tbuckley/cabot-search huggingface dataset:
Cardiac fibroblast paracrine factors alter impulse conduction and ion channel expression of neonatal rat cardiomyocytes
Authors: Dawn M. Pedrotty, Rebecca Y. Klinger, Robert D. Kirkton, Nenad Bursac
Journal: Cardiovascular Research (2009)

The pathological proliferation of cardiac fibroblasts (CFs) in response to heart injury results in fibrosis, which correlates with arrhythmia generation and heart failure. Here we systematically examined the effect of fibroblast-derived paracrine factors on electrical propagation in cardiomyocytes. Neonatal rat cardiac monolayers were exposed for 24 h to media conditioned by CFs. Optical mapping, sharp microelectrode recordings, quantitative RT–PCR, and immunostaining were used to assess the changes in the propagation and shape of the action potential and underlying changes in gene and protein expression. The fibroblast paracrine factors produced a 52% reduction in cardiac conduction velocity, a 217% prolongation of action potential duration, a 64% decrease of maximum capture rate, a 21% increase in membrane resting potential, and an 80% decrease of action potential upstroke velocity. These effects were dose dependent and partially reversible with removal of the conditioned media. No fibroblast proliferation, cardiomyocyte apoptosis, or decreased connexin-43 expression, phosphorylation, and function were found in conditioned cardiac cultures. In contrast, the expression of the fast sodium, inward rectifying potassium, and transient outward potassium channels were, respectively, reduced 3.8-, 6.6-fold, and to undetectable levels. The expression of β-myosin heavy chain increased 17.4-fold. No electrophysiological changes were observed from media conditioned by CFs in the presence of cardiomyocytes. Paracrine factors from neonatal CFs alone produced significant electrophysiological changes in neonatal rat cardiomyocytes resembling those found in several cardiac pathologies.
Phase II Study of Single-Agent Orteronel (TAK-700) in Patients with Nonmetastatic Castration-Resistant Prostate Cancer and Rising Prostate-Specific Antigen
Authors: Maha Hussain, Paul G. Corn, M. Dror Michaelson, Hans J. Hammers, Joshi J. Alumkal, Charles J. Ryan, Justine Y. Bruce, Susan Moran, Shih-Yuan Lee, H. Mark Lin, Daniel J. George
Journal: Clinical Cancer Research (2014)

Orteronel (TAK-700) is an investigational, nonsteroidal, oral, inhibitor of androgen synthesis with greater specificity for 17,20-lyase than for 17α-hydroxylase. We investigated orteronel without steroids in patients with nonmetastatic castration-resistant prostate cancer (nmCRPC; M0).Patients with nmCRPC and rising prostate-specific antigen (PSA) received orteronel 300 mg twice daily until PSA progression, metastases, or unacceptable toxicity. The primary endpoint was percentage of patients achieving PSA ≤0.2 ng/mL (undetectable levels) at 3 months. Secondary endpoints included safety, PSA response, time to metastases, and correlated endpoints.Thirty-nine patients with a median baseline PSA doubling time of 2.4 months (range, 0.9-9.2) received a median of fourteen 28-day treatment cycles. PSA decreased >30% in 35 patients and 6 (16%) achieved PSA ≤ 0.2 ng/mL at 3 months. Median times to PSA progression and metastasis were 13.8 and 25.4 months, respectively. Kaplan-Meier estimates of freedom from PSA progression were 57% and 42% at 12 and 24 months, and of freedom from metastasis were 94% and 62% at 12 and 24 months, respectively. At 3 months, median testosterone declined by 89% from baseline. Adverse events led to therapy discontinuation in 12 patients and grade ≥3/4 adverse events occurred in 22 patients. Most frequent all-cause adverse events included fatigue (64%), hypertension (44%), diarrhea (38%), and nausea (33%), which were primarily grade 1/2.Single-agent orteronel produced marked and durable declines in PSA in patients with nmCRPC. Orteronel has moderate but manageable toxicities and its chronic administration without steroids appears feasible.
FasL gene knock-down therapy enhances the antiglioma immune response
Authors: Timothy Jansen, Betty Tyler, Joseph L. Mankowski, Violette Renard Recinos, Gustavo Pradilla, Federico Legnani, John Laterra, Alessandro Olivi
Journal: Neuro-Oncology (2010)

