tbuckley/cabot-search huggingface dataset:
Approaches to Phase 1 Clinical Trial Design Focused on Safety, Efficiency, and Selected Patient Populations: A Report from the Clinical Trial Design Task Force of the National Cancer Institute Investigational Drug Steering Committee
Authors: S. Percy Ivy, Lillian L. Siu, Elizabeth Garrett-Mayer, Larry Rubinstein
Journal: Clinical Cancer Research (2010)

The goals and objectives of phase 1 clinical trials are changing to include further evaluation of endpoints such as molecular targeted effects, in addition to dose-toxicity profile of the investigational agent. Because of these changes in focus, the National Cancer Institute and Investigational Drug Steering Committee's Task Force on Clinical Trial Design met to evaluate the most efficient ways to design and implement early clinical trials with novel therapeutics. Clinical approaches discussed included the conventional 3 + 3 cohort expansion phase 1 design, multi-institutional phase 1 studies, accelerated titration designs, continual reassessment methods, the study of specific target patient populations, and phase 0 studies. Each of these approaches uniquely contributes to some aspect of the phase 1 study, with all focused on dose and schedule determination, patient safety, and limited patient exposure to ineffective doses of investigational agent. The benefit of labor-intensive generation of preliminary biomarker evidence of target inhibition, as well as the value of molecular profiling of the study population, is considered. New drug development is expensive and the failure rate remains high. By identifying patient populations expected to respond to the study agent and tailoring the treatment with a novel drug, investigators will be one step closer to personalizing cancer treatment. The "fail early and fast" approach is acceptable if the appropriate patient population is evaluated in the phase 1 trial. The approaches outlined in this overview address the merits, advantages, disadvantages, and obstacles encountered during first in human studies.
Familiality of Polarity at Illness Onset in Bipolar Affective Disorder
Authors: Layla Kassem, Victor Lopez, Don Hedeker, Jo Steele, Peter Zandi, NIMH Genetics Initiative Bipolar Disorder Consortium, Francis J. McMahon
Journal: American Journal of Psychiatry (2006)

Objective: Bipolar affective disorder is clinically heterogeneous, and clinical features that run in families may help define more homogeneous phenotypes. The authors sought to establish whether polarity at illness onset, which is related to severity and course, is a familial feature of bipolar affective disorder. Method: The authors studied 971 subjects from 507 families ascertained through sibling pairs with bipolar I or schizoaffective bipolar disorder. Self-reported ages at onset of mania and major depression were used to code polarity at onset as manic, major depressive, or both (mania and major depression in the same onset year). Familial clustering was estimated by using mixed-effects regression analysis, and the relationship between polarity at onset and several other clinical features was assessed. As a preliminary test of genetic validity, the authors assessed the impact of polarity at onset on genetic linkage findings previously detected in this sample. Results: Polarity at onset was significantly familial in this sample. This largely reflected relative pairs concordant for mania at onset, which occurred significantly more frequently than would be expected by chance. Mania at onset substantially increased the genetic linkage signal on chromosome 16p (maximum lod score=4.5) but had no effect on linkage to chromosome 6q. Mania at onset occurred at a later age on average than major depression at onset and was less likely to be complicated by panic attacks or alcoholism. Conclusions: Polarity at illness onset is a familial feature of bipolar affective disorder and is associated with important clinical indicators, which may help define more homogeneous subtypes of bipolar affective disorder.
Vascular Actions of Estrogens: Functional Implications
Authors: Virginia M. Miller, Sue P. Duckles
Journal: Pharmacological Reviews (2008)

