tbuckley/cabot-search huggingface dataset:
RNF126 Quenches RNF168 Function in the DNA Damage Response
Authors: Lianzhong Zhang, Zhenzhen Wang, Ruifeng Shi, Xuefei Zhu, Jiahui Zhou, Bin Peng, Xingzhi Xu
Journal: Genomics Proteomics & Bioinformatics (2018)

Abstract DNA damage response (DDR) is essential for maintaining genome stability and protecting cells from tumorigenesis. Ubiquitin and ubiquitin-like modifications play an important role in DDR, from signaling DNA damage to mediating DNA repair. In this report, we found that the E3 ligase ring finger protein 126 (RNF126) was recruited to UV laser micro-irradiation-induced stripes in a RNF8-dependent manner. RNF126 directly interacted with and ubiquitinated another E3 ligase, RNF168. Overexpression of wild type RNF126, but not catalytically-inactive mutant RNF126 (CC229/232AA), diminished ubiquitination of H2A histone family member X (H2AX), and subsequent bleomycin-induced focus formation of total ubiquitin FK2, TP53-binding protein 1 (53BP1), and receptor-associated protein 80 (RAP80). Interestingly, both RNF126 overexpression and RNF126 downregulation compromised homologous recombination (HR)-mediated repair of DNA double-strand breaks (DSBs). Taken together, our findings demonstrate that RNF126 negatively regulates RNF168 function in DDR and its appropriate cellular expression levels are essential for HR-mediated DSB repair.
Abstract 17331: Statins and Venous Thromboembolism: Systematic Review and Meta-analysis of Prospective Cohort and Randomized Intervention Studies
Authors: Setor K Kunutsor, Samuel Seidu, Kamlesh Khunti
Journal: Circulation (2016)

Introduction: Venous thromboembolism (VTE), which includes deep vein thrombosis and pulmonary embolism, is associated with significant morbidity and mortality. Statins, which are well established f...
Preclinical development of huARH460-16-2, a humanized antibody to the CD44 cancer stem cell target
Authors: Luis da Cruz, Nadine Chouinard, Ningping Feng, Daad Sayegh, Daniel Pereira, Daniel Rubinstein, Susan Hahn, David Young
Journal: Cancer Research (2008)

3975  CD44 has been identified on cancer stem cells in several solid and liquid tumors (breast, colon, prostate, pancreatric cancer and AML) where it is thought to play key roles in tumor maintenance, adhesion, migration and invasion. A monoclonal antibody targeting CD44, ARH460-16-2, was generated using the ARIUS’ FunctionFIRST™ platform. Murine and chimeric ARH460-16-2 (chARH460-16-2) demonstrated potent anti-tumor efficacy in models of human breast (CD44+CD24-/lo), liver and prostate cancer as well as AML. With respect to mechanism of action, chARH460-16-2 induced apoptosis and suppressed phosphorylation of the Tie-1 receptor tyrosine kinase in breast cancer cells. Immunohistochemistry showed that the epitope for ARH460-16-2 is present on the majority of human adenocarcinomas including breast, prostate, colon, and liver cancers. Limited binding to normal human tissues was observed, predominantly to myeloid cells in bone marrow, with no binding observed to erythroid cells, megakaryocytes, endothelium, fibroblasts, smooth muscle, eye, heart, liver, ovary and colon epithelium. The binding pattern was not substantially different in cynomolgus monkey tissues, although some differences in intensity were seen. A dose-ranging toxicology study was carried out in cynomolgus monkeys with chARH460-16-2. In the first phase, monkeys (2 per group) were given a single 1 hr infusion of 10, 30 or 95 (high dose) mg/kg chARH460-16-2. A second cohort of 3 monkeys was infused with 25 mg/kg chARH460-16-2 once per week for 2 doses. There were no drug related effects on clinical chemistry parameters, coagulation, or hematology (blood cell counts or morphology). In one of the high-dose treated monkeys, and in 3 monkeys of the second cohort there was transient reddening of the skin which resolved after a few days. Histopathology of the second cohort, sacrificed 15 days after the first dose, revealed no findings in the skin of 2 tested animals, while the third had a crusting dermatitis. In all cases there no findings in bone marrow smears or in lung sections.  A CHO cell line producing the humanized version of the antibody (huARH460-16-2) has been developed. huARH460-16-2 is equivalent to chARH460-16-2 using the following criteria: affinity to recombinant CD44 by BiaCore and ELISA, FACS binding to cancer cell lines, ability to induce apoptosis, and ability to induce tumor regression in the established MDA-MB-231 breast cancer model. In addition, the EC50 of huARH460-16-2 binding to lymphocytes, monocytes and granulocytes of human and cynomolgus monkeys was similar as assessed by FACS. Taken together, these results support the clinical development of a humanized therapeutic monoclonal antibody targeting the cancer stem cell antigen CD44
Dropping acid: why is cystic fibrosis mucus abnormal?
Authors: Bruce K. Rubin, David J. Thornton
Journal: European Respiratory Journal (2018)

