tbuckley/cabot-search huggingface dataset:
First prospective study of allogeneic peripheral blood stem cell (PBSC) transplantation in patients with myelofibrosis in the United States: Interim analysis of MPD-RC 101 protocol.
Authors: D. Rondelli, M. W. Boyer, L. M. Isola, T. Shore, A. Bacigalupo, R. B. Klisovic, R. Marchioli, J. D. Goldberg, R. Hoffman, L. R. Silverman
Journal: Journal of Clinical Oncology (2010)

6535 Background: The Myeloproliferative Disorder-Research Consortium (MPD-RC) designed the first U.S. prospective phase II study of allogeneic PBSC transplantation in patients with primary myelofibrosis (PMF) or MF secondary to essential thrombocythemia (ET-MF) or polycythemia vera (PV-MF). Methods: Between April 2007 and December 2009, 42 patients were transplanted with HLA matched PBSC from related (MRD) (n = 23) or unrelated (MUD) (n = 19) donors. A regimen with fludarabine/melphalan (FluMel) ± ATG was used. Patients with PMF (n = 25), ET-MF (n = 13) or PV-MF (n = 4) were all at intermediate/high risk according to the Lille score system and the majority had grade 3 marrow fibrosis. Median age was 54 years (range: 36-64). Splenomegaly was present in 79% of the patients while 17% had prior splenectomy. Results: Neutrophil and platelet engraftment occurred on d26 (range: 9-57) and d27 (range: 9-365), respectively. Graft failure/rejection occurred in 5 MUD patients. At a median follow-up of 185 days (range: 15-742), 78% of MRD patients are alive; 9 of 19 MUD cases (47%) died and 3 were taken off study. Causes of death in 5 cases in the MRD group were: GVHD (n = 2), hemorrhage, secondary cancer and relapse; and in 9 cases in the MUD group were: GVHD (n = 2), hemorrhage (n = 2), renal failure (n = 2), pulmonary toxicity, venous occlusive disease and infection. Acute GVHD ≥ grade 2 in MRD and MUD was 45% (15% grade 3-4) and 47% (10% grade 3-4), respectively. Overall clinical response according to the International Working Group criteria in patients with > 6 months follow-up in the MRD group was 79%, with CR/PR 47% and clinical improvement 32%.Transplant-related mortality (TRM) was 13%. Analysis of response rate in MUD cases has been limited by the high TRM (47%). Overall and event-free survival were superior in MRD vs MUD transplants (p = 0.005). Conclusions: Our initial findings confirm that FluMel regimen is effective and causes low toxicity in MRD transplant in MF patients. The higher TRM observed in MUD transplants may suggest a need for a more reduced intensity chemotherapy in this setting. No significant financial relationships to disclose.
Phase II Safety and Efficacy Study of CT-011, a Humanized Anti-PD-1 Monoclonal Antibody, in Combination with Rituximab in Patients with Relapsed Follicular Lymphoma
Authors: Jason R. Westin, Fuliang Chu, Luis E Fayad, Larry W Kwak, Nathan H Fowler, Jorge E Romaguera, F.B. Hagemeister, Michelle Fanale, Felipe Samaniego, Rochelle Allen, Lei Feng, Veerabhadran Baladandayuthapani, Rinat Rotem-Yehudar, Sattva Neelapu
Journal: Blood (2012)
Differential activity of afatinib (AFAT), cetuximab (CET), and erlotinib (E) in a patient-derived xenograft (PDX) model of acquired E resistance.
Authors: Philip C. Mack, Neal Goodwin, William S. Holland, Karen Kelly, Primo Lara, David R. Gandara
Journal: Journal of Clinical Oncology (2013)