Malignant glioma is a lethal form of brain cancer that is very difficult to treat. The aggressive behavior of these neoplasms and their limited responsiveness to therapy has been attributed in part to the ability of these tumors to evade the immune system. Gliomas, like many other solid tumors, express components of numerous immune escape mechanisms, including immunosuppressive proteins such as TGF-β, IL-10, and FasL. Here, we show that FasL expression can support the growth of experimental intracranial glioma. We show that FasL is readily detected in human glioblastoma multiforme clinical specimens. FasL was found to be expressed by three well-characterized rat glioma cell lines (9L, F98, and C6) and glioma cell-derived FasL mediated the death of phytohemagglutinin-stimulated Jurkat T-lymphocytes when cocultured with glioma cells in vitro. We asked if inhibiting 9L-derived FasL altered the growth of experimental glioma. FasL expression knockdown using shRNA reduced the growth of subcutaneous and intracranial 9L gliomas by ∼50% in immune competent Fisher 344 rats. In contrast, FasL expression knockdown had no affect on the growth of intracranial 9L glioma in T-cell deficient athymic rats. Intracranial tumors derived from FasL knockdown 9L glioma cells contained up to 3-fold more tumor infiltrating T-cells than tumors derived from control 9L cells. These results demonstrate that down-regulating FasL expression and/or function in glial malignancies can enhance T-cell tumor infiltration and inhibit tumor growth. The findings suggest that targeting endogenous FasL in glial malignancies could enhance the efficacy of emerging immune-based treatment strategies.
Update on Treatment Recommendations From the Fourth International Workshop on Waldenström's Macroglobulinemia
Authors: Meletios Athanasios Dimopoulos, Morie A. Gertz, Efstathios Kastritis, Ramon Garcia-Sanz, Eva K. Kimby, Veronique LeBlond, Jean-Paul Fermand, Giampaolo Merlini, Pierre Morel, Enrica Morra, Enrique M. Ocio, Roger Owen, Irene M. Ghobrial, John Seymour, Robert A. Kyle, Steven P. Treon
Journal: Journal of Clinical Oncology (2008)

Waldenström macroglobulinemia (WM) is a distinct B-cell lymphoproliferative disorder characterized by lymphoplasmacytic bone marrow infiltration along with an immunoglobulin M (IgM) monoclonal gammopathy. Patients with disease-related cytopenias, bulky adenopathy or organomegaly, symptomatic hyperviscosity, severe neuropathy, amyloidosis, cryoglobulinemia, cold agglutinin disease, or evidence of disease transformation should be considered for immediate therapy. Initiation of therapy should not be based on serum IgM levels alone, and asymptomatic patients should be observed. Individual patient considerations should be considered when deciding on a first-line agent including the presence of cytopenias, need for rapid disease control, age, and candidacy for autologous transplantation. Therapeutic outcomes should be evaluated using updated criteria. As part of the Fourth International Workshop on Waldenström's Macroglobulinemia, a consensus panel updated its recommendations on both first-line and salvage therapy in view of recently published and ongoing clinical trials. The panel considered encouraging results from recent studies of first-line combinations such as rituximab with nucleoside analogs with or without alkylating agents or with cyclophosphamide-based therapies (eg, cyclophosphamide, doxorubicin, vincristine, and prednisone or cyclophosphamide and dexamethasone) or the combination of rituximab with thalidomide. Such therapeutic approaches are likely to yield responses at least as good as, if not better than, monotherapy with any of the alkylating agents, nucleoside analogs, or rituximab. In the salvage setting, reuse of a first-line regimen or use of a different regimen should be considered along with bortezomib, alemtuzumab, autologous transplantation, and, in selected circumstances, allogeneic transplantation. Finally, the panel reaffirmed its encouragement of the active enrollment of patients with WM onto innovative clinical trials whenever possible.
Histone γH2AX and Poly(ADP-Ribose) as Clinical Pharmacodynamic Biomarkers
Authors: Christophe E. Redon, Asako J. Nakamura, Yong-Wei Zhang, Jiuping (Jay) Ji, William M. Bonner, Robert J. Kinders, Ralph E. Parchment, James H. Doroshow, Yves Pommier
Journal: Clinical Cancer Research (2010)

