tbuckley/cabot-search huggingface dataset:
Abstract IA03: Towards the next clinical option: Experience from a precision cancer medicine trial
Authors: Mark A. Rubin
Journal: Cancer Research (2015)

Abstract Understanding molecular mechanisms of response and resistance to anticancer therapies requires prospective patient follow-up and clinical and functional validation of both common and low frequency mutations. We describe an evidence-based precision medicine program designed to bring whole exome sequencing (WES) into clinical practice and illustrate how this can be utilized to identify novel predictive biomarkers associated with exceptional systemic response. Metastatic and treatment-resistant cancer patients are prospectively enrolled for paired metastatic tumor and normal WES. Using a comprehensive computational pipeline, point mutations, indels and copy number alterations are detected. Mutations are categorized as Category I-III based on actionability and a report is generated and discussed in tumor board. Patients are followed prospectively for correlation of molecular information with clinical response and patient outcomes. A rapid response functional team follows on key findings to expand actionability based on the WES results. In the first year, 154 tumor-normal pairs from 97 patients were sequenced, with an average coverage of 95X of over 21,000 genes and 16 somatic alterations detected on average per patient. In total, 16 mutations were Category I, 98 were Category II, and 1474 were Category III. Tumor purity ranged from 14 to near 100%. Among unexpected findings, a prostate cancer exceptional responder was identified that harbored a somatic hemizygous deletion of the DNA repair gene FANCA and likely loss of function of the second allele through germline missense variant. Follow-up experiments established that loss of FANCA function was associated with platinum hypersensitivity both in vitro and in patient-derived xenografts, thus providing biologic rationale and functional evidence for his extreme clinical response. The establishment of a clinical program for whole exome sequencing of metastatic tumors with prospective follow-up of patients can help identify candidate predictive biomarkers of response. Citation Format: Mark A. Rubin. Towards the next clinical option: Experience from a precision cancer medicine trial. [abstract]. In: Proceedings of the AACR Special Conference on Computational and Systems Biology of Cancer; Feb 8-11 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 2):Abstract nr IA03.
Efficacy and safety of rivaroxaban in Brazilian oncologic patients with thrombosis.
Authors: Gustavo Dos Santos Fernandes, Flavia Xavier, Maria Ignez Braghiroli, Karime Machado, Karla Teixeira Souza, Ana Carolina Carvalho Rocha Paterlini, Fernando Sergio Blumm Ferreira, Paulo Marcelo Hoff
Journal: Journal of Clinical Oncology (2015)

e20643 Background: Cancer is an independent risk factor for venous thromboembolic events (VTE) that ultimately leads to hypercoagulable state. Thromboembolic events are common and potentially fatal complication in cancer patients, corresponding to the second cause of death. Recently the oral anticoagulant rivaroxaban, that directs inhibits factor Xa, was approved for the treatment of VTE, however only 4.7% of the trial population had an active malignancy. Methods: We conducted a retrospective study including patients (pt) treated from January 2009 to February 2014 who had diagnosis of cancer, used rivaroxaban for at least 3 months and had a normal renal function. Chi-square test was used to evaluate efficacy (prevention of re-thrombosis) and safety (bleeding events) in comparison to published literature based on enoxaparin/vitamin K antagonist (VKA). Results: 41 pt were included with median age of 62.5 years. Most frequent tumor histology was adenocarcinoma (78%) and primary was colon (26.8%). 87.8% of patients had advanced disease. Other thrombotic risk factors were less common: immobilization (19.5%), recently surgery (7.3%), obesity (2.4%), diabetes (24.4%), hypertension (24.4%), dyslipidemia (9.8%), smoking (12.2%), active infection (2.4%) and hereditary thrombophilia (2.4%). 70.7% of pt had implantable central venous catheter (CVC-associated DVT occurred in 41.4% pt). ASCO VTE risk assessment score classified pt as low (12.5%), intermediate (50%) and high risk (35.5%). Pulmonary thromboembolism was reported in 41.4%, but DVT was detected in only 14.6%. 43.9% pt were started on low molecular weight heparin (LMWH) before starting rivaroxaban. Rivaroxaban was used for a median time of 5.5 months. There were 12.2% of minor bleeding and one case of moderate bleeding. In our study, rivaroxaban was as safe as enoxaparin/VKA (p = 0.54).Rethrombosis occurred in 12.2% of patients during rivaroxaban treatment. Efficacy of rivaroxaban was not different from traditional enoxaparin/VKA (p = 0.25). Conclusions: Although it is a retrospective analysis, our results suggests that in this cohort of oncologic patients, rivaroxaban was safe and efficient when compared to the literature data using LMWH and VKA.
Abstract 23231: The Impact of Dual Antiplatelet Therapy on Mortality: A Patient-Level Meta-Analysis
Authors: Sammy Elmariah, Gheorghe Doros, Oscar R Benavente, Deepak L Bhatt, Stuart J Connolly, Steven Steinhubl, Salim Yusuf, Yuyin Liu, Robert W Yeh, Laura Mauri
Journal: Circulation (2016)