8110 Background: The UC Davis - Jackson Labs Consortium has established a PDX resource of over 50 NSCLC models (12 EGFR mutant) for experimental therapeutics and personalized medicine, using the NSG mouse. Here we report on a unique PDX model, LG703, derived from a patient at time of acquired E resistance. This tumor harbors EGFR L858R with no T790M mutation, high MET and very high EGFR protein expression. The patient is in remission following treatment with AFAT-CET. In this model, we investigated the respective contribution of CET and AFAT relative to E on tumor growth and signal transduction. Methods: Individual mice implanted with LG703 tumor fragments were randomized to E (50 mg/kg qd po), AFAT (20 mg/kg qd po), CET (10 mg/kg twice weekly iv), AFAT-CET, or vehicle control (n per arm = 12) for 3 weeks followed by a 75-day monitoring period. Changes in signal transduction mediators and RTKs were assessed after 6 and 24h treatment exposures using kinase arrays (R&amp;D systems) and immunoblotting. Results: AFAT, CET and AFAT-CET resulted in complete tumor response (CR) during the 21-day treatment period; whereas E resulted in temporary growth delay. After cessation of treatment, E-treated mice progressed rapidly and AFAT-treated mice progressed within 2 weeks. Mice treated with CET or AFAT-CET remained in complete remission. At 6h, E and AFAT significantly (&gt;70%) reduced EGFR phosphorylation as well as that of AKT1, AKT2, ERK1, p38a, RSK1 and p70S6K. At 24h, E-treated tumors had returned to baseline-like states for all factors, AFAT showed an intermediate response, and CET, alone or with AFAT, achieved the greatest inhibition of pEGFR with sustained inhibition of all downstream effectors. Conclusions: In the LG703 PDX model, CET and AFAT+CET resulted in CRs, mirroring the patient's response to similar therapy, associated with sustained inhibition of pEGFR and multiple downstream signaling factors. In contrast, E exhibited only temporary growth delay associated with transient inhibition of EGFR pathway factors. These experiments demonstrate the potential of this PDX resource to assess new therapeutic strategies in models representing individual patients. Supported by BJALCF.
Outcomes of CLL patients treated with sequential kinase inhibitor therapy: a real world experience
Authors: Anthony R. Mato, Chadi Nabhan, Paul M. Barr, Chaitra S. Ujjani, Brian T. Hill, Nicole Lamanna, Alan P. Skarbnik, Christina Howlett, Jeffrey J. Pu, Alison R. Sehgal, Lauren E. Strelec, Alexandra Vandegrift, Danielle M. Fitzpatrick, Clive S. Zent, Tatyana Feldman, Andre Goy, David F. Claxton, Spencer Henick Bachow, Gurbakhash Kaur, Jakub Svoboda, Sunita Dwivedy Nasta, David Porter, Daniel J. Landsburg, Stephen J. Schuster, Bruce D. Cheson, Pavel Kiselev, Andrew M. Evens
Journal: Blood (2016)
State-of-the-Art Evaluation of Emergency Department Patients Presenting With Potential Acute Coronary Syndromes
Authors: Judd E. Hollander, Martin Than, Christian Mueller
Journal: Circulation (2016)

It is well established that clinicians cannot use clinical judgment alone to determine whether an individual patient who presents to the emergency department has an acute coronary syndrome. The history and physical examination do not distinguish sufficiently between the many conditions that can cause acute chest pain syndromes. Cardiac risk factors do not have sufficient discriminatory ability in symptomatic patients presenting to the emergency department. Most patients with non-ST-segment-elevation myocardial infarction do not present with electrocardiographic evidence of active ischemia. The improvement in cardiac troponin assays, especially in conjunction with well-validated clinical decision algorithms, now enables the clinician to rapidly exclude myocardial infarction. In patients in whom unstable angina remains a concern or there is a desire to evaluate for underlying coronary artery disease, coronary computed tomography angiography can be used in the emergency department. Once a process that took ≥24 hours, computed tomography angiography now can rapidly exclude myocardial infarction and coronary artery disease in patients in the emergency department.
VASCULAR EXPRESSION OF PVEGFR2 IN PEDIATRIC PILOCYTIC ASTROCYTOMA SUGGESTS THERAPEUTIC POTENTIAL AS A TARGET FOR ANTI-ANGIOGENIC TREATMENT STRATEGIES
Authors: A. H. Sikkema, E. S. J. M. de Bont, G. Molema, A. Dimberg, P. J. Zwiers, S. H. Diks, Eelco W. Hoving, W. A. Kamps, M. P. Peppelenbosch, W. F. A. den Dunnen
Journal: Neuro-Oncology (2010)
New Appliances
Authors: J E SEMPLE
Journal: BMJ (1960)