The impact of estrogen exposure in preventing or treating cardiovascular disease is controversial. But it is clear that estrogen has important effects on vascular physiology and pathophysiology, with potential therapeutic implications. Therefore, the goal of this review is to summarize, using an integrated approach, current knowledge of the vascular effects of estrogen, both in humans and in experimental animals. Aspects of estrogen synthesis and receptors, as well as general mechanisms of estrogenic action are reviewed with an emphasis on issues particularly relevant to the vascular system. Recent understanding of the impact of estrogen on mitochondrial function suggests that the longer lifespan of women compared with men may depend in part on the ability of estrogen to decrease production of reactive oxygen species in mitochondria. Mechanisms by which estrogen increases endothelial vasodilator function, promotes angiogenesis, and modulates autonomic function are summarized. Key aspects of the relevant pathophysiology of inflammation, atherosclerosis, stroke, migraine, and thrombosis are reviewed concerning current knowledge of estrogenic effects. A number of emerging concepts are addressed throughout. These include the importance of estrogenic formulation and route of administration and the impact of genetic polymorphisms, either in estrogen receptors or in enzymes responsible for estrogen metabolism, on responsiveness to hormone treatment. The importance of local metabolism of estrogenic precursors and the impact of timing for initiation of treatment and its duration are also considered. Although consensus opinions are emphasized, controversial views are presented to stimulate future research.
CURRENT KNOWLEDGE AND ATTITUDE TOWARD CONCUSSION AMONG JAPANESE JUNIOR HIGH SCHOOL TEACHERS AND COACHES, AND EFFECTIVENESS OF EDUCATIONAL INTERVENTION
Authors: M Otomo, S Torii, T Fukubayashi
Journal: British Journal of Sports Medicine (2014)

Background Recent studies have emphasized the concussion education for all individuals who are involved in school sanctioned athletic activities. Objective (1) to investigate current knowledge and awareness of concussion among junior high school teachers and coaches; and (2) to assess the effectiveness of educational intervention on concussion for junior high school teachers and coaches. Design Questionnaire study (retrospective data). “Heads Up: Concussion in Youth Sports” and “Pocket SCAT 2” were translated to Japanese by the researcher and used in the educational intervention. Setting This study setting was youth sports. Participants 122 junior high school teachers and coaches. Interventions We did a survey immediately before and after lecture on the same day. Main outcome measurements The questionnaire showed 34 percent of the participants reported the concussions of the students in their activities. Also, compared with PE and nursing teachers, other teachers had less awareness of the concussions. Results Participants might have misconceptions on the concussions; thus there were potentially more participants whose students experienced the concussions. At the lecture, there were high satisfaction levels with items that the participants wanted to know in the lecture. It was necessary to consider the time when to start the lecture and length of the lecture. Furthermore, the questionnaire taken after the lecture showed lack of the knowledge on the concussion; thus the lecture could have great effectiveness to the individuals related to student-athletes' activity. Conclusion All participants might have misconceptions on the concussions. But their knowledge and attitude toward concussion was heightened by our lecture. In future research, it is important to increase subjects of the questionnaire and to identify effectiveness of long-term lectures. Furthermore, subjects of future research should involve student-athletes and their parents in order for all individual who related to athletic activities to obtain proper knowledge and awareness of the concussion.
Evaluation of the Patient with Recurrent Bacterial Infections
Authors: Steven M. Holland, John I. Gallin
Journal: Annual Review of Medicine (1998)

Recurrent bacterial infection is a complaint encountered regularly in the course of both adult and pediatric care. Defects of neutrophils and monocytes are most commonly associated with recurrent infection, but abnormalities of immunoglobulins and complement must be considered. Defensins, small antibacterial peptides, have been implicated recently in some of the infectious diathesis of cystic fibrosis. A thorough history and physical examination focused on severity, sequelae, and microbiology of infections can usually determine whether a patient needs further evaluation. The diseases and syndromes most frequently associated with recurrent infection are presented, along with discriminating clinical, pathologic, and microbiologic features.
Transcriptional activation of endoglin and transforming growth factor-β signaling components by cooperative interaction between Sp1 and KLF6: their potential role in the response to vascular injury
Authors: Luisa M. Botella, Tilman Sánchez-Elsner, Francisco Sanz-Rodriguez, Soichi Kojima, Jun Shimada, Mercedes Guerrero-Esteo, Michael P. Cooreman, Vlad Ratziu, Carmen Langa, Calvin P. H. Vary, Jose R. Ramı́rez, Scott Friedman, Carmelo Bernabéu
Journal: Blood (2002)
Immunosurveillance of alveolar echinococcosis by specific humoral and cellular immune tests: long-term analysis of the Swiss chemotherapy trial (1976–2001)
Authors: Rudolf W. Ammann, Elisabeth C. Renner, Bruno Gottstein, Felix Grimm, Johannes Eckert, Eberhard L. Renner, None Swiss Echinococcosis Study Group
Journal: Journal of Hepatology (2004)
Mechanisms of ATP release and signalling in the blood vessel wall
Authors: A. W. Lohman, M. Billaud, B. E. Isakson
Journal: Cardiovascular Research (2012)

The nucleotide adenosine 5′-triphosphate (ATP) has classically been considered the cell's primary energy currency. Importantly, a novel role for ATP as an extracellular autocrine and/or paracrine signalling molecule has evolved over the past century and extensive work has been conducted to characterize the ATP-sensitive purinergic receptors expressed on almost all cell types in the body. Extracellular ATP elicits potent effects on vascular cells to regulate blood vessel tone but can also be involved in vascular pathologies such as atherosclerosis. While the effects of purinergic signalling in the vasculature have been well documented, the mechanism(s) mediating the regulated release of ATP from cells in the blood vessel wall and circulation are now a key target of investigation. The aim of this review is to examine the current proposed mechanisms of ATP release from vascular cells, with a special emphasis on the transporters and channels involved in ATP release from vascular smooth muscle cells, endothelial cells, circulating red blood cells, and perivascular sympathetic nerves, including vesicular exocytosis, plasma membrane F1/F0-ATP synthase, ATP-binding cassette (ABC) transporters, connexin hemichannels, and pannexin channels.
GLIOMA SPECIFIC PEPTIDES: A PLATFORM FOR MOLECULAR IMAGING AND THERAPEUTIC TARGETING
Authors: D. L. Senger, J. J. Rahn, X. Hao, X. W. X. Lun, J. G. Cairncross, S. Weiss, C. Venugopal, N. M. McFarlane, S. K. Singh, S. M. Robbins, D. L. Senger
Journal: Neuro-Oncology (2014)

BACKGROUND: Despite intense investigation, the ability to treat high-grade glioma (HGG) has remained dismal, in part due to molecular and phenotypic heterogeneity. The cancer stem cell, a cell believed to be the clonogenic core of tumors including human glioma, has been a major focus for the development of new therapies but emerging evidence has exposed the dynamic and heterogenous characteristics of this stem-like population that facilitates evasion from current therapies. METHODS: To capture and target the complexity and heterogeneity of glioma, we employed a combinatorial phage-display biopanning strategy to isolate peptides that specifically bind and home in vivo to key disease reservoirs within glioma; namely the invasive and stem-like populations of glioma cells (GSC). Synthetic peptides, individually or in combination, were conjugated to gadolinium or a chemotherapeutic agent and administered to animals bearing orthotopic tumors established from human glioma-like-stem cells. RESULTS: Using this approach we identified a panel of peptides with the ability to detect the heterogeneity of patient gliomas in vivo successfully imaging a range of tumors including diffuse infiltrating tumours that are otherwise invisible by conventional imaging technologies. In addition, we identified peptides with multifunctional capabilities including peptides that functionally block glioma invasion, define a subpopulation of GSCs, and target chemotherapeutic agents in vivo. CONCLUSIONS: These data highlight the utility of the identified peptides as platforms for the precise and sensitive imaging of these heterogenous tumors and for the development of molecularly targeted therapeutics. SECONDARY CATEGORY: Tumor Biology.
A Note on the Tendon Reflexes in Uraemia
Authors: W. M. Stevens
Journal: BMJ (1904)

IMEDICAL J'OLRNAL numerous in the cervical region, scanty in the dorsal and lumbar regions (see Figs.I and 2).A very few scattered de- generated fibres were seen in Burdach'& columns.Degenerated fibres (indicated by black dots) were also seen in the intrame- dullary course of theposteriorner4e roots, between the posterior surface of the cord and the posterior born of grey matter, and to the median side of the posterior horn (see Fig. 3).This degeneration of the intramedullary portion of the posterior root fibres was best seen in the lumbar and cervical regions.The posterior roots, external to the spinal cord, generally presented no degenerated fibres in sections stained according to Marchi's method.In, a few sections, however, degenerated fibres (stained black) were seen in the posterior roots for a very short distance, just outside the pia mater; but this degeneration ended very abruptly close to the cord.'T'he spinal changes here described are probably secondary, and due to the altered blood condition in diabetes mellitus.At the region where the posterior root fibres pass through the pia mater, on the posterior surface of the cord, they lose their myelin sheaths for a very short distance; and it appears probable that at this point the fibres are specially liable to suffer from the action of toxic substances in the blood.3The changes in the intramedullary portion of the posterior root fibres could be traced to this point in the case here recorded.Similar changes in the intramedullary fibres of the posterior root may be detected in tabes.The knee-jerks and tendo-Achillis reflexes were absent in the case just recorded.These signs have been attributed to changes in the peripheral nerves, and no doubt this is the explanation in many cases.But I have found the peripheral nerves (in diabetes) of normal appearance on microscopical examination, when the knee-jerks have been absent.It is possible that the loss of knee-jerks and tendo-Achillis re- flexes may sometimes be due to changes in the intra- medullary fibres of the posterior nerve roots.In the case here recorded there were no symptoms of peripheral neuritis beyond the loss of the reflexes just mentioned, but the peripheral nerves were not examined pathologically.The changes in the intramedullary fibres of the posterior roots were, however, sufficient to account for the absence of the re- flexes.REFERENCES.
Discordance in ERα, PR and HER2 receptor status across different distant breast cancer metastases within the same patient
Authors: L.D.C. Hoefnagel, P. van der Groep, M.J. van de Vijver, J.E. Boers, P. Wesseling, J. Wesseling, E. van der Wall, P.J. van Diest
Journal: Annals of Oncology (2013)
Injuries in amateur horse racing (point to point racing) in Great Britain and Ireland during 1993–2006
Authors: G. Balendra, M. Turner, P. McCrory, W. Halley
Journal: British Journal of Sports Medicine (2006)