Cystic fibrosis (CF) is associated with the production of viscous and adherent mucus in the airway. Indeed, in some countries, CF is still called "mucoviscidosis". Mucus is a weak hydrogel exhibiting viscoelastic properties and these properties are important for normal function as they enable mucus to flow after secretion, to be effectively propelled by beating cilia (mucociliary clearance), and to provide a protective coating of the mucosal surfaces of our body that prevents dehydration and an exposure to external foreign substances and infectious agents. Mucus that is too thick or too thin can be difficult to transport by mucociliary clearance, and the production and accumulation of thick mucus in the airways eventually leads to mucostasis. The failure in function of mucus in airway clearance can lead to longer resident times of inhaled particulates including infectious agents, which results in chronic infection in the airway, lung damage and risk of death. Mucostasis and its associated problems are pathognomic features of the CF airway, and thus understanding the causes of abnormal mucus properties in CF is key to helping ameliorate the relentless progression of pulmonary disease. In cystic fibrosis, abnormal mucus viscosity and mucociliary clearance are due to decreased water and more solids, and not to changes in mucus pH <http://ow.ly/NvBS30myLwk>
Mandatory, cost-driven switching from originator etanercept to its biosimilar SB4: possible fallout on non-medical switching
Authors: Fabrizio Cantini, Maurizio Benucci
Journal: Annals of the Rheumatic Diseases (2018)

We read with great interest the recently published results from DANBIO registry on switching from originator etanercept (ETA) to the biosimilar SB4.1 The study includes a really impressive number of patients who underwent mandatory switching to SB4, and at first glance the results show a good evidence of efficacy and safety of the procedure. However, in our opinion, how these results may be applied on non-medical switching strategy is rather questionable. A careful reading of the paper raises several concerns related to the demographic and clinical characteristics of switchers and non-switchers, and to the timing of clinical evaluations that may generate misleading biases.

First, switchers had longer previous ETA treatment duration and fewer previous bDMARDs compared with non-switchers suggesting a less severe disease. This seems to be confirmed by the baseline lower disease activity both …
Use of a Single CAR T Cell and Several Bispecific Adapters Facilitates Eradication of Multiple Antigenically Different Solid Tumors
Authors: Yong Gu Lee, Isaac Marks, Madduri Srinivasarao, Ananda Kumar Kanduluru, Sakkarapalayam M. Mahalingam, Xin Liu, Haiyan Chu, Philip S. Low
Journal: Cancer Research (2018)

Abstract Most solid tumors are comprised of multiple clones that express orthogonal antigens, suggesting that novel strategies must be developed in order to adapt chimeric antigen receptor (CAR) T-cell therapies to treat heterogeneous solid tumors. Here, we utilized a cocktail of low-molecular-weight bispecific adapters, each comprised of fluorescein linked to a different tumor-specific ligand, to bridge between an antifluorescein CAR on the engineered T cell and a unique antigen on the cancer cell. This formation of an immunologic synapse between the CAR T cell and cancer cell enabled use of a single antifluorescein CAR T cell to eradicate a diversity of antigenically different solid tumors implanted concurrently in NSG mice. Based on these data, we suggest that a carefully designed cocktail of bispecific adapters in combination with antifluorescein CAR T cells can overcome tumor antigen escape mechanisms that lead to disease recurrence following many CAR T-cell therapies. Significance: A cocktail of tumor-targeted bispecific adapters greatly augments CAR T-cell therapies against heterogeneous tumors, highlighting its potential for broader applicability against cancers where standard CAR T-cell therapy has failed.
Improving PROMs collection rate in an outpatient palliative care clinic.
Authors: Isaac S. Chua, Jocelyn Siegel, Victoria Hayne, Nadine Jackson McCleary
Journal: Journal of Clinical Oncology (2018)