Abstract Tumor cells are often deficient in DNA damage response (DDR) pathways, and anticancer therapies are commonly based on genotoxic treatments using radiation and/or drugs that damage DNA directly or interfere with DNA metabolism, leading to the formation of DNA double-strand breaks (DSB), and ultimately to cell death. Because DSBs induce the phosphorylation of histone H2AX (γH2AX) in the chromatin flanking the break site, an antibody directed against γH2AX can be employed to measure DNA damage levels before and after patient treatment. Poly(ADP-ribose) polymerases (PARP1 and PARP2) are also activated by DNA damage, and PARP inhibitors show promising activity in cancers with defective homologous recombination (HR) pathways for DSB repair. Ongoing clinical trials are testing combinations of PARP inhibitors with DNA damaging agents. Poly(ADP-ribosylation), abbreviated as PAR, can be measured in clinical samples and used to determine the efficiency of PARP inhibitors. This review summarizes the roles of γH2AX and PAR in the DDR, and their use as biomarkers to monitor drug response and guide clinical trials, especially phase 0 clinical trials. We also discuss the choices of relevant samples for γH2AX and PAR analyses. Clin Cancer Res; 16(18); 4532–42. ©2010 AACR.
Health Care Workforce for the Twenty-First Century: The Impact of Nonphysician Clinicians
Authors: Richard A. Cooper
Journal: Annual Review of Medicine (2001)

▪ Abstract For many years, nonphysician clinicians (NPCs) have participated in the care of patients. However, their numbers were small and their licensed prerogatives were narrow. Over the past decade, these characteristics have changed in three important ways. First, training in many of the NPC disciplines has increased substantially, and the growth of these disciplines is accelerating. Second, state laws and regulations have expanded both the practice prerogatives of NPCs and their autonomy from physician supervision. Third, payers have increased their access to reimbursement. As a consequence, NPCs are undertaking many elements of care that previously were provided by physicians. Their participation is generally cost-effective and is met with a high degree of patient satisfaction. This presents both opportunities and challenges to physicians as they forge new relationships with NPCs and as their own spectrum of responsibilities evolves.
Stimulatory and inhibitory effects of interleukin (IL)-4 and IL-13 on the production of cytokines by human peripheral blood mononuclear cells: priming for IL-12 and tumor necrosis factor alpha production.
Authors: A D'Andrea, X Ma, M Aste-Amezaga, C Paganin, G Trinchieri
Journal: The Journal of Experimental Medicine (1995)

The production of cytokines in monocytes/macrophages is regulated by several different cytokines that have activating or inhibitory effects. Interleukin (IL)-10, IL-4, IL-13, and transforming growth factor (TGF)-beta are usually considered to be the most important macrophage-deactivating factors, with inhibitory effects on cytokine production. Unlike IL-10 and TGF-beta, which appear to act as downmodulators of many phagocytic cell functions, the mode of action of IL-4 and IL-13 is more complex. Addition of IL-4 and IL-13 to peripheral blood mononuclear cell (PBMC) cultures inhibited production of IL-12, tumor necrosis factor (TNF)-alpha, IL-10, and IL-1 beta induced by lipopolysaccharide (LPS) or Staphylococcus aureus added simultaneously with the cytokines. However, pretreatment of PBMC with IL-4 or IL-13 for &amp;gt; or = 20 h enhanced the production of IL-12 and TNF-alpha in response to LPS or S. aureus several fold in these cells; this IL-4-induced priming for the two cytokines was inhibited by anti-IL-4 neutralizing antibodies. IL-4 priming also enhanced the accumulation of IL-12 and TNF-alpha mRNA induced by LPS and S. aureus. The enhanced accumulation of transcripts for the IL-12 p35 and p40 chains by IL-4 priming was reflected in enhanced secretion of both the IL-12 free p40 chain and the p70 heterodimer. These results suggest an unexpected complexity in the regulatory role of IL-4 and IL-13 in immune responses.
Patients, Psychiatric Problems, and Nonpsychiatrist Physicians in a Prepaid Group Practice Medical Program
Authors: BEN Z. LOCKE
Journal: American Journal of Psychiatry (1966)

Nonpsychiatric physicians in a prepaid medical care program diagnosed 15 percent of their patients to have a psychiatric problem. This report reviews the patients' awareness of their psychiatric problems and their assessment of the nonpsychiatric medical care received and gives an overview of all services given in connection with their condition. Patients with psychiatric problems considered their illnesses to be of more recent onset than did their physicians, but both were in agreement that in many instances the problem was minor or not primary. With qualifications, the patients in this study felt that physicians could be helpful. Views of these patients toward drugs, friends, specified outside activities, etc., as a means of helping people who are nervous or depressed are presented. Over-all, patients are not optimistic about such aids or activities. About one out of four patients reported being helped by a psychiatrist. Patients, in the main, expressed satisfaction with medical and ancillary services received. Nevertheless, this medical group felt that patients with psychiatric problems needed specific psychiatric services and initiated such benefits in their prepaid program. Studies to evaluate the effect of such benefits are planned.
US scientists extend the life of human cells
Authors: D. Josefson
Journal: BMJ (1998)

Scientists in the United States have significantly extended the life span of cultured human cells, with no sign of abnormalities, by adding an enzyme called telomerase. The work has sparked widespread excitement, leading some to believe that many age related ailments can be curtailed and that the human life span could be extended beyond 120 years.

