tbuckley/cabot-search huggingface dataset:
Intratracheal Administration of a Nanoparticle-Based Therapy with the Angiotensin II Type 2 Receptor Gene Attenuates Lung Cancer Growth
Authors: Atsushi Kawabata, Abdulgader Baoum, Naomi Ohta, Stephanie Jacquez, Gwi-Moon Seo, Cory Berkland, Masaaki Tamura
Journal: Cancer Research (2012)

Abstract Targeted gene delivery, transfection efficiency, and toxicity concerns remain a challenge for effective gene therapy. In this study, we dimerized the HIV-1 TAT peptide and formulated a nanoparticle vector (dTAT NP) to leverage the efficiency of this cell-penetrating strategy for tumor-targeted gene delivery in the setting of intratracheal administration. Expression efficiency for dTAT NP–encapsulated luciferase or angiotensin II type 2 receptor (AT2R) plasmid DNA (pDNA) was evaluated in Lewis lung carcinoma (LLC) cells cultured in vitro or in vivo in orthotopic tumor grafts in syngeneic mice. In cell culture, dTAT NP was an effective pDNA transfection vector with negligible cytotoxicity. Transfection efficiency was further increased by addition of calcium and glucose to dTAT/pDNA NP. In orthotopic tumor grafts, immunohistochemical analysis confirmed that dTAT NP successfully delivered pDNA to the tumor, where it was expressed primarily in tumor cells along with the bronchial epithelium. Notably, gene expression in tumor tissues persisted at least 14 days after intratracheal administration. Moreover, bolus administration of dTAT NP–encapsulated AT2R or TNF-related apoptosis-inducing ligand (TRAIL) pDNA markedly attenuated tumor growth. Taken together, our findings offer a preclinical proof-of-concept for a novel gene delivery system that offers an effective intratracheal strategy for administering lung cancer gene therapy. Cancer Res; 72(8); 2057–67. ©2012 AACR.
Early Improvement As a Predictor of Later Response to Antipsychotics in Schizophrenia: A Diagnostic Test Review
Authors: Myrto T. Samara, Claudia Leucht, Mariska M. Leeflang, Ion-George Anghelescu, Young-Chul Chung, Benedicto Crespo-Facorro, Helio Elkis, Kotaro Hatta, Ina Giegling, John M. Kane, Monica Kayo, Martin Lambert, Ching-Hua Lin, Hans-Jürgen Möller, José María Pelayo-Terán, Michael Riedel, Dan Rujescu, Benno G. Schimmelmann, Alessandro Serretti, Christoph U. Correll, Stefan Leucht
Journal: American Journal of Psychiatry (2015)

How long clinicians should wait before considering an antipsychotic ineffective and changing treatment in schizophrenia is an unresolved clinical question. Guidelines differ substantially in this regard. The authors conducted a diagnostic test meta-analysis using mostly individual patient data to assess whether lack of improvement at week 2 predicts later nonresponse.The search included EMBASE, MEDLINE, BIOSIS, PsycINFO, Cochrane Library, CINAHL, and reference lists of relevant articles, supplemented by requests to authors of all relevant studies. The main outcome was prediction of nonresponse, defined as <50% reduction in total score on either the Positive and Negative Syndrome Scale (PANSS) or Brief Psychiatric Rating Scale (BPRS) (corresponding to at least much improved) from baseline to endpoint (4-12 weeks), by <20% PANSS or BPRS improvement (corