tbuckley/cabot-search huggingface dataset:
Pharmacogenetics, Pharmacogenomics, and Individualized Medicine
Authors: Qiang Ma, Anthony Y. H. Lu
Journal: Pharmacological Reviews (2011)

Individual variability in drug efficacy and drug safety is a major challenge in current clinical practice, drug development, and drug regulation. For more than 5 decades, studies of pharmacogenetics have provided ample examples of causal relations between genotypes and drug response to account for phenotypic variations of clinical importance in drug therapy. The convergence of pharmacogenetics and human genomics in recent years has dramatically accelerated the discovery of new genetic variations that potentially underlie variability in drug response, giving birth to pharmacogenomics. In addition to the rapid accumulation of knowledge on genome-disease and genome-drug interactions, there arises the hope of individualized medicine. Here we review recent progress in the understanding of genetic contributions to major individual variability in drug therapy with focus on genetic variations of drug target, drug metabolism, drug transport, disease susceptibility, and drug safety. Challenges to future pharmacogenomics and its translation into individualized medicine, drug development, and regulation are discussed. For example, knowledge on genetic determinants of disease pathogenesis and drug action, especially those of complex disease and drug response, is not always available. Relating the many gene variations from genomic sequencing to clinical phenotypes may not be straightforward. It is often very challenging to conduct large scale, prospective studies to establish causal associations between genetic variations and drug response or to evaluate the utility and cost-effectiveness of genomic medicine. Overcoming the obstacles holds promise for achieving the ultimate goal of effective and safe medication to targeted patients with appropriate genotypes.
Ofatumumab As Single-Agent CD20 Immunotherapy in Fludarabine-Refractory Chronic Lymphocytic Leukemia
Authors: William G. Wierda, Thomas J. Kipps, Jiří Mayer, Stephan Stilgenbauer, Cathy D. Williams, Andrzej Hellmann, Tadeusz Robak, Richard R. Furman, Peter Hillmen, Marek Trneny, Martin J.S. Dyer, Swami Padmanabhan, Magdalena Piotrowska, Tomas Kozak, Geoffrey Chan, Randy Davis, Nedjad Losic, Joris Wilms, Charlotte A. Russell, Anders Österborg
Journal: Journal of Clinical Oncology (2010)

New treatments are needed for patients with fludarabine- and alemtuzumab-refractory (FA-ref) chronic lymphocytic leukemia (CLL) or patients with fludarabine-refractory CLL with bulky (> 5 cm) lymphadenopathy (BF-ref) who are less suitable for alemtuzumab treatment; these groups have poor outcomes with available salvage regimens. Ofatumumab (HuMax-CD20) is a human monoclonal antibody targeting a distinct small-loop epitope on the CD20 molecule. We conducted an international clinical study to evaluate the efficacy and safety of ofatumumab in patients with FA-ref and BF-ref CLL.Patients received eight weekly infusions of ofatumumab followed by four monthly infusions during a 24-week period (dose 1 = 300 mg; doses 2 to 12 = 2,000 mg); response by an independent review committee (1996 National Cancer Institute Working Group criteria) was assessed every 4 weeks until week 24 and then every 3 months until month 24.This planned interim analysis included 138 treated patients with FA-ref (n = 59) and BF-ref (n = 79) CLL. The overall response rates (primary end point) were 58% [corrected] and 47% in the FA-ref and BF-ref groups, respectively. Complete resolution of constitutional symptoms and improved performance status occurred in 57% and 48% of patients, respectively. Median progression-free survival and overall survival times were 5.7 and 13.7 months in the FA-ref group, respectively, and 5.9 and 15.4 months in the BF-ref group, respectively. The most common adverse events during treatment were infusion reactions and infections, which were primarily grade 1 or 2 events. Hematologic events during treatment included anemia and neutropenia.Ofatumumab is an active, well-tolerated treatment providing clear clinical improvements for fludarabine-refractory patients with very poor-prognosis CLL.
Psychiatric Diagnosis: Lessons from the DSM-IV Past and Cautions for the DSM-5 Future
Authors: Allen J. Frances, Thomas Widiger
Journal: Annual Review of Clinical Psychology (2012)