Background: Continuation of clopidogrel therapy beyond 12 months after percutaneous coronary intervention reduced the risk of stent thrombosis and major adverse cardiovascular (CV) and cerebrovascu...
Abstract 115: A Decrease in Mitochondrial, but Not Cytosolic, Iron Protects Against Cardiac Ischemia-reperfusion Damage Through a Reduction in Ros
Authors: Hsiang-Chun Chang, Rongxue Wu, Hossein Ardehali
Journal: Circulation Research (2015)

Introduction: Iron is essential for the activity of several cellular proteins, but excess free iron can cause cellular damage through production of reactive oxygen species (ROS). Iron accumulation in mitochondria, the major site of cellular iron homeostasis, leads to cardiomyopathy. However, it is not known whether a reduction in baseline mitochondrial iron (as opposed to iron in other cellular compartments) can protect against ischemia-reperfusion (I/R) injury in the heart. We hypothesized that since mitochondria are the major site of iron homeostasis and that mitochondrial iron can lead to oxidative damage, a reduction in mitochondrial iron at baseline would be sufficient to protect against I/R injury. Results: Transgenic (TG) mice with cardiomyocyte-specific overexpression of the mitochondrial iron export protein ATP-binding cassette (ABC)-B8 had significantly lower mitochondrial iron in the heart than nontransgenic (NTG) littermates at baseline, but their cardiac function and the expression of key antioxidant systems were similar to NTG littermates. In response to I/R, TG mice displayed significantly less apoptosis and lipid peroxidation products and better preserved cardiac function than NTG littermates, suggesting that a reduction in mitochondrial iron protects against I/R injury. To confirm these results, we next took a pharmacological approach to assess the effects of a reduction in mitochondrial vs cytosolic iron on the response to I/R using 2,2’-bipyridyl (BPD, a mitochondria-accessible iron chelator) and deferoxamine (DFO, an iron chelator that can only reduce cytosolic iron). Mice pretreated with BPD but not DFO are protected against I/R injury. In addition, BPD but not DFO treatment in rat cardiomyoblast H9C2 cells significantly lowered chelatable mitochondrial iron and protected against H2O2 induced cell death. These results suggest that a reduction in baseline mitochondrial, but not cytosolic, iron is sufficient to protect against I/R injury. Conclusions: Our findings demonstrate that selective reduction in mitochondrial iron is protective in I/R injury. Thus, targeting mitochondrial iron with selective iron chelators may provide a novel approach for treatment of ischemic heart disease.
Multidimensional Immunophenotyping Identifies Hallmarks of Systemic Light-Chain Amyloidosis (AL) and Maps the Disease in the Crossroad between MGUS and Multiple Myeloma (MM)
Authors: Noemi Puig, Bruno Paiva, Marta Lasa, Leire Burgos, José J Pérez, Juana Merino, Cristina Moreno, Maria-Belen Vidriales, Dolores Gómez, María Teresa Cedena, Enrique M. Ocio, Ramon Lecumberri, Alfonso García de Coca, Jorge Labrador, Esther González Garcia, Luis Palomera, Mercedes Gironella, Valentin Cabañas, Maria Casanova, Albert Oriol, Isabel Krsnik, Albert Pérez, Javier De La Rubia, José Enrique de la Puerta, Felipe De Arriba, Felipe Prosper, Joaquin Martinez Lopez, Quentin Lecrevisse, Javier Verde, Maria-Victoria Mateos, Juan Jose Lahuerta, Alberto Orfao, Jesús F San-Miguel
Journal: Blood (2018)
Measuring particle size distribution of nanoparticle enabled medicinal products, the joint view of EUNCL and NCI-NCL. A step by step approach combining orthogonal measurements with increasing complexity
Authors: F. Caputo, J. Clogston, L. Calzolai, M. Rösslein, A. Prina-Mello
Journal: Journal of Controlled Release (2019)