105 Background: From January 2018 to March 2018, Dana Farber Cancer Institute (DFCI) launched a pilot to collect Patient-Reported Outcomes of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) within the adult palliative care (APC) clinic using smart tablets. We had a limited response rate—only 20% of patients attempted to complete the questionnaire. After the pilot ended on March 2018, smart tablets were discontinued and were replaced with a paper version of PRO-CTCAE from April to June 2018. Our aim was to increase the patient attempt and collection rate of the paper PRO-CTCAE from 20% to 50%. Methods: Our primary outcome measure was the percentage of paper PRO-CTCAE attempted and collected. Eligible patients were established patients scheduled to see a provider in the APC clinic. We implemented several Plan-Do-Study-Act (PDSA) cycles including the implementation of the paper version of the questionnaire, training and educating front desk staff, and posting provider reminders in exam rooms. We used a statistical process control (SPC) chart to track percentage of attempted and collected questionnaires over time and to differentiate between special cause and common cause variation. Results: From April 2018 to June 2018, the PRO-CTCAE collection rate improved from 20% to 48%. Special cause variation was associated with implementation of the paper version of the PRO-CTCAE and increased front desk staff engagement. Increased provider satisfaction was also associated with the paper version of the PRO-CTCAE. Conclusions: Implementing a high-reliability process for collecting patient reported outcome measures in an outpatient palliative care clinic is complex and requires cohesive multi-disciplinary teamwork, a user-friendly patient-facing and provider-facing interface, and a streamlined workflow. The electronic version of PRO-CTCAE will resume in September 2018. We will implement lessons learned from the paper PRO-CTCAE implementation, including ongoing front desk staff engagement and an enhanced provider view in the electronic medical record.
Carfilzomib vs bortezomib in patients with multiple myeloma and renal failure: a subgroup analysis of ENDEAVOR
Authors: Meletios Dimopoulos, David Siegel, Darrell J. White, Ralph Boccia, Karim S. Iskander, Zhao Yang, Amy S. Kimball, Khalid Mezzi, Heinz Ludwig, Ruben Niesvizky
Journal: Blood (2018)
Vitiligo and major depressive disorder: A bidirectional population-based cohort study
Authors: Isabelle A. Vallerand, Ryan T. Lewinson, Laurie M. Parsons, Jori Hardin, Richard M. Haber, Mark W. Lowerison, Cheryl Barnabe, Scott B. Patten
Journal: Journal of the American Academy of Dermatology (2018)
Abstract 19375: Transaortic Extended Septal Myectomy for Hypertrophic Obstructive Cardiomyopathy Patients With Midventricular Obstruction
Authors: Yajie Tang, yunhu song
Journal: Circulation (2017)

Midventricular obstruction(MVO) is a rare subset of hypertrophic obstructive cardiomyopathy(HOCM), prone to cause worse prognosis and residual gradients after myectomy. Surgical methods about it are limited and previous studies reported the difficulties of complete resection for hypertrophied septum in mid-ventricle, especially for patients with small aortic annulus or long distance of obstruction. We describe transaortic extended myectomy to reach complete resection for MVO patients with satisfied outcomes. We consider transaortic extended myectomy can be efficacious for MVO patients. Forty patients with gradient≥30mmHg at midventricular level were identified from 427 HOCM patients in our surgical team, from Oct-2002 to Oct-2016, by one surgeon. Patients’ characteristics, echocardiography, MRI, surgical procedure and outcomes were measured and analyzed. The average diameter of aortic annulus was 22.1±2.3mm(19-28mm), mean distance from caudal point of obstruction to aortic annulus was 55.6±6.4mm(40-66mm),...
Cuba begins pulling 8300 doctors out of Brazil following Bolsonaro’s comments
Authors: Owen Dyer
Journal: BMJ (2018)

Millions of Brazilian patients in deprived and underserved areas are facing cancelled appointments and deep uncertainty as charter aircraft hired by Cuba’s government began repatriating 8332 doctors who had worked in Brazil under an international agreement, following comments from its new far right president-elect Jair Bolsonaro which Cuba called “contemptuous and threatening” towards its doctors.1

Questioning the abilities of Cuban doctors, and suggesting that they had committed “barbarities,” Bolsonaro declared that they would have to submit to the Brazilian examination for foreign doctors known as the Revalida.

The agreement that brought the Cubans to Brazil to support former president Dilma Rousseff’s More Doctors (Mais Medicos) programme, negotiated through the Pan-American Health …
Cause of Death in Follicular Lymphoma in the First Decade of the Rituximab Era: A Pooled Analysis of French and US Cohorts
Authors: Clémentine Sarkozy, Matthew J. Maurer, Brian K. Link, Hervé Ghesquieres, Emmanuelle Nicolas, Carrie A. Thompson, Alexandra Traverse-Glehen, Andrew L. Feldman, Cristine Allmer, Susan L. Slager, Stephen M. Ansell, Thomas M. Habermann, Emmanuel Bachy, James R. Cerhan, Gilles Salles
Journal: Journal of Clinical Oncology (2018)

Purpose Although the life expectancy of patients with follicular lymphoma (FL) has increased, little is known of their causes of death (CODs) in the rituximab era. Patients and Methods We pooled two cohorts of newly diagnosed patients with FL grade 1-3A. Patients were enrolled between 2001 and 2013 in two French referral institutions (N = 734; median follow-up 89 months) and 2002 and 2012 in the University of Iowa and Mayo Clinic Specialized Program of Research Excellence (SPORE; N = 920; median follow-up 84 months). COD was classified as being a result of lymphoma, other malignancy, treatment related, or all other causes. Results Ten-year overall survival was comparable in the French (80%) and US (77%) cohorts. We were able to classify COD in 248 (88%) of 283 decedents. In the overall cohort, lymphoma was the most common COD, with a cumulative incidence of 10.3% at 10 years, followed by treatment-related mortality (3.0%), other malignancy (2.9%), other causes (2.2%), and unknown (3.0%). The 10-year cumulative incidence of death as a result of lymphoma or treatment was higher than death as a result of all other causes for each age group (including patients ≥ 70 years of age at diagnosis [25.4% v 16.6%]) Follicular Lymphoma International Prognostic Index score 3 to 5 (27.4% v 5.2%), but not Follicular Lymphoma International Prognostic Index score 0 to 1 (4.0% v 3.7%); for patients who failed to achieve event-free survival within 24 months from diagnosis (36.1% v 7.0%), but not for patients who achieved event-free survival within 24 months of diagnosis (6.7% v 5.7%); and for patients with a history of transformed FL (45.9% v 4.7%), but not among patients without (8.1% v 6.2%). Overall, 77 of 140 deaths as a result of lymphoma occurred in patients whose FL transformed after diagnosis. Conclusion Despite the improvement in overall survival in patients with FL in the rituximab era, their leading COD remains lymphoma, especially after disease transformation. Treatment-related mortality also represents a concern, which supports the need for less-toxic therapies.
Assessment of Pregabalin Postapproval Trials and the Suggestion of Efficacy for New Indications
Authors: Carole A. Federico, Taiji Wang, Adélaïde Doussau, Jeffrey S. Mogil, Dean Fergusson, Jonathan Kimmelman
Journal: JAMA Internal Medicine (2018)

After a drug receives regulatory approval, researchers often pursue small, underpowered trials, called exploratory trials, aimed at testing additional indications. If favorable early findings from exploratory trials are not promptly followed by confirmatory trials, then physicians, patients, and payers can be left uncertain about a drug's clinical value (clinical agnosticism). Such findings may encourage the off-label use of ineffective drugs.To characterize the relationship between exploratory and confirmatory postapproval trials for the blockbuster drug, pregabalin (Lyrica).Ovid MEDLINE and Embase databases were used to identify clinical trials published prior to January 2018 and that tested the efficacy of pregabalin for nonapproved indications. Indications, trial outcomes, publication dates, and trial design elements were recorded. Time elapsed was calculated between the generation of clinical agnosticism about pregabalin (ie, publications reporting positive or inconclusive evidence of efficacy on a primary endpoint) and it being addressed (publication of at least 1 confirmatory trial in the same indication, regardless of outcome).There were 238 trials identified that tested the efficacy of pregabalin in at least 33 indications; 5 indications eventually received European Medicines Agency and/or US Food and Drug Administration marketing approval. Sixty-seven percent (22 of 33) of first publications for new indications may have generated clinical agnosticism. Of those indications with at least 5 years of follow-up, 63% (17 of 27) may have generated agnosticism that was not addressed in confirmatory trials within 5 years. As pregabalin development expanded from indications that received regulatory approval to other indications, the linkage of exploratory to confirmatory trial publication diminished.After initial approval, exploratory evidence suggesting the value of pregabalin for new indications often went unconfirmed for extended periods of time. Poor coordination between exploratory and confirmatory testing may represent an important vehicle through which off-label prescription is recommended in clinical practice guidelines and encouraged in the absence of confirmatory trial evidence.
The patient specific functional scale in outpatient cancer rehabilitation.
Authors: Sarah Sangermano, Terrence Pugh, Vishwa Raj
Journal: Journal of Clinical Oncology (2018)

