tbuckley/cabot-search huggingface dataset:
FDA Approval: Palbociclib for the Treatment of Postmenopausal Patients with Estrogen Receptor–Positive, HER2-Negative Metastatic Breast Cancer
Authors: Julia A. Beaver, Laleh Amiri-Kordestani, Rosane Charlab, Wei Chen, Todd Palmby, Amy Tilley, Jeanne Fourie Zirkelbach, Jingyu Yu, Qi Liu, Liang Zhao, Joyce Crich, Xiao Hong Chen, Minerva Hughes, Erik Bloomquist, Shenghui Tang, Rajeshwari Sridhara, Paul G. Kluetz, Geoffrey Kim, Amna Ibrahim, Richard Pazdur, Patricia Cortazar
Journal: Clinical Cancer Research (2015)

Abstract On February 3, 2015, the FDA granted accelerated approval to palbociclib (IBRANCE, Pfizer Inc.), an inhibitor of cyclin-dependent kinases 4 and 6 (CDK4 and CDK6), for use in combination with letrozole for the treatment of postmenopausal women with estrogen receptor (ER)–positive, HER2-negative advanced breast cancer as initial endocrine-based therapy for their metastatic disease. The approval is based on a randomized, multicenter, open-label phase I/II trial (PALOMA-1) in 165 patients randomized to palbociclib (125 mg orally daily for 21 consecutive days, followed by 7 days off treatment) plus letrozole (2.5 mg orally daily) or letrozole alone. The phase II portion of the trial was divided into two cohorts: cohort 1 enrolled 66 biomarker-unselected patients and cohort 2 enrolled 99 biomarker-positive patients. The major efficacy outcome measure was investigator-assessed progression-free survival (PFS). A large magnitude of improvement in PFS was observed in patients receiving palbociclib plus letrozole compared with patients receiving letrozole alone (HR, 0.488; 95% confidence interval, 0.319–0.748). Multiple sensitivity analyses were supportive of clinical benefit. The most common adverse reaction in patients receiving palbociclib plus letrozole was neutropenia. This article summarizes the FDA thought process and data supporting accelerated approval based on PALOMA-1 that may be contingent upon verification and description of clinical benefit in the ongoing and fully accrued confirmatory trial PALOMA-2. Clin Cancer Res; 21(21); 4760–6. ©2015 AACR.
BCG Immunotherapy for Superficial Bladder Cancer
Authors: Tim Lane
Journal: Journal of the Royal Society of Medicine (2001)

Mr Lockyer and Mr Gillatt (March 2001 JRSM, pp. 119-123) refer to the importance of fibronectin in promoting adhesion of BCG to bladder tumour cells. The basic mechanism is likely to be the same for all types of BCG, since all are ultimately derived from the original developed at the Pasteur Institute. According to some reports, response rates are adversely affected by medications that interfere with clotting1.

I am surprised that Lockyer and Gillatt ask their patients to retain intravesically administered BCG for only one hour. The manufacturers of Tice BCG (widely used in the UK as a 12.5 mg preparation) recommend two hours. Whilst some patients with irritative lower urinary tract symptoms will be unable to retain the preparation for so long, clinicians should bear in mind that the immunotherapeutic response depends at least partly on the time available for BCG to adhere to the bladder mucosa.
Effect of Periodontitis on Overt Nephropathy and End-Stage Renal Disease in Type 2 Diabetes
Authors: Frank N. Varon
Journal: Diabetes Care (2007)

The research study by Shultis et al. (1), which sought to establish a correlation between periodontal disease and overt nephropathy and end-stage renal disease in type 2 diabetes, raises several concerns.

First, while the analysis of the data attempted to preclude those with known risk factors, it fell short of accounting for many other common complications of diabetes and their direct and indirect impact on oral diseases. Diabetes risk factors and complications that might be associated with alveolar bone changes …
Brief Antecedent Ischemia Attenuates Platelet-Mediated Thrombosis in Damaged and Stenotic Canine Coronary Arteries
Authors: Katsuya Hata, Peter Whittaker, Robert A. Kloner, Karin Przyklenk
Journal: Circulation (1998)