The particle size distribution (PSD) and the stability of nanoparticles enabled medicinal products (NEP) in complex biological environments are key attributes to assess their quality, safety and efficacy. Despite its low resolution, dynamic light scattering (DLS) is the most common sizing technique since the onset of NEP in pharmaceutical technologies. Considering the limitations of the existing sizing measurements and the challenges posed by complex NEPs both scientists and regulators encourage the combination of multiple orthogonal high-resolution approaches to shed light in the NEP sizing space (e.g. dynamic light scattering, electron microscopy, field flow fractionation coupled to online sizing detectors, centrifugal techniques, particle tracking analysis and tunable resistive pulse sensing). The pharmaceutical and biotechnology developers are now challenged to find their own pragmatic characterisation approaches, which should be fit for purpose and minimize costs at the same time, in a complicated landscape where only a few standards exist. In order to support the community, the European Nanomedicine Characterisation Laboratory (EUNCL) and the US National Cancer Institute Nanotechnology Characterization Laboratory (NCI-NCL) have jointly developed multiple standard operating procedures (SOPs) for NEP assessment, including the measurements of particle size distribution, and are offering wide access to their 'state of the art' characterisation platforms, in addition to making SOPs publicly available. This joint perspective article would like to present the NCI-NCL and EUNCL multi-step approach of incremental complexity to measure particle size distribution and size stability of NEPs, consisting of a quick preliminary step to assess sample integrity and stability by low resolution techniques (pre-screening), followed by the combination of complementary high resolution sizing measurements performed both in simple buffers and in complex biological media. Test cases are presented to demonstrate: i) the need for employing at least one high-resolution sizing technique, ii) the importance of selecting the correct sizing techniques for the purpose, and iii) the robustness of utilizing orthogonal sizing techniques to study the physical properties of complex NEP samples.
Abstract 402: Cardiac-Specific Gene Expression after Systemic Administration to Adult Mice Using Pseudotyped AAV Vectors and the Cardiac Troponin-T Promoter: Comparison with Direct Injection
Authors: Konkal-Matt R Prasad, Yaqin Xu, Zequan Yang, Stuart S Berr, Brent A French
Journal: Circulation (2007)

Introduction: AAV serotypes 8 and 9 provide robust, early-onset, cardiac-specific gene expression after direct injection into the adult murine heart. We hypothesized that gene expression could also...
Cancer screening in the United States, 2016: A review of current American Cancer Society guidelines and current issues in cancer screening
Authors: Robert A. Smith, Kimberly Andrews, Durado Brooks, Carol E. DeSantis, Stacey A. Fedewa, Joannie Lortet‐Tieulent, Deana Manassaram‐Baptiste, Otis W. Brawley, Richard C. Wender
Journal: CA A Cancer Journal for Clinicians (2016)

Each year the American Cancer Society (ACS) publishes a summary of its guidelines for early cancer detection, data and trends in cancer screening rates, and select issues related to cancer screening. In this issue of the journal, we summarize current ACS cancer screening guidelines, including the update of the breast cancer screening guideline, discuss quality issues in colorectal cancer screening and new developments in lung cancer screening, and provide the latest data on utilization of cancer screening from the National Health Interview Survey.
New Hope in Prostate Cancer Precision Medicine? miRNA Replacement and Epigenetics
Authors: Anders Bjartell
Journal: Clinical Cancer Research (2019)

SPINK1+/ETS- prostate cancer is an aggressive disease with poor clinical outcome. New data suggest a novel treatment by upregulating the expression of miR-338-5p/-421 through epigenetic modulation or by miRNA replacement. This is a new and interesting concept that warrants further exploration in clinical trials.See related article by Bhatia et al., p. 2755.
Chronic myeloid leukemia: 2018 update on diagnosis, therapy and monitoring
Authors: Elias Jabbour, Hagop Kantarjian
Journal: American Journal of Hematology (2018)