94 Background: Cancer rehabilitation is an underutilized service within the oncology care spectrum. Approximately 65% of survivors have functional impairments, while only 6% receive services. The effectiveness of cancer rehabilitation must be demonstrated to increase access to care, however there are no nationally recognized outcome tools for use with the oncology population across therapy disciplines. The Patient Specific Functional Scale (PSFS) is validated for use in many traditional rehabilitation populations, and has been referenced in one study with breast cancer patients. The purpose of this quality improvement project was to investigate the utility of the PSFS with cancer patients seen in an outpatient therapy setting. Methods: The PSFS was selected for its comprehensiveness and the ability to use across rehabilitation therapy disciplines. The PSFS measures patient perception of functional improvement during rehabilitation. Patients select up to three limiting activities and rate them on an 11-point scale. An average score is computed. Occupational, physical, and speech therapists were trained on administration, scoring, and reporting of the PSFS. The initial score was obtained at evaluation and the final score was collected during the last treatment session. PSFS scores were collected over a one-year period. Results: 307 new patients were evaluated in the outpatient clinic and 65 of those patients completed the PSFS at both the initial and final visits. Most patients had breast, prostate, and brain cancers. Barriers to completion of PSFS included patients not being appropriate for treatment, therapist compliance with the tool, and patients not returning for their final therapy appointment. Of the 65 patients, 86% reported the minimal clinically important change of 2-points or greater. The average increase in PSFS score was 3.7 points. Conclusions: The PSFS was successfully utilized in the outpatient rehabilitation setting with oncology patients. Therapists perceived the tool as quick, patient-centered, and easy to use. Patients showed functional improvement using the PSFS. Further research is necessary to understand the psychometric properties of the PSFS with the oncology population.
68Ga–Prostate-Specific Membrane Antigen PET/CT
Authors: Vincenzo Militano, Asim Afaq, Jamshed Bomanji
Journal: Clinical Nuclear Medicine (2018)

Abstract This case highlights that liposarcoma shows 68 Ga–prostate-specific membrane antigen avidity and should be included in the differential diagnosis of patients with avid muscle lesions to avoid an incorrect diagnosis of metastasis.
A human-derived antibody targets misfolded SOD1 and ameliorates motor symptoms in mouse models of amyotrophic lateral sclerosis
Authors: Marcel Maier, Tobias Welt, Fabian Wirth, Fabio Montrasio, Daniel Preisig, Jordan McAfoose, Fernando G. Vieira, Luka Kulic, Claudia Späni, Thilo Stehle, Steve Perrin, Markus Weber, Christoph Hock, Roger M. Nitsch, Jan Grimm
Journal: Science Translational Medicine (2018)

Mutations in the gene encoding superoxide dismutase 1 (SOD1) lead to misfolding and aggregation of SOD1 and cause familial amyotrophic lateral sclerosis (FALS). However, the implications of wild-type SOD1 misfolding in sporadic forms of ALS (SALS) remain unclear. By screening human memory B cells from a large cohort of healthy elderly subjects, we generated a recombinant human monoclonal antibody (α-miSOD1) that selectively bound to misfolded SOD1, but not to physiological SOD1 dimers. On postmortem spinal cord sections from 121 patients with ALS, α-miSOD1 antibody identified misfolded SOD1 in a majority of cases, regardless of their SOD1 genotype. In contrast, the α-miSOD1 antibody did not bind to its epitope in most of the 41 postmortem spinal cord sections from non-neurological control (NNC) patients. In transgenic mice overexpressing disease-causing human SOD1G37R or SOD1G93A mutations, treatment with the α-miSOD1 antibody delayed the onset of motor symptoms, extended survival by up to 2 months, and reduced aggregation of misfolded SOD1 and motor neuron degeneration. These effects were obtained whether α-miSOD1 antibody treatment was administered by direct brain infusion or peripheral administration. These results support the further development of α-miSOD1 antibody as a candidate treatment for ALS involving misfolding of SOD1.