Recent studies suggest that patients with angina before myocardial infarction exhibit improved recovery of coronary perfusion after thrombolysis by an as-yet-unknown mechanism. We therefore proposed that brief antecedent ischemia/reperfusion may, via release of adenosine, improve vessel patency in damaged and stenotic coronary arteries.Anesthetized dogs underwent coronary injury + stenosis, resulting in repeated cyclic variations in coronary blood flow (CFVs) caused by the formation/dislodgment of platelet-rich thrombi. Vessel patency was assessed for 3 hours after stenosis by quantification of the nadir of the CFVs, duration of total thrombotic occlusion (flow=0), and area of the flow-time profile (expressed as percent of baseline flow x 180 minutes). In protocol 1, dogs received 10 minutes of coronary occlusion + 10 minutes of reflow or a comparable 20-minute control period before injury + stenosis. The median nadir of the CFVs was higher (4.0 versus 0.3 mL/min), median zero flow duration per 30-minute time interval was shorter (0.4 versus 15.1 minutes), and mean percent flow-time area was greater (54+/-8% versus 28+/-9%) in dogs that received antecedent ischemia versus controls (P<.05). These benefits of antecedent ischemia/reperfusion were largely mimicked by a 10-minute intracoronary adenosine infusion (400 microg/min) in lieu of brief ischemia (protocol 2) and were abolished by administration of the adenosine A1/A2 receptor antagonist PD 115,199 (3 mg/kg i.v.) before brief antecedent coronary occlusion (protocol 3).Brief antecedent ischemia attenuates subsequent platelet-mediated thrombosis in damaged and stenotic canine coronary arteries, due, in large part, to an adenosine-mediated mechanism.
Effect of Early vs Late Tracheostomy Placement on Survival in Patients Receiving Mechanical Ventilation
Authors: Duncan Young, David A. Harrison, Brian H. Cuthbertson, Kathy Rowan, for the TracMan Collaborators
Journal: JAMA (2013)

<h3>Importance</h3>Tracheostomy is a widely used intervention in adult critical care units. There is little evidence to guide clinicians regarding the optimal timing for this procedure.<h3>Objective</h3>To test whether early vs late tracheostomy would be associated with lower mortality in adult patients requiring mechanical ventilation in critical care units.<h3>Design and Setting</h3>An open multicentered randomized clinical trial conducted between 2004 and 2011 involving 70 adult general and 2 cardiothoracic critical care units in 13 university and 59 nonuniversity hospitals in the United Kingdom.<h3>Participants</h3>Of 1032 eligible patients, 909 adult patients breathing with the aid of mechanical ventilation for less than 4 days and identified by the treating physician as likely to require at least 7 more days of mechanical ventilation.<h3>Interventions</h3>Patients were randomized 1:1 to early tracheostomy (within 4 days) or late tracheostomy (after 10 days if still indicated).<h3>Main Outcomes and Measures</h3>The primary outcome measure was 30-day mortality and the analysis was by intention to treat.<h3>Results</h3>Of the 455 patients assigned to early tracheostomy, 91.9% (95% CI, 89.0%-94.1%) received a tracheostomy and of 454 assigned to late tracheostomy, 44.9% (95% CI, 40.4%-49.5%) received a tracheostomy. All-cause mortality 30 days after randomization was 30.8% (95% CI, 26.7%-35.2%) in the early and 31.5% (95% CI, 27.3%-35.9%) in the late group (absolute risk reduction for early vs late, 0.7%; 95% CI, −5.4% to 6.7%). Two-year mortality was 51.0% (95% CI, 46.4%-55.6%) in the early and 53.7% (95% CI, 49.1%-58.3%) in the late group (P = .74). Median critical care unit length of stay in survivors was 13.0 days in the early and 13.1 days in the late group (P = .74). Tracheostomy-related complications were reported for 6.3% (95% CI, 4.6%-8.5%) of patients (5.5% in the early group, 7.8% in the late group).<h3>Conclusions and Relevance</h3>For patients breathing with the aid of mechanical ventilation treated in adult critical care units in the United Kingdom, tracheostomy within 4 days of critical care admission was not associated with an improvement in 30-day mortality or other important secondary outcomes. The ability of clinicians to predict which patients required extended ventilatory support was limited.<h3>Trial Registration</h3>isrctn.org Identifier: ISRCTN28588190
Input of DNA Microarrays to Identify Novel Mechanisms in Multiple Myeloma Biology and Therapeutic Applications
Authors: Karène Mahtouk, Dirk Hose, John De Vos, Jérôme Moreaux, Michel Jourdan, Jean François Rossi, Thierry Rème, Harmut Goldschmidt, Bernard Klein
Journal: Clinical Cancer Research (2007)

Multiple myeloma is a B-cell neoplasia characterized by the proliferation of a clone of malignant plasma cells in the bone marrow. We review here the input of gene expression profiling of myeloma cells and of their tumor microenvironment to develop new tumor classifiers, to better understand the biology of myeloma cells, to identify some mechanisms of drug sensitivity and resistance, to identify new myeloma growth factors, and to depict the complex interactions between tumor cells and their microenvironment. We discuss how these findings may improve the clinical outcome of this still incurable disease.
Will the olympics survive?.
Authors: T. Khosla
Journal: British Journal of Sports Medicine (1977)

The United States of America dominated 58 events in athletics, field and swimming, which between them accounted for 35 per cent of all events in the Munich Olympiad. 1972; these events favour taller individuals. But, in 25 per cent of other events (1) cycling, (2) fencing, (3) gymnastics, (4) judo, (5) weightlifting and (6) Graeco Roman wrestling the U.S.A. did not win a single medal. The failure of the U.S.A. to maintain her lead in Munich was largely due to weaknesses in these other events in many of which the potential medallists can be derived from the lower half of the height distribution (events 3 to 6). These weaknesses are Russia's strength and they continued to remain unstrengthened at Montreal. Also, the domination held by the U.S.A. in swimming was seriously challenged by East Germany. The present trends indicate that the U.S.A.'s ranking is likely to slip further to the third position in Moscow 1980. Factors inhibiting the survival of the Olympics are pointed.
Salivary gland progenitor cells induced by duct ligation differentiate into hepatic and pancreatic lineages
Authors: Kenji Okumura, Kimitoshi Nakamura, Yuichiro Hisatomi, Koji Nagano, Yasuhiko Tanaka, Kunihiko Terada, Toshihiro Sugiyama, Kazuhiro Umeyama, Kozo Matsumoto, Tetsuro Yamamoto, Fumio Endo
Journal: Hepatology (2003)

Tissue damage can be assessed based on regenerative responses, including progenitor cell proliferation. In the salivary gland, tissue damage induced by ligation of main ducts leads to the disappearance of acinar cells and to marked proliferation of ductal cells. Reopening of the ducts leads to repopulation of acinar cells within 1 to 2 weeks, which suggests activation of tissue progenitor cells in a damaged state. Because submandibular glands derive from the endoderm and ectoderm, we investigated the possibility of the presence of endodermal progenitor cells. We cultured cells obtained from the ligated salivary gland and identified colonies of epithelium-like cells. We singled out and purified the cells by limited dilution, and one of the cells designated SGP-1 was used for further experiments. The SGP-1 expresses both alpha6beta1 integrin and cytoplasmic laminin. The hematopoietic stem cell marker CD34 and hepatic oval cell markers such as albumin, alpha-fetoprotein (AFP), and cytokeratin 19 are all negative. However, when SGP-1 cells were transplanted into the liver via the portal vein, these cells were integrated into hepatic trabecula and produced albumin. When SGP-1 cells formed clusters on type I collagen-coated dishes, they differentiated into endodermal lineage and 2 major types of clusters appeared: one contained cells positive for AFP and/or albumin (hepatic cluster) and the other positive for glucagon and/or insulin (pancreatic cluster). On laminin-coated dishes, SGP-1 selectively differentiated into hepatic-type cells. In conclusion, the multipotent progenitor cells isolated from the rat salivary gland have characteristics of tissue stem cells and can differentiate into cells of endodermal lineages.
Application of the whole-transcriptome shotgun sequencing approach to the study of Philadelphia-positive acute lymphoblastic leukemia
Authors: I Iacobucci, A Ferrarini, M Sazzini, E Giacomelli, A Lonetti, L Xumerle, A Ferrari, C Papayannidis, G Malerba, D Luiselli, A Boattini, P Garagnani, A Vitale, S Soverini, F Pane, M Baccarani, M Delledonne, G Martinelli
Journal: Blood Cancer Journal (2012)