part of the graft continued to grow.This was strictly in accordance with homotransplants of adult bone and cartilage, and suggested that nothing was to be gained by transplantation of immature tissue.It was interesting to note that, as the isograft continued to grow with progressive replacement of bone but not subjected to the normal stresses, the secondary characteristics of the bone disappeared.In the homograft, where the cartilage continued to grow but was not replaced by bone, the shape of the bone accurately persisted, all the secondary characteristics being well defined.
Genetic Misdiagnoses and the Potential for Health Disparities
Authors: Arjun K. Manrai, Birgit H. Funke, Heidi L. Rehm, Morten S. Olesen, Bradley A. Maron, Peter Szolovits, David M. Margulies, Joseph Loscalzo, Isaac S. Kohane
Journal: New England Journal of Medicine (2016)

For more than a decade, risk stratification for hypertrophic cardiomyopathy has been enhanced by targeted genetic testing. Using sequencing results, clinicians routinely assess the risk of hypertrophic cardiomyopathy in a patient's relatives and diagnose the condition in patients who have ambiguous clinical presentations. However, the benefits of genetic testing come with the risk that variants may be misclassified.Using publicly accessible exome data, we identified variants that have previously been considered causal in hypertrophic cardiomyopathy and that are overrepresented in the general population. We studied these variants in diverse populations and reevaluated their initial ascertainments in the medical literature. We reviewed patient records at a leading genetic-testing laboratory for occurrences of these variants during the near-decade-long history of the laboratory.Multiple patients, all of whom were of African or unspecified ancestry, received positive reports, with variants misclassified as pathogenic on the basis of the understanding at the time of testing. Subsequently, all reported variants were recategorized as benign. The mutations that were most common in the general population were significantly more common among black Americans than among white Americans (P<0.001). Simulations showed that the inclusion of even small numbers of black Americans in control cohorts probably would have prevented these misclassifications. We identified methodologic shortcomings that contributed to these errors in the medical literature.The misclassification of benign variants as pathogenic that we found in our study shows the need for sequencing the genomes of diverse populations, both in asymptomatic controls and the tested patient population. These results expand on current guidelines, which recommend the use of ancestry-matched controls to interpret variants. As additional populations of different ancestry backgrounds are sequenced, we expect variant reclassifications to increase, particularly for ancestry groups that have historically been less well studied. (Funded by the National Institutes of Health.).
Dual Roles for CXCL4 Chemokines and CXCR3 in Angiogenesis and Invasion of Pancreatic Cancer
Authors: Cathy Quemener, Jessica Baud, Kevin Boyé, Alexandre Dubrac, Clotilde Billottet, Fabienne Soulet, Florence Darlot, Laurent Dumartin, Marie Sire, Renaud Grepin, Thomas Daubon, Fabienne Rayne, Harald Wodrich, Anne Couvelard, Raphael Pineau, Martin Schilling, Vincent Castronovo, Shih-Che Sue, Kim Clarke, Abderrahim Lomri, Abdel-Majid Khatib, Martin Hagedorn, Hervé Prats, Andreas Bikfalvi
Journal: Cancer Research (2016)

The CXCL4 paralog CXCL4L1 is a less studied chemokine that has been suggested to exert an antiangiogenic function. However, CXCL4L1 is also expressed in patient tumors, tumor cell lines, and murine xenografts, prompting a more detailed analysis of its role in cancer pathogenesis. We used genetic and antibody-based approaches to attenuate CXCL4L1 in models of pancreatic ductal adenocarcinoma (PDAC). Mechanisms of expression were assessed in cell coculture experiments, murine, and avian xenotransplants, including through an evaluation of CpG methylation and mutation of critical CpG residues. CXCL4L1 gene expression was increased greatly in primary and metastatic PDAC. We found that myofibroblasts triggered cues in the tumor microenvironment, which led to induction of CXCL4L1 in tumor cells. CXCL4L1 expression was also controlled by epigenetic modifications at critical CpG islands, which were mapped. CXCL4L1 inhibited angiogenesis but also affected tumor development more directly, depending on the tumor cell type. In vivo administration of an mAb against CXCL4L1 demonstrated a blockade in the growth of tumors positive for CXCR3, a critical receptor for CXCL4 ligands. Our findings define a protumorigenic role in PDAC development for endogenous CXCL4L1, which is independent of its antiangiogenic function. Cancer Res; 76(22); 6507-19. ©2016 AACR.
MPL expression on AML blasts predicts peripheral blood neutropenia and thrombocytopenia
Authors: Philipp J. Rauch, Jana M. Ellegast, Corinne C. Widmer, Kristin Fritsch, Jeroen S. Goede, Peter J. M. Valk, Bob Löwenberg, Hitoshi Takizawa, Markus G. Manz
Journal: Blood (2016)
Three in four are unaware of obesity link to cancer, says charity
Authors: Anne Gulland
Journal: BMJ (2016)

Cancer Research UK has urged the government to act to curb the obesity epidemic, as the charity released a survey showing that three in four adults are unaware of the link between obesity and cancer.1

An online survey found that 75% of respondents (2457/3293) were unaware that being overweight or obese increased a person’s risk of cancer.

When asked about specific cancers, respondents were more likely to see a link between being overweight or obese and cancers of the bowel (60% of respondents), liver (55%), and pancreas …
Tissue Boundaries: Mimicking Tissue Boundaries by Sharp Multiparameter Matrix Interfaces (Adv. Healthcare Mater. 15/2016)
Authors: Jiranuwat Sapudom, Stefan Rubner, Steve Martin, Tilo Pompe
Journal: Advanced Healthcare Materials (2016)

Engineering interfaces of extracellular compartments mimicking native tissues is key to study cell behavior in a physiologically relevant context and for a successful translation of these new biomaterials engineering principles in regenerative and therapeutic applications. Tilo Pompe and co-workers demonstrate a strategy to engineer multiparameter matrix interfaces using a sequential reconstitution of two well-defined Collagen I based matrices on page 1861. Such matrix interfaces trigger cell migration directionality normal to the interface plane in dependence on matrix pore size.
Contributions of family social structure to the development of ultrasociality in humans
Authors: Benjamin C Nephew, Florent Pittet
Journal: Behavioral and Brain Sciences (2016)

Abstract The evolution of ultrasociality in humans may have involved the evolutionarily significant mechanisms that govern family social structure in many animal species. Adverse effects of ultrasociality in humans may be mediated by maladaptive effects of modern civilization on family groups, as many of the effects on both families and societies are especially severe in dense populations made possible by agriculture.
Clinical and pathologic outcome analysis with the preoperative systemic therapy in operable breast cancer.
Authors: P. Pillai, Y. Ma, V. K. Sandilya, J. Innocent, R. R. Rubin, N. Popnikolov, D. L. Topolsky, P. A. Crilley, L. Newman, M. Styler
Journal: Journal of Clinical Oncology (2010)