Abstract Disease overview Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm with an incidence of 1‐2 cases per 100 000 adults. It accounts for approximately 15% of newly diagnosed cases of leukemia in adults. Diagnosis CML is characterized by a balanced genetic translocation, t(9;22)(q34;q11.2), involving a fusion of the Abelson gene ( ABL1 ) from chromosome 9q34 with the breakpoint cluster region ( BCR ) gene on chromosome 22q11.2. This rearrangement is known as the Philadelphia chromosome. The molecular consequence of this translocation is the generation of a BCR‐ABL1 fusion oncogene, which in turn translates into a BCR‐ABL1 oncoprotein. Frontline therapy : Four tyrosine kinase inhibitors (TKIs), imatinib, nilotinib, dasatinib, and bosutinib are approved by the United States Food and Drug Administration for first‐line treatment of patients with newly diagnosed CML in chronic phase (CML‐CP). Clinical trials with second generation TKIs reported significantly deeper and faster responses; this has not translated into improved long‐term survival, because of the availability of effective salvage therapies. Salvage therapy : For patients who fail frontline therapy, second‐line options include second and third generation TKIs. Second and third generation TKIs, although potent and selective, exhibit unique pharmacological profiles and response patterns relative to different patient and disease characteristics, such as patients’ comorbidities, disease stage, and BCR‐ABL1 mutational status. Patients who develop the T315I “gatekeeper” mutation display resistance to all currently available TKIs except ponatinib. Allogeneic stem cell transplantation remains an important therapeutic option for patients with CML‐CP who have failed at least 2 TKIs, and for all patients in CML advanced phases.
Update in Cystic Fibrosis 2007
Authors: Frank J. Accurso
Journal: American Journal of Respiratory and Critical Care Medicine (2008)

Cystic fibrosis (CF) is a chronic condition involving several organ systems that results in life-long morbidity and premature mortality (1).CF is caused by abnormalities in the gene that codes for the CF transmembrane conductance regulator (CFTR), a membrane glycoprotein found in secretory and absorptive epithelial surfaces.CFTR is a chloride channel, but also participates in regulating ion flux through interactions with other proteins.Lung disease in CF, believed to be caused by dehydration of airway surface liquid layers, is the major killer through a complex process involving impairment of mucociliary clearance, infection, inflammation, and structural injury.This update of studies reported during 2007 focuses on issues in clinical care and clinical research relating to CF, but with some attention to basic investigations through model systems.
Progress Toward Global Eradication of Dracunculiasis, January 2014–June 2015
Authors: Donald R. Hopkins, Ernesto Ruiz-Tiben, Mark L. Eberhard, Sharon L. Roy
Journal: MMWR Morbidity and Mortality Weekly Report (2015)

Dracunculiasis (Guinea worm disease) is caused by Dracunculus medinensis, a parasitic worm. Approximately 1 year after a person acquires infection from contaminated drinking water, the worm emerges through the skin, usually on the lower limb. Pain and secondary bacterial infection can cause temporary or permanent disability that disrupts work and schooling. The campaign to eradicate dracunculiasis worldwide began in 1980 at CDC. In 1986, the World Health Assembly called for dracunculiasis elimination, and the global Guinea Worm Eradication Program, led by the Carter Center and supported by the World Health Organization (WHO), United Nations Children's Fund (UNICEF), CDC, and other partners, began assisting ministries of health in countries where dracunculiasis was endemic. In 1986, an estimated 3.5 million cases occurred each year in 20 countries in Africa and Asia. Since then, although the goal of eradicating dracunculiasis has not been achieved, considerable progress has been made. Compared with the 1986 estimate, the annual number of reported cases in 2015 has been reduced by 99% and cases are confined to four endemic countries. This report updates published and unpublished surveillance data reported by ministries of health and describes progress toward dracunculiasis eradication from January 2014 through June 2015. During 2014, a total of 126 cases were reported from four countries (Chad [13 cases], Ethiopia [three], Mali [40], and South Sudan [70]), compared with 148 cases reported in 2013, from the same four countries. The overall 15% reduction in cases during 2013–2014 was less than that experienced in recent years, but the rate of decline increased again to 70% in the first 6 months of 2015 compared with the same period during 2014. Continued active surveillance with aggressive detection and appropriate management of cases are essential program components; however, epidemiologic challenges and civil unrest and insecurity pose potential barriers to eradication.
Abstract 11978: Impact of Heart Rate and Beta-blockers on Mortality in Patients With Heart Failure and Preserved Ejection Fraction
Authors: Takeshi KITAI, Justin L Grodin, W.H.Wilson Tang
Journal: Circulation (2016)