Although the pathogenesis of BCR-ABL1-positive acute lymphoblastic leukemia (ALL) is mainly related to the expression of the BCR-ABL1 fusion transcript, additional cooperating genetic lesions are supposed to be involved in its development and progression. Therefore, in an attempt to investigate the complex landscape of mutations, changes in expression profiles and alternative splicing (AS) events that can be observed in such disease, the leukemia transcriptome of a BCR-ABL1-positive ALL patient at diagnosis and at relapse was sequenced using a whole-transcriptome shotgun sequencing (RNA-Seq) approach. A total of 13.9 and 15.8 million sequence reads was generated from de novo and relapsed samples, respectively, and aligned to the human genome reference sequence. This led to the identification of five validated missense mutations in genes involved in metabolic processes (DPEP1, TMEM46), transport (MVP), cell cycle regulation (ABL1) and catalytic activity (CTSZ), two of which resulted in acquired relapse variants. In all, 6390 and 4671 putative AS events were also detected, as well as expression levels for 18 315 and 18 795 genes, 28% of which were differentially expressed in the two disease phases. These data demonstrate that RNA-Seq is a suitable approach for identifying a wide spectrum of genetic alterations potentially involved in ALL.
Predeployment Personality Traits and Exposure to Trauma as Predictors of Posttraumatic Stress Symptoms: A Prospective Study of Former Peacekeepers
Authors: Inge Bramsen, Anja J.E. Dirkzwager, Henk M. van der Ploeg
Journal: American Journal of Psychiatry (2000)

The authors' goal was to study the contribution of predeployment personality traits and exposure to traumatic events during deployment to the development of symptoms of posttraumatic stress disorder (PTSD) in individuals involved in military peacekeeping activities.Five hundred seventy-two male veterans who participated in the United Nations Protection Force mission in the former Yugoslavia completed a short form of the Dutch MMPI before deployment. Following deployment, they participated in a survey of all Dutch military veterans who had been deployed in the years 1990-1995 and completed the Self-Rating Inventory for PTSD.Exposure to traumatic events during deployment had the highest unique contribution to the prediction of PTSD symptom severity, followed by the personality traits of negativism and psychopathology, followed by age.Both pretrauma vulnerabilities and exposure to traumatic events were found to be important factors in the etiology of posttraumatic stress symptoms. The current study replicates in a non-American sample of peacekeepers findings obtained among American Vietnam veterans. Particularly, there is accumulating evidence for an etiological role of the personality trait of psychoneuroticism in the development of posttraumatic stress symptoms.
The pro-metastasis tyrosine phosphatase, PRL-3 (PTP4A3), is a novel mediator of oncogenic function of BCR-ABL in human chronic myeloid leukemia
Authors: Jianbiao Zhou, Lip-Lee Cheong, Shaw-Cheng Liu, Phyllis SY Chong, Sylvia Mahara, Chonglei Bi, Kelly OK Ong, Qi Zeng, Wee Joo Chng
Journal: Molecular Cancer (2012)

Abstract Background Resistance to tyrosine kinase inhibitors (TKIs) remains a challenge in management of patients with chronic myeloid leukemia (CML). A better understanding of the BCR-ABL signalling network may lead to better therapy. Findings Here we report the discovery of a novel downstream target of BCR-ABL signalling, PRL-3 ( PTP4A3 ), an oncogenic tyrosine phosphatase. Analysis of CML cancer cell lines and CML patient samples reveals the upregulation of PRL-3. Inhibition of BCR-ABL signalling either by Imatinib or by RNAi silencing BCR-ABL reduces PRL-3 and increases cleavage of PARP. In contrast, the amount of PRL-3 protein remains constant or even increased in response to Imatinib treatment in drug resistant cells expressing P210 T315I. Finally, analysis with specific shRNA shows PRL-3 involvement in the proliferation and self-renewal of CML cells. Conclusions These data support a role for PRL-3 in BCR-ABL signalling and CML biology and may be a potential therapeutic target downstream of BCR-ABL in TKI resistant mutant cells.
Hepatocyte free cholesterol lipotoxicity results from JNK1-mediated mitochondrial injury and is HMGB1 and TLR4-dependent
Authors: Lay T. Gan, Derrick M. Van Rooyen, Mark E. Koina, Robert S. McCuskey, Narcissus C. Teoh, Geoffrey C. Farrell
Journal: Journal of Hepatology (2014)
“Sundowning” and Other Temporally Associated Agitation States in Dementia Patients
Authors: David Bachman, Peter Rabins
Journal: Annual Review of Medicine (2005)

The behavioral and neuropsychiatric symptoms of dementia and Alzheimer's disease have become an increasingly important focus of clinical research. These symptoms also pose a tremendous challenge to families and caregivers. The late afternoon/evening exacerbation of behavioral symptoms in dementia has been recognized by clinicians for >60 years. Researchers have utilized a variety of increasingly sophisticated tools to examine the circadian, hormonal, physiological, and epidemiological correlations with sundowning behavior. Although treatment remains largely empirical, an improved understanding of the complex relationships that drive sundowning behavior should lead to more effective therapies in the future.
GOTax: investigating biological processes and biochemical activities along the taxonomic tree
Authors: Andreas Schlicker, Jörg Rahnenführer, Mario Albrecht, Thomas Lengauer, Francisco S Domingues
Journal: Genome biology (2007)