e11094 Background: Preoperative treatment is been increasingly used in early-stage breast cancer. The identification of intermediate markers that correlate with outcome (pathologic response and or survival) in carefully selected patient groups may have clinical utility. Methods: Retrospective, university-based single institution tumor registry data analysis. Results: 41 patients (54% Caucasian, 41% African American), median age of 52 years with stage I-III breast cancer underwent preoperative systemic therapy at our institution between 1998 and 2008. Pathology details were available in 35 patients. There were 88% ductal, 10% lobular, 34% hormone receptors positive, 28% HER2-neu positive and 43% triple negatives. IHC assessment of the nuclear antigen Ki-67 was performed in 13 patients on the diagnostic biopsy. Anthracycline and or taxane chemotherapy was given to 66% and 54% patients respectively for a median of 17 weeks. Three patients received preoperative trastuzumab. Mastectomy and BCS were performed in 44% and 41% respectively. Eight (23%) patients achieved pCR following preoperative therapy. In the group with pCR, 38% had high Ki-67 on the diagnostic biopsy. Among the rest of 27 patients with < pCR, 19% had local residual DCIS. Bad prognostic features including high Ki-67 (30%), nuclear grade 3 (33%) and angio-lymphatic invasion (37%) were seen in <pCR group. Postoperative radiation therapy and chemotherapy were documented in eight and 21 patients respectively. The median DFS and OS were 27 and 34 months for the entire group. There was no significant difference in median survival on subgroup analysis (32 months in pCR vs. 36 months in < pCR, p = 0.28). Among the group with < pCR, patients with bad prognostic features including triple negatives, HER2-neu positive, high residual Ki-67, nuclear grade 3 and or angio-lymphatic invasion had a similar median survival of 36 months. Conclusions: In this retrospective series, conventional prognostic markers did not appear to predict for response to or long term survival following neoadjuvant therapy. Newer markers, such as those identified by micro-array analysis, will be necessary to identify those patients who will benefit most from the neoadjuvant approach. No significant financial relationships to disclose.
A phase I, first-in-human single ascending dose study of the MEK inhibitor WX-554 given to healthy male subjects.
Authors: C. Mala, N. G. Neville, E. Haindl, M. Buergle, W. Schmalix, P. Bevan
Journal: Journal of Clinical Oncology (2010)

e13666 Background: WX-554 is a small molecule inhibitor targeting mitogen-activated protein kinase kinase (MEK1 and MEK2). The Ras/Raf/MEK/ERK pathway is one of the major signal transduction pathways that cells use to control proliferation and survival. WX-554, originally developed by UCB, is one of several MEK inhibitors currently in development. The study is designed to deliver reliable PK and PD data to guide rational drug dose and therapeutic regimen. WX-554 is being administered as a single dose i.v. to healthy volunteers and with the aim of delivering the benchmark dose(s) for a subsequent oral study, ideally in the same healthy volunteer population. Methods: Treatment groups will consist of 5 subjects each. The targeted number of evaluable subjects is 25. The planned single doses of WX-554 will be in the range 0.05 mg/kg to 5.0 mg/kg in accordance with the adaptive Verweij approach. Dose escalation will continue until maximum pERK inhibition is observed provided that no dose limiting toxicity (DLT) occurs. Plasma levels of WX-554 will be determined at various intervals after dosing. pERK and TNF alpha inhibition in PBMCs will be assessed. Results: The first two cohorts have been successfully completed and show excellent target inhibition with no worrisome drug-related side-effects. Conclusions: Dose-escalation will therefore continue. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration WILEX
Preparation and evaluation of duloxetine hydrochloride enteric-coated pellets with different enteric polymers
Authors: Chen Kuang, Yinghua Sun, Bing Li, Rui Fan, Jing Zhang, Yumin Yao, Zhonggui He
Journal: Asian Journal of Pharmaceutical Sciences (2016)