The groundbreaking research was a collaborative effort between investigators at the University of Texas Southwestern Medical School in Dallas and scientists at Geron, a biotechnology firm in California ( Science 1998;279:334-5, 339-52). They studied the cellular aging of human fibroblasts, retinal epithelial cells, and vascular endothelial cells.

Normal human cells undergo a finite number of cell divisions before entering a non-replicative state known as senescence, which is followed by cell death. The number of divisions varies between 40 and 90, depending on cell type, and is known as the Hayflick number, after Leonard Hayflick, who discovered this phenomenon in 1965. On occasion, cells can escape this fate and continue to replicate. Human …
Differentiation of normal human pre-B cells in vitro.
Authors: J G Villablanca, J M Anderson, M Moseley, C L Law, R L Elstrom, T W LeBien
Journal: The Journal of Experimental Medicine (1990)

The differentiation of surface Ig- pre-B cells into surface Ig+ B cells is a critical transition in mammalian B cell ontogeny. Elucidation of the growth factor requirements and differentiative potential of human pre-B cells has been hampered by the absence of a reproducible culture system that supports differentiation. Fluorescence-activated cell sorting and magnetic bead depletion were used to purify fetal bone marrow CD10+/surface mu- cells, which contain 60-70% cytoplasmic mu+ pre-B cells. CD10+/surface mu- cells cultured for 2 d were observed to differentiate into surface mu+ cells. Analysis by Southern blotting provided direct evidence that rearrangement of kappa light chain genes occurs in culture, and flow cytometric analysis revealed the appearance of surface Ig+ B cells expressing mu/kappa or mu/lambda. Unexpectedly, the kappa/lambda ratio in differentiated cells was the inverse of what is normally observed in adult peripheral blood. Differentiation occurs in the absence of exogenous growth factors or cytokines, suggesting that a stimulus-independent differentiative inertia might characterize pre-B cells in vivo. Future use of this model will facilitate our understanding of normal and abnormal human pre-B cell differentiation.
Molecular Pathways: BCR-ABL
Authors: Daniela Cilloni, Giuseppe Saglio
Journal: Clinical Cancer Research (2011)

Aberrant tyrosine kinase activity plays a critical role in many hematologic disorders, including chronic myeloid leukemia characterized by the constitutive activity of BCR-ABL. ABL therefore represents a crucial target for new therapeutic strategies. Here, we summarize the molecular pathways that are abnormally activated by the oncoprotein. Such pathways may provide additional opportunities to develop new drugs to overcome the resistance to tyrosine kinase inhibitors. In particular, the phosphoinositide 3-kinase (PI3K)/AKT pathway can be effectively blocked by mTOR inhibitors, and several compounds can hit the RAS pathway and the resulting mitogen-activated protein (MAP) extracellular signal-regulated kinase (ERK)1/2 (MEK) and MAP kinase activation. Furthermore, mitotic kinases can be blocked by Aurora kinase inhibitors, and Pim kinases can be blocked by selective serine-threonine kinase inhibitors. Finally, the abnormal pathways that sustain the self-renewal of leukemic stem cells are described as possible targets to completely eradicate leukemic clones. Such pathways include the Hedgehog pathway, which can be blocked by Smoothened inhibitors, and the CXCR4/SDF1 axis, which can be targeted by specific antagonists.
Clinical Characteristics of Patients Who Report Incorrect Data of Home-Measured Blood Pressure
Authors: Shinobu Matsumoto, Michiaki Fukui, Masahide Hamaguchi, Emi Ushigome, Mayuko Kadono, Kanae Matsushita, Takuya Fukuda, Kazuteru Mitsuhashi, Saori Majima, Masahiro Yamazaki, Goji Hasegawa, Naoto Nakamura
Journal: Diabetes Care (2014)

Diabetic patients are at a higher risk for cardiovascular events. It is important to control dyslipidemia and blood pressure (BP) as well as to control blood glucose for the prevention of cardiovascular events. In addition, home BP (HBP) measurement has been found to have a stronger relation with target organ damage and with a risk of cardiovascular events when compared with clinic BP measurement (1–3). Therefore, the significance of HBP measurement has been widely recognized. However, there are no studies evaluating the reliability of HBP measurement in patients with type 2 diabetes. The aim of this study was to investigate the clinical characteristics in patients with the lowest quartile (quartile 1) of concordance rate between self-reported and stored HBP measurements.