We describe GOTax, a comparative genomics platform that integrates protein annotation with protein family classification and taxonomy. User-defined sets of proteins, protein families, annotation terms or taxonomic groups can be selected and compared, allowing for the analysis of distribution of biological processes and molecular activities over different taxonomic groups. In particular, a measure of functional similarity is available for comparing proteins and protein families, establishing functional relationships independent of evolution.
Transcellular Transport of Vitamin B12 in LLC-PK1 Renal Proximal Tubule Cells
Authors: RIKKE NIELSEN, BOE SANDAHL SØRENSEN, HENRIK BIRN, ERIK ILSØ CHRISTENSEN, EBBA NEXØ
Journal: Journal of the American Society of Nephrology (2001)

The transcobalamin-vitamin B(12) complex is responsible for the transport of B(12) from plasma and into the tissues. The complex is filtered in the renal glomeruli and is a high-affinity ligand for the endocytic receptor megalin expressed in the proximal tubule. This study shows by the use of the proximal tubule LLC-PK1 cell line that transcobalamin-B(12) is internalized by megalin-mediated endocytosis. After endocytosis and accumulation in endosomes, transcobalamin is degraded and the B(12) molecule is released from the cells in complex with newly synthesized proteins. The release is polarized in such a way that vitamin in the apical medium is bound to proteins with the size of haptocorrin, whereas the B(12) released at the basolateral side is complexed to two different proteins with the sizes of transcobalamin and haptocorrin. Furthermore, transcobalamin mRNA was identified by reverse transcription-PCR in LLC-PK1 cells and human and pig kidney, whereas haptocorrin mRNA was identified only in LLC-PK1 cells. The results strongly suggest that megalin located in the proximal tubule cells is important for receptor-mediated tubular reabsorption followed by transcellular transport and release of vitamin B(12) complexed to newly synthesized carrier proteins. This mechanism is likely to play a significant role in the maintenance of B(12) homeostasis by returning filtered B(12) to the pool of circulating vitamin.
Mediators of neutrophil recruitment in human abdominal aortic aneurysms
Authors: Xavier Houard, Ziad Touat, Véronique Ollivier, Liliane Louedec, Monique Philippe, Uriel Sebbag, Olivier Meilhac, Patrick Rossignol, Jean-Baptiste Michel
Journal: Cardiovascular Research (2009)

Neutrophils/platelet interactions are involved in abdominal aortic aneurysm (AAA). The intraluminal thrombus (ILT) is a human model of platelet/neutrophil interactions. The present study focused on mediators involved in neutrophil recruitment in AAA.Conditioned media from luminal, intermediate, and abluminal layers of 29 human ILTs were analysed for neutrophil markers [elastase/alpha1-antitrypsin and MMP9/NGAL complexes, myeloperoxidase (MPO), and alpha-defensin peptides], RANTES, platelet factor 4 (PF4), and interleukin-8 (IL-8). Their time-dependent release into serum from clots generated in vitro and their plasma concentrations in AAA patients and controls were determined. Immunohistochemistry for neutrophils, platelets, IL-8, PF4, and RANTES on AAA sections was performed; and molecules involved in ILT neutrophil chemotactic function were analysed in vitro. Neutrophils and platelets colocalized in the luminal layer of the thrombus. Consistently, neutrophil markers and platelet-derived RANTES and PF4 were released predominantly by the luminal thrombus pole, where their concentrations were significantly correlated. The luminal ILT layer was also the main source of IL-8, whose immunostaining colocalized with neutrophils. All were also released time dependently from clots and were increased in plasma of AAA patients. Luminal ILT layers displayed potent neutrophil chemotactic activity in vitro, which was inhibited by RANTES- and IL-8-blocking antibodies as well as by reparixin, an antagonist of the IL-8 receptors CXCR1 and CXCR2.Taken together, these results suggest that platelet-derived RANTES and neutrophil-derived IL-8 are involved in attracting neutrophils to the luminal layer of AAA ILT.
Vasoactive side effects of intravenous immunoglobulin preparations in a rat model and their treatment with recombinant platelet-activating factor acetylhydrolase
Authors: Wim K. Bleeker, Jessica L. Teeling, Arthur J. Verhoeven, Gemma M. M. Rigter, Jacques Agterberg, Anton T. J. Tool, Anky H. L. Koenderman, Taco W. Kuijpers, C. Erik Hack
Journal: Blood (2000)