The main purpose of the present study was to prepare duloxetine hydrochloride (DXH) enteric-coated pellets using different enteric polymers. Three layers (drug-loaded layer, barrier layer, and enteric-coated layer) were applied to the inert core pellets, successively. The optimal formulation was manufactured by employing suspension layering method in fluidized bed processor (FBP) with varieties of enteric polymers like Aqoat® AS-LF, Eudragit® L30D55 and HPMCP-HP55. The prepared pellets were measured for physical characterization and the in vitro dissolution profile. Scanning electron microscopy (SEM) was conducted to observe the morphology of pellets, and different kinetic models were applied to analyze the release mechanism of Cymbalta® and home-made pellets. The coating weight gain of enteric-coated layer containing Eudragit® L30D55, Aqoat® AS-LF and HP-55 were determined to be 35%, 26% and 24%, respectively. The similarity factors (f2 ) of self-made capsules with above polymers and commercially available capsules (Cymbalta®) were above 50 in the dissolution medium of pH 6.8 phosphate buffer solution (PBS). SEM figures showed the smooth surfaces of self-prepared pellets using Eudragit® L30D55 and Aqoat® AS-LF, whereas rough surface was found in the HP-55 pellets at day 0, and an impurity was appearing in the condition of 40 °C/75% relative humidity for 1 month. In conclusion, the pellets prepared by utilizing Eudragit® L30D55 and Aqoat® AS-LF were the optimal preparations based on the dissolution profile and stability.
HIV-associated Hodgkin's lymphoma (HIV-HL): Results of a prospective multicenter trial.
Authors: M. Hentrich, M. Berger, C. Hoffmann, J. M. Siehl, T. Wolf, J. Rockstroh, G. Fätkenheuer, K. Arastéh, F. A. Mosthaf, C. Wyen
Journal: Journal of Clinical Oncology (2010)

8035 Background: The outcome of patients (pts) with HIV-HL has improved since the introduction of highly active antiretroviral therapy (HAART). The current trial was initiated to investigate a risk adapted treatment strategy in pts with HIV-HL as established in HIV-negative pts with HL. Methods: Pts were planned to receive 2x ABVD + 30 Gy involved field (IF) radiation for early stage (ES) favourable HL (stage I/II without risk factors), 4x BEACOPP baseline + 30 Gy IF for ES unfavourable HL (extranodal involvement, large mediastinal mass, ≥ 3 lymph node areas involved), and 6-8 × BEACOPP baseline for advanced stage HL. BEACOPP should be replaced by ABVD in pts with far advanced HIV-infection. HAART was given concomitantly with chemotherapy. The primary endpoint was tolerability and treatment related mortality. Secondary endpoints include event free survival (EFS) and overall survival (OS). Results: 93 pts (7 females) were included in the trial. 18/93 pts (19%) had ES favourable HL, 13 (14%) ES unfavourable HL, and 62 (67%) advanced stage HL. 23/87 pts (26%) had a prior AIDS defining illness. The median CD4 count at HL diagnosis was 212/μ l. Grade 3/4 toxicity occurred in 69% under ABVD and 79% under BEACOPP. 4 pts with advanced stage HL died of neutropenic sepsis after the first, seventh (n=2) and eighth course of BEACOPP, respectively. So far response data are available from 78 pts. After a median follow-up of 13.5 months 19/19 pts (100%) with ES favourable HL and 11/11 pts (100%) with ES unfavourable HL achieved a CR/CRu. In pts with advanced HL the CR/CRu rate was 83% (40/48). Of 5 pts having relapsed 2 received an autologous stem cell transplant resulting in a second remission. 7 of 93 pts (8%) have died. Apart from neutropenic sepsis causes of death were progressive HL (n=2) and progressive HIV-infection (PML, n=1). The 12-months OS of the entire study population is 88.3%. EFS and OS are significantly longer in pts with ES HL than in advanced stage HL (p=0.021 and 0.047, respectively). Conclusions: In pts with HIV-HL risk-adapted CT and concomitant HAART is feasible and effective. However, pts must closely be monitored for neutropenic infections. These data suggest that the prognosis of HIV-HD may approach results achieved in the HIV-negative population with HL. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Abbott Laboratories, Bristol-Myers Squibb, Boehringer Ingelheim, GlaxoSmithKline, MSD, Pfizer, Schering, Vertex, Gilead Abbott Laboratories, Bristol Myers-Squibb, Boehringer Ingelheim, GlaxoSmithKline, MSD, Pfizer, Schering, Vertex, Gilead, Pfizer, Gilead, Abbott, GlaxoSmithKline, Boehringer Ingelheim Abbott Laboratories, Roche, MSD