To provide a breakdown of injury incidence from amateur jump racing (also known as point to point racing) in Great Britain and Ireland during 1993-2006 and to compare the injury epidemiology with professional horse racing in Great Britain, Ireland and France.Retrospective review.Great Britain and Ireland.Amateur jockeys.Injury rates.Injury data suggest that point to point racing is more dangerous from an injury point of view than professional jump racing, which has previously been shown to be more dangerous than flat racing. Amateur jockeys have more falls than their professional counterparts, and this in turn puts them at greater risk of sustaining more serious injuries.Amateur (point to point) jockeys represent a sporting population that previously has been little studied. They represent a group at high risk of injury, and hence formal injury surveillance tracking and counter measures for injury prevention are recommended.
Platelet-derived S100 family member myeloid-related protein-14 regulates thrombosis
Authors: Yunmei Wang, Chao Fang, Huiyun Gao, Matthew L. Bilodeau, Zijie Zhang, Kevin Croce, Shijian Liu, Toshifumi Morooka, Masashi Sakuma, Kohsuke Nakajima, Shuichi Yoneda, Can Shi, David Zidar, Patrick Andre, Gillian Stephens, Roy L. Silverstein, Nancy Hogg, Alvin H. Schmaier, Daniel I. Simon
Journal: Journal of Clinical Investigation (2014)

Expression of the gene encoding the S100 calcium-modulated protein family member MRP-14 (also known as S100A9) is elevated in platelets from patients presenting with acute myocardial infarction (MI) compared with those from patients with stable coronary artery disease; however, a causal role for MRP-14 in acute coronary syndromes has not been established. Here, using multiple models of vascular injury, we found that time to arterial thrombotic occlusion was markedly prolonged in Mrp14⁻/⁻ mice. We observed that MRP-14 and MRP-8/MRP-14 heterodimers (S100A8/A9) are expressed in and secreted by platelets from WT mice and that thrombus formation was reduced in whole blood from Mrp14⁻/⁻ mice. Infusion of WT platelets, purified MRP-14, or purified MRP-8/MRP-14 heterodimers into Mrp14⁻/⁻ mice decreased the time to carotid artery occlusion after injury, indicating that platelet-derived MRP-14 directly regulates thrombosis. In contrast, infusion of purified MRP-14 into mice deficient for both MRP-14 and CD36 failed to reduce carotid occlusion times, indicating that CD36 is required for MRP-14-dependent thrombosis. Our data identify a molecular pathway of thrombosis that involves platelet MRP-14 and CD36 and suggest that targeting MRP-14 has potential for treating atherothrombotic disorders, including MI and stroke.
Chlorambucil plus ofatumumab versus chlorambucil alone in previously untreated patients with chronic lymphocytic leukaemia (COMPLEMENT 1): a randomised, multicentre, open-label phase 3 trial
Authors: Peter Hillmen, Tadeusz Robak, Ann Janssens, K Govind Babu, Janusz Kloczko, Sebastian Grosicki, Michael Doubek, Panagiotis Panagiotidis, Eva Kimby, Anna Schuh, Andrew R Pettitt, Thomas Boyd, Marco Montillo, Ira V Gupta, Oliver Wright, Iestyn Dixon, Jodi L Carey, Chai-Ni Chang, Steen Lisby, Astrid McKeown, Fritz Offner
Journal: The Lancet (2015)
Radiological findings in symphyseal and adductor-related groin pain in athletes: a critical review of the literature
Authors: Sonia Branci, Kristian Thorborg, Michael Bachmann Nielsen, Per Hölmich
Journal: British Journal of Sports Medicine (2013)