The American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders provides the authoritative list of what are considered to be mental disorders. This list has a tremendous impact on research, funding, and treatment, as well as a variety of civil and forensic decisions. The development of this diagnostic manual is an enormous responsibility. Provided herein are lessons learned during the course of the development of the fourth edition. Noted in particular is the importance of obtaining and publishing critical reviews, restraining the unbridled creativity of experts, conducting field trials that address key issues and concerns, and conducting forthright risk-benefit analyses. It is suggested that future editions of the diagnostic manual be developed under the auspices of the Institute of Medicine. The goal would be broad representation, an evidence-based approach, disinterested recommendations, and a careful attention to the risks and benefits of each suggestion for change to the individual patient, to public policy, and to forensic applications.
Development of a New Vaccine for the Prevention of Lassa Fever
Authors: Thomas W Geisbert, Steven Jones, Elizabeth A Fritz, Amy C Shurtleff, Joan B Geisbert, Ryan Liebscher, Allen Grolla, Ute Ströher, Lisa Fernando, Kathleen M Daddario, Mary C Guttieri, Bianca R Mothé, Tom Larsen, Lisa E Hensley, Peter B Jahrling, Heinz Feldmann
Journal: PLoS Medicine (2005)

Recent importation of Lassa fever into Germany, the Netherlands, the United Kingdom, and the United States by travelers on commercial airlines from Africa underscores the public health challenge of emerging viruses. Currently, there are no licensed vaccines for Lassa fever, and no experimental vaccine has completely protected nonhuman primates against a lethal challenge.
Influence of the pH of the extraction medium on the composition of birch <i>(Betula verrucas a)</i> pollen extracts
Authors: P. Cadot, M. Lejoly, E. M. Van Hoeyveld, E. A. M. Stevens
Journal: Allergy (1995)

Extracts from birch (Betula verrucosa) pollen were prepared at different pH, with constant pH monitoring and adjustment to preset values in the range 5.5-8.5. The total protein content of these extracts was directly correlated with the pH. Coomassie brilliant blue-stained isoelectric focusing and SDS-PAGE gels and immunoblot analysis demonstrated qualitative differences: some proteins were lost while others appeared when pH was changed. At pH 8.5, formerly unknown birch pollen allergens were detected with pI 9, 9.10, and 9.30 by about 30% of birch pollen-sensitive sera. Birch pollen extracts prepared at a pH close to neutrality, namely, 6.5 and 7.5, showed the greatest protein and different allergen diversity. Thus, extraction pH values are necessary to analyze the whole pattern of allergenic components in an extract.
Corrigendum to: ?The ubiquitin?proteasome system in cardiovascular diseases?a hypothesis extended? 6Cardiovasc. Res. 61 (2004) 11?219
Authors: J HERRMANN
Journal: Cardiovascular Research (2004)

As an addendum to our recent review, entitled “The ubiquitin–proteasome system in cardiovascular diseases—a hypothesis extended” [Cardiovasc. Res. 61 (2004) 11–21], it should be noted that boronate-type proteasome inhibitors are eventually reversible in their effect, …
Closing Loopholes in the Federal Research Regulations: Some Practical Problems
Authors: David B. Resnik
Journal: The American Journal of Bioethics (2008)

Click to increase image sizeClick to decrease image size Acknowledgment This research was supported by the Intramural Program of the National Institute of Environmental Health Science (NIEHS), National Institutes of Health (NIH). It does not represent the views of the NIEHS or NIH.
STUDIES ON THE VIRULENCE OF TUBERCLE BACILLI
Authors: Hubert Bloch
Journal: The Journal of Experimental Medicine (1950)

On the basis of earlier observations dealing with the relation of a petroleum ether-soluble material (cord factor) obtained from young cultures of virulent tubercle bacilli to the pathogenicity of these organisms, it was expected that young cultures yielding more cord factor than older ones of the same strain would also be more virulent for susceptible animals. By infecting mice with equal numbers of bacteria from 3 day and 3 week old cultures, significant differences in the character of disease produced were observed. The mice infected with the younger cultures died of a rapid, septicemic infection with tuberculous lesions in many organs including the heart. A tuberculous myocarditis was probably the immediate cause of death. Mice infected with the older bacteria died of a chronic disease corresponding to the well known mouse tuberculosis. In these cases, the heart was completely free of lesions. No histologic tissue reactions typical of tuberculosis were seen in the animals dying from the acute type of the disease. A similar rapidly progressing infection was observed in rabbits infected with bacteria from young cultures. The symptoms corresponded to the ones seen in the disease known as the Yersin type of tuberculosis. It seems that the pathology of this latter can be produced with every type of pathogenic mycobacteria, human as well as bovine and avian, provided the cultures used are young. Thus it may be inferred that the acute type of tuberculosis is more frequent than commonly accepted both in experimental infection and in the naturally occurring disease. It is proposed to explain the mechanism of this acute infection within the framework of the cord factor hypothesis.
Airway remodelling and its relationship to inflammation in cystic fibrosis
Authors: N. Regamey, P. K. Jeffery, E. W. F. W. Alton, A. Bush, J. C. Davies
Journal: Thorax (2010)