Background: Heart failure (HF) can be associated with a higher resting heart rate (HR) and an elevated HR is associated with adverse long-term events in patients with HF and reduced ejection fraction (EF). However, the mechanistic and causal role of HR in HF and preserved EF (HFpEF) is unclear. This study aimed to investigate the association between HR and clinical outcomes as well as an interaction with beta-blocker therapy in patients with HFpEF. Methods and Results: Among 3,445 HFpEF patients who were enrolled in the Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist (TOPCAT) Trial, we studied 2542 (74%) patients without atrial fibrillation or pacemaker implantaion. In our study cohort (mean age 67±9 years, 54% male and 32% diabetic), the median baseline HR was 68 bpm (interquartile range 60 to 74 bpm) and 1954 (77%) patients had beta-blocker medication at baseline although all the study patients had preserved EF (&gt;45%). There were 329 deaths during median follow-up of 3.5 years. Higher HR was associated with poor long-term survival (Quartile-4 versus 1: hazard ratio [95% confidence interval] 1.82 [1.28 to 2.36], P &lt; 0.001, Figure), while the prognosis was comparable between patients with and without beta-blocker medication (P=0.27). After adjusting for age, gender, hypertension, dyslipidemia, diabetes mellitus, serum creatinine level, coronary artery disease, stroke, beta-blocker and angiotensin converting enzyme inhibitor or angiotensin receptor antagonist, HR was still independently associated with mortality risk (2.09 [1.44 to 2.75], P &lt; 0.001). Beta-blocker medication had no significant interaction effects with HR. Conclusions: Higher HR was associated with poor survival in HFpEF patients with or without beta-blocker. Further studies are warranted to investigate whether HR modification improve outcomes in patients with HFpEF.
Avoidable deaths: falling in England; stalled in Scotland and Wales; and up in Northern Ireland
Authors: Nigel Hawkes
Journal: BMJ (2019)

Avoidable deaths in the UK fell significantly in 2017 compared with the previous year, but the improvement was largely because of trends in England, the only constituent part of the UK to show a statistically significant fall.1

Scotland, Wales, and Northern Ireland not only had much higher rates of avoidable deaths to begin with, but showed decreases that failed to reach statistical significance (Scotland and Wales) or an actual increase (Northern Ireland).

The new data, released by the Office for National Statistics (ONS), cannot be compared with NHS statistics of avoidable deaths in hospital, which are defined differently.

The ONS definition, first used in 2014, characterises deaths in three categories—amenable for …
<i>Notes from the Field:</i> Measles Outbreak in an Era of Stricter Immunization Requirements — California, March 2018
Authors: George Han, Neale Batra, Alvin Vallejo, Robert Schechter, Jennifer Zipprich, Kathleen Harriman
Journal: MMWR Morbidity and Mortality Weekly Report (2019)

On March 4, 2018, an unvaccinated adolescent boy, aged 15 years, who had recently returned from England and Wales, where measles outbreaks were occurring, was evaluated by a physician for fever, cough, coryza, conjunctivitis, Koplik spots, and rash. Measles virus nucleic acid was detected in an oropharyngeal swab and in urine tested at the Santa Clara County (California) Public Health Department.
Role of pro- and anti-apoptotic proteins in prostate cancer cells sensitive and resistant to histone deacetylase inhibitor induced cell death
Authors: Weisheng Xu, Lang Ngo, Perez Gisela, Milos Dokmanovic, Paul A. Marks
Journal: Cancer Research (2006)

4676  Histone deacetylase (HDAC) inhibitor (HDACi) is a promising class of anti-tumor drugs. The HDACi, suberoylanilide hydroxamic acid (SAHA), has shown anti-tumor activity at well-tolerated doses in patients with both hematological and solid tumors. The anti-tumor mechanism of HDACi is not completely understood. Previous studies have suggested that HDACi can induce both mitochondria-mediated apoptosis and non-caspase dependent transformed cell death. We have examined the effect of SAHA on the expression of proteins that regulate mitochondria apoptosis pathway in four human prostate cancer cell lines (LNCaP, DU145, LAPC4 and PC3), including the proapoptotic Bcl-2 family proteins Bax, Bak, Bok and BH3-only proteins, the antiapoptotic Bcl-2 family proteins Bcl-2, Bcl-XL, Bcl-w, Bfl-1/A1 and MCL-1, inhibitor of apoptotic proteins (IAPs), mitochondrial apoptotic proteins cytochrome C, AIF, EndoG and Smac/Diablo, caspase-3, -8 and -9. SAHA induced over 60% cell death in LNCaP and DU145 within 48 hrs of culture, but less than 40% in LAPC4. PC3 was resistant to SAHA induced cell death. There are significant differences in the expression of these proteins in the 4 cell lines, eg. DU145 lacks detectable Bax or Bim, LAPC4 has no detectable Bak or Bim. SAHA caused different patterns of changes in these pro- and anti-apoptotic proteins in the sensitive cell lines, LNCaP and DU145, than in the PC3 resistant cells. The present data suggest that HDACi induced transformed cell death of certain prostate cancer cells involves effects on apoptosis regulating proteins which determine the sensitivity or resistance to these agents. Further, these studies point to potential for synergistic effects of HDACi that modulates levels of pro- and anti-apoptotic proteins in combination with other agents to overcome the resistance of certain prostate cancer to therapy.