HBP measurements were performed in 280 patients with type 2 …
Body-Buffer Zone in Violent Prisoners
Authors: AUGUSTUS F. KINZEL
Journal: American Journal of Psychiatry (1970)

Comparative measurement of the body-buffer zones of eight violent and six non-violent prisoners showed the zones of the violent group to be almost four times larger. In the violent group the rear zones were larger than the front zones; in the non-violent group the front zones were larger. The large zones of the violent group may reflect a pathological body image state. The author discusses potential application of body-buffer zone measurements in the detection, treatment, and prognosis of individuals predisposed to violent behavior.
Efficacy of acupuncture in asthma: systematic review and meta-analysis of published data from 11 randomised controlled trials
Authors: J. Martin, A.N.A. Donaldson, R. Villarroel, M.K.B. Parmar, E. Ernst, I.J. Higginson
Journal: European Respiratory Journal (2002)

Contradictory results from randomised controlled trials of acupuncture in asthma suggest both a beneficial and detrimental effect. The authors conducted a formal systematic review and meta-analysis of all randomised clinical trials in the published literature that have compared acupuncture at real and placebo points in asthma patients. The authors searched for trials published in the period 1970–2000. Trials had to measure at least one of the following objective outcomes: peak expiratory flow rate, forced expiratory volume in one second (FEV 1 ) and forced vital capacity. Estimates of the standarised mean difference, between acupuncture and placebo were computed for each trial and combined to estimate the overall effect. Hetereogeneity was investigated in terms of the characteristics of the individual studies. Twelve trials met the inclusion criteria but data from one could not be obtained. Individual patient data were available in only three. Standardised differences between means ranging from 0.071 to 0.133, in favour of acupuncture, were obtained. The overall effect was not conventionally significant and it corresponds to an approximate difference in FEV 1 means of 1.7. After exploring hetereogenenity, it was found that studies where bronchoconstriction was induced during the experiment showed a conventionally significant effect. This meta-analysis did not find evidence of an effect of acupuncture in reducing asthma. However, the meta-analysis was limited by shortcomings of the individual trials, in terms of sample size, missing information, adjustment of baseline characteristics and a possible bias against acupuncture introduced by the use of placebo points that may not be completely inactive. There was a suggestion of preferential publication of trials in favour of acupuncture. There is an obvious need to conduct a full-scale randomised clinical trial addressing these limitations and the prognostic value of the aetiology of the disease.
COMPARABLE ESTIMATES OF MORTALITY AND TRENDS FOR CARDIOVASCULAR DISEASES INCLUDING CONGENITAL HEART DISEASE IN 21 WORLD REGIONS IN 1990 AND 2010: THE GLOBAL BURDEN OF DISEASES, INJURIES AND RISK FACTORS STUDY
Authors: George A. Mensah, Mohammad H. Forouzanfar, Mohsen Naghavi, Rafael Lozano, Majid Ezzati, Andrew Moran, Valery Feigin, Theo Vos, Christopher J.L. Murray
Journal: Journal of the American College of Cardiology (2013)
Report from the 67th Annual Meeting of the American Academy of Dermatology
Authors: A.B. Alexandroff, R.A.C. Graham-Brown
Journal: British Journal of Dermatology (2009)

The 67th Annual Meeting of the American Academy of Dermatology took place in San Francisco on 6-10 March 2009. The flavour of this busy but well-organized convention was a mixture of practical, hands-on teaching sessions, led and delivered by experts, with breakthrough cutting-edge scientific sessions. Aesthetic dermatology comprised a significant part of the meeting. It is impossible to encompass all the important presentations made at the meeting and satellite symposiums, but we highlight here a few medical pearls on dermoscopy, melanoma and oncology, inflammatory dermatoses and community-acquired methicillin-resistant Staphylococcus aureus. Our report is not intended as a substitute for reading the conference proceedings, educational session handouts, online updates and related references quoted in this article.