Pulmonary disease is the most important cause of morbidity and mortality in cystic fibrosis (CF). Most patients with CF die from respiratory failure with extensive airway destruction. Airway remodelling, defined as structural airway wall changes, begins early in life in CF but the sequence of remodelling events in the disease process is poorly understood. Airway remodelling in CF has traditionally been thought to be solely the consequence of repeated cycles of inflammation and infection. However, new evidence obtained from developmental, physiological and histopathological studies suggests that there might instead be multiple mechanisms leading to airway remodelling in CF including (1) changes related to infection and inflammation; (2) changes specific to CF as a result of CF transmembrane conductance regulator (CFTR) dysfunction in the airway wall, independent of infection and inflammation; and (3) protective responses to (1) and/or (2). Recent advances in bronchoscopic techniques have allowed airway mucosal (endobronchial) biopsies to be taken in children and even infants. Endobronchial biopsy studies may provide insight into the role and relative contribution of the different mechanisms of airway remodelling in CF, with the main limitation that they assess only changes in proximal large airways and not in peripheral small airways from where CF disease is thought to originate. Findings from biopsy studies could encourage the development of novel therapeutic strategies targeting structural changes in addition to infection and inflammation.
Tracing a Syphilis Outbreak Through Cyberspace
Authors: Jeffrey D. Klausner
Journal: JAMA (2000)

A recent outbreak of syphilis among users of an Internet chat room challenged traditional methods of partner notification and community education because locating information on sexual partners was limited to screen names and privacy concerns precluded identifying sexual partners through the Internet service provider.To determine the association of Internet use and acquisition of syphilis and to describe innovative methods of partner notification in cyberspace.Outbreak investigation conducted at the San Francisco (Calif) Department of Public Health (SFDPH) in June-August 1999 of 7 cases of early syphilis among gay men linked to an online chat room; case-control study of 6 gay men with syphilis reported to SFDPH in July-August 1999 (cases) and 32 gay men without syphilis who presented to a city clinic in April-July 1999 (controls).Association of syphilis infection with Internet use, Internet use among cases vs controls, and partner notification methods and partner evaluation indexes.During the outbreak, cases were significantly more likely than controls to have met their sexual partners through use of the Internet (67% vs 19%; odds ratio, 8.7; P =.03). We notified and confirmed testing for 42% of named partners; the mean number of sexual partners medically evaluated per index case was 5.9.In this study, meeting sexual partners through the Internet was associated with acquisition of syphilis among gay men. Public health efforts must continually adapt disease control procedures to new venues, carefully weighing the rights to privacy vs the need to protect public health. JAMA. 2000;284:447-449
Thrombospondin-1 supports blood pressure by limiting eNOS activation and endothelial-dependent vasorelaxation
Authors: Eileen M. Bauer, Yan Qin, Thomas W. Miller, Russell W. Bandle, Gabor Csanyi, Patrick J. Pagano, Philip M. Bauer, Jurgen Schnermann, David D. Roberts, Jeff S. Isenberg
Journal: Cardiovascular Research (2010)

AimsThrombospondin-1 (TSP1), via its necessary receptor CD47, inhibits nitric oxide (NO)-stimulated soluble guanylate cyclase activation in vascular smooth muscle cells, and TSP1-null mice have increased shear-dependent blood flow compared with wild-type mice. Yet, the endothelial basement membrane should in theory function as a barrier to diffusion of soluble TSP1 into the arterial smooth muscle cell layer. These findings suggested that endothelial-dependent differences in blood flow in TSP1-null mice may be the result of direct modulation of endothelial NO synthase (eNOS) activation by circulating TSP1. Here we tested the hypothesis that TSP1 inhibits eNOS activation and endothelial-dependent arterial relaxation.
T<scp>RANSCRIPTIONAL</scp> C<scp>ONTROL OF</scp> A<scp>DIPOGENESIS</scp>
Authors: Shamina M. Rangwala, Mitchell A. Lazar
Journal: Annual Review of Nutrition (2000)

