With <i>in vivo</i> Two-Photon Microscopy
Authors: Marc A. Santos, David E. Goertz, Kullervo Hynynen
Journal: Theranostics (2017)

The future of nanomedicines in oncology requires leveraging more than just the passive drug accumulation in tumors through the enhanced permeability and retention effect.Promising results combining mild hyperthermia (HT) with lyso-thermosensitive liposomal doxorubicin (LTSL-DOX) has led to improved drug delivery and potent antitumor effects in pre-clinical studies.The ultimate patient benefit from these treatments can only be realized when robust methods of HT can be achieved clinically.One of the most promising methods of non-invasive HT is the use of focused ultrasound (FUS) with MRI thermometry for anatomical targeting and feedback.MRI-guided focused ultrasound (MRgFUS) is limited by respiratory motion and large blood vessel cooling.In order to translate exciting pre-clinical results to the clinic, novel heating approaches capable of overcoming the limitations on clinical MRgFUS+HT must be tested and evaluated on their ability to locally release drug from LTSL-DOX.Methods: In this work, a new system is described to integrate focused ultrasound (FUS) into a two-photon microscopy (2PM) setting to image the release of drug from LTSL-DOX in real-time during FUS+HT in vivo.A candidate scheme for overcoming the limitations of respiratory motion and large blood vessel cooling during MRgFUS+HT involves applying FUS+HT to 42°C in short ~30s bursts.The spatiotemporal drug release pattern from LTSL-DOX as a result is quantified using 2PM and compared against continuous (3.5min and 20min at 42°C) FUS+HT schemes and unheated controls.Results: It was observed for the first time in vivo that these short duration temperature elevations could produce substantial drug release from LTSL-DOX.Ten 30s bursts of FUS+HT was able to achieve almost half of the interstitial drug concentration as 20min of continuous FUS+HT.There was no significant difference between the intravascular area under the concentration-time curve for ten 30s bursts of FUS+HT and 3.5min of continuous FUS+HT. Conclusion:We have successfully combined 2PM with FUS+HT for imaging the release of DOX from LTSL-DOX in vivo in real-time, which will permit the investigation of FUS+HT heating schemes to improve drug delivery from LTSL-DOX.We have evaluated the ability to release DOX in short 30s FUS+HT bursts to 42°C as a method to overcome limitations on clinical MRgFUS+HT and have found that such exposures are capable of releasing measurable amounts of drug.Such an exposure has the potential to overcome limitations that hamper conventional MRgFUS+HT treatments in targets that are associated with substantial tissue motion.
Comprehensive Clinical Genomic Profiling Defines Age-Associated Molecular Targets in Pediatric and Adult Acute Myeloid Leukemia
Authors: Katherine Tarlock, Shan Zong, Ries E Rhonda, Mark Bailey, Samantha Morley, Sohail Balasubramanian, Rachel Erlich, Doron Lipson, Geoff Otto, Jo-Anne Vergillo, Cu Nguyen, Qingron Chen, Daoud Meerzaman, E. Anders Kolb, Jeff Ross, Tariq I Mughal, Phil Stephens, Vincent A. Miller, Soheil Meshinchi, Jie He
Journal: Blood (2016)
A memorable patient: A dog's life
Authors: M. Sutherland
Journal: BMJ (2001)

In my role as respiratory educator in a family practice I made several follow up visits to a patient discharged from hospital with his first exacerbation of chronic obstructive pulmonary disease (COPD). These visits were to ensure that the patient, John, was recovering, had appropriate support, and understood his COPD self management plan.

On the first visit my arrival was heralded by an ageing, puffing, wheezing, snappy, arthritic chihuahua, which refused to leave me alone despite a volley of colourful language from his owner. The cluttered living area of John's home, where most of his time was spent, had an old cardboard box that the dog slept in, another for the cat, and a large cage for the cockatiel. The outside temperature was 30°C and it was hotter inside. The television set was …
A Translation of Galen's Hygiene (De sanitate tuenda)
Authors: Dorothy M. Schullian
Journal: JAMA (1952)

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