Long-standing symphyseal and adductor-related groin pain is a common problem for many athletes, and requires a multidisciplinary approach. Radiological evaluation of symptomatic individuals is a cornerstone in the diagnostic workup, and should be based on precise and reliable diagnostic terms and imaging techniques. The authors performed a review of the existing original evidence-based radiological literature involving radiography, ultrasonography and MRI in athletes with long-standing symphyseal and adductor-related groin pain. Our search yielded 17 original articles, of which 12 were dedicated to MRI, four to radiography and one to ultrasonography. Four main radiological findings seem to consistently appear: degenerative changes at the pubic symphyseal joint, pathology at the adductor muscle insertions, pubic bone marrow oedema and the secondary cleft sign. However, the existing diagnostic terminology is confusing, and the interpretation of radiological findings would benefit from imaging studies using a more systematic approach.
Lamina-Specific Deficits in Parvalbumin-Immunoreactive Varicosities in the Prefrontal Cortex of Subjects With Schizophrenia: Evidence for Fewer Projections From the Thalamus
Authors: David A. Lewis, Dianne A. Cruz, Darlene S. Melchitzky, Joseph N. Pierri
Journal: American Journal of Psychiatry (2001)

Neuronal number in the mediodorsal thalamic nucleus, the principal source of thalamic projections to the prefrontal cortex, has been reported to be lower in subjects with schizophrenia. The authors tested the hypothesis that schizophrenia is associated with a selective deficit in a marker of thalamic axon terminals in the middle layers of the prefrontal cortex, the primary zone of termination of thalamic axons.The densities of parvalbumin-immunoreactive varicosities (putative axon terminals) were determined in the superficial and middle layers of prefrontal cortex area 9 from 20 matched pairs of subjects with schizophrenia and normal comparison subjects. In order to determine the specificity of these observations, similar studies were conducted in subjects with major depressive disorder and in monkeys after 9-12 months of haloperidol treatment.The relative densities of parvalbumin-immunoreactive varicosities did not differ between schizophrenic and comparison subjects in the superficial layers. However, in the middle layers, mean varicosity density was significantly lower (24% difference) in the subjects with schizophrenia. In contrast, neither subjects with major depressive disorder nor haloperidol-treated monkeys exhibited a middle-layer density of parvalbumin-immunoreactive varicosities that was lower than that of their matched comparison groups.Although not definitive, these findings are consistent with the hypothesis of fewer projections from the mediodorsal thalamic nucleus to the prefrontal cortex in schizophrenic subjects and thus converge with other lines of evidence demonstrating an abnormality in thalamo-prefrontal cortical circuitry in persons with schizophrenia.
Association Between Nucleoside Analogues and Risk of Hepatitis B Virus–Related Hepatocellular Carcinoma Recurrence Following Liver Resection
Authors: Chun-Ying Wu, Yi-Ju Chen, Hsiu J. Ho, Yao-Chun Hsu, Ken N. Kuo, Ming-Shiang Wu, Jaw-Town Lin
Journal: JAMA (2012)

THE STANdard curative treatment option for hepatocellular carcinoma (HCC).However, the rate of long-term disease-free survival after liver resection remains unsatisfactory due to persistent high incidences of HCC recurrence. 1 Many factors affect HCC recurrence risk after liver resection, including tumor size and stage, serum ␣-fetoprotein level, cirrhosis, hepatitis B e antigen (HBeAg) status, and hepatitis B virus (HBV) viral load. 2-4Among these factors, HBV viral load is the most clinically controllable.Higher HBV viral load has been reported to be an independent risk factor for HCC recurrence in patients with HBV-related HCC. 5,6Nucleoside analogues are effective in suppressing HBV replication and in ameliorating HBVrelated liver disease. 7,8They have been shown to be associated with a lower risk of HCC and other cirrhosis-related complications in those with chronic hepatitis 9,10 and cirrhosis. 11However, studies on the effectiveness of nucleo-