▪ Abstract The major transcriptional factors involved in the adipogenic process include proteins belonging to the CCAAT/enhancer binding protein family, peroxisome proliferator-activated receptor γ, and adipocyte determination and differentiation dependent factor 1, also known as sterol regulatory element-binding protein 1. This process has been characterized with the aid of cell lines that represent various stages in the path of adipocyte commitment, ranging from pluripotent mesodermal fibroblasts to preadipocytes. Molecular analyses have led to a cascade model for adipogenesis based on timed expression of CCAAT/enhancer-binding proteins and peroxisome proliferator-activated receptor γ. Gene targeting and transgenic-mouse technologies, which allow the manipulation of endogenous genes for these transcription factors, have also contributed to the understanding of adipogenesis. This review aims to integrate this information to gain an understanding of the transcriptional regulation of fat cell formation.
Identification of two cytotoxic T lymphocyte-recognized epitopes in the Ras protein.
Authors: J Skipper, H J Stauss
Journal: The Journal of Experimental Medicine (1993)

We have investigated the possibility of inducing cytotoxic T lymphocytes (CTL) to Ras containing a mutation at position 61 or to normal Ras, using recombinant vaccinia viruses expressing these proteins. CTL from C57Bl/10 mice immunized with vaccinia expressing mutant Ras showed specificity for the mutant Ras protein and recognition of normal Ras was inefficient. The opposite specificity was observed after immunization with vaccinia expressing normal Ras, since CTL isolated from these mice recognized normal Ras well and mutant Ras inefficiently. Levels of endogenous Ras expression were insufficient for lysis by these CTL. One CTL epitope mapped to amino acids 60-67 and residue 61 was critical for T cell recognition. CTL generated against mutant Ras protein recognized peptide 60-67 containing mutant residue 61, while anti-normal Ras CTL recognized the wild-type 60-67 sequence. A second epitope mapped to residues 152-159 of Ras and was recognized equally well by CTL raised to normal or mutant Ras. The murine data raise the possibility of exploiting Ras-specific CTL for targeted immunotherapy of certain human cancers.
Low GSK-3beta Immunoreactivity in Postmortem Frontal Cortex of Schizophrenic Patients
Authors: Nitsan Kozlovsky, R.H. Belmaker, Galila Agam
Journal: American Journal of Psychiatry (2000)

OBJECTIVE: Glycogen synthase kinase-3 (GSK-3) is a protein kinase that is highly abundant in the brain. It is involved in signal transduction cascades of multiple cellular processes, particularly neurodevelopment. In an attempt to explore possible involvement of GSK-3β in psychiatric disorders, the authors examined its levels in postmortem brain tissue.METHOD: Western blot analysis was performed to measure GSK-3β in the frontal cortex of 14 schizophrenic patients, 15 patients with bipolar disorder, 15 patients with unipolar depression, and 14 normal comparison subjects.RESULTS: GSK-3β levels were 41% lower in the schizophrenic patients than in the comparison subjects. Other diagnostic groups did not differ from the comparison subjects.CONCLUSIONS: These results are consistent with the notion that schizophrenia involves neurodevelopmental pathology. It remains to be investigated whether the active fraction of GSK-3β, or its activity, is also low in frontal cortex of schizophrenic patients and if this is also reflected in other brain regions.
Toll-like Receptor 9–Dependent and –Independent Dendritic Cell Activation by Chromatin–Immunoglobulin G Complexes
Authors: Melissa W. Boulé, Courtney Broughton, Fabienne Mackay, Shizuo Akira, Ann Marshak-Rothstein, Ian R. Rifkin
Journal: The Journal of Experimental Medicine (2004)

Dendritic cell (DC) activation by nucleic acid–containing immunoglobulin (Ig)G complexes has been implicated in systemic lupus erythematosus (SLE) pathogenesis. However, the mechanisms responsible for activation and subsequent disease induction are not completely understood. Here we show that murine DCs are much more effectively activated by immune complexes that contain IgG bound to chromatin than by immune complexes that contain foreign protein. Activation by these chromatin immune complexes occurs by two distinct pathways. One pathway involves dual engagement of the Fc receptor FcγRIII and Toll-like receptor (TLR)9, whereas the other is TLR9 independent. Furthermore, there is a characteristic cytokine profile elicited by the chromatin immune complexes that distinguishes this response from that of conventional TLR ligands, notably the induction of BAFF and the lack of induction of interleukin 12. The data establish a critical role for self-antigen in DC activation and explain how the innate immune system might drive the adaptive immune response in SLE.
Angiotensin Production by the Heart
Authors: Jorge P. van Kats, A. H. Jan Danser, Jan R. van Meegen, Loes M. A. Sassen, Pieter D. Verdouw, Maarten A. D. H. Schalekamp
Journal: Circulation (1998)

Background —Beneficial effects of ACE inhibitors on the heart may be mediated by decreased cardiac angiotensin II (Ang II) production. Methods and Results —To determine whether cardiac Ang I and Ang II are produced in situ or derived from the circulation, we infused 125 I-labeled Ang I or II into pigs (25 to 30 kg) and measured 125 I-Ang I and II as well as endogenous Ang I and II in cardiac tissue and blood plasma. In untreated pigs, the tissue Ang II concentration (per gram wet weight) in different parts of the heart was 5 times the concentration (per milliliter) in plasma, and the tissue Ang I concentration was 75% of the plasma Ang I concentration. Tissue 125 I-Ang II during 125 I-Ang II infusion was 75% of 125 I-Ang II in arterial plasma, whereas tissue 125 I-Ang I during 125 I-Ang I infusion was &lt;4% of 125 I-Ang I in arterial plasma. After treatment with the ACE inhibitor captopril (25 mg twice daily), Ang II fell in plasma but not in tissue, and Ang I and renin rose both in plasma and tissue, whereas angiotensinogen did not change in plasma and fell in tissue. Tissue 125 I-Ang II derived by conversion from arterially delivered 125 I-Ang I fell from 23% to &lt;2% of 125 I-Ang I in arterial plasma. Conclusions —Most of the cardiac Ang II appears to be produced at tissue sites by conversion of in situ–synthesized rather than blood-derived Ang I. Our study also indicates that under certain experimental conditions, the heart can maintain its Ang II production, whereas the production of circulating Ang II is effectively suppressed.
Cystic fibrosis and survival to 40 years: a study of cystic fibrosis transmembrane conductance regulator function
Authors: N. J. Simmonds, L. D'Souza, M. Roughton, E. W. F. W. Alton, J. C. Davies, M. E. Hodson
Journal: European Respiratory Journal (2010)

Significant survival heterogeneity exists in cystic fibrosis. Our aim was to determine whether residual function of the cystic fibrosis transmembrane conductance regulator (CFTR) is present in long-term survivors with severe mutations. Nasal potential difference (PD) and sweat chloride were measured in 34 long-term survivors (aged ≥ 40 yrs) and compared with young patients (18-23 yrs) with severe (n = 30) and mild (n = 31) lung disease. Baseline PD was not significantly different across the three groups (long-term survivors, -42.8 (range -71.0- -20.5) mV; young/mild, -40.5 (-58.8- -19.5) mV; young/severe,-46.3 (-74.0- -20.0) mV). Response to amiloride (ΔAmil) was significantly different across the three groups (p = 0.01); long-term survivors had values (27.8 (range 8.5-46) mV) which were not different to either young group, but the young/severe group had significantly higher values (29.5 (11-47) mV) than those in the young/mild group (22.0 (7-39) mV; p<0.01). Baseline PD and ΔAmil were associated with forced expiratory volume in 1 s (FEV₁) (co-efficient (95% CI) -0.13 (-0.23- -0.03); p = 0.009 and -0.12 (-0.20- -0.04); p = 0.003, respectively). Sweat chloride was lowest (p <0.05) in the young/severe group (93.5 (74-111) mmol·L⁻¹ versus 98.8 (76.5-116.0) mmol·L⁻¹; long-term survivors; and 99.5 (80.0-113.5) mmol·L⁻¹; young/mild). Δ Amil is associated with FEV₁ but our findings indicate that long-term survival cannot be explained by residual CFTR function when measurements are taken in later life.
Somatic inactivation of E-cadherin and p53 in mice leads to metastatic lobular mammary carcinoma through induction of anoikis resistance and angiogenesis
Authors: Patrick W.B. Derksen, Xiaoling Liu, Francis Saridin, Hanneke van der Gulden, John Zevenhoven, Bastiaan Evers, Judy R. van Beijnum, Arjan W. Griffioen, Jacqueline Vink, Paul Krimpenfort, Johannes L. Peterse, Robert D. Cardiff, Anton Berns, Jos Jonkers
Journal: Cancer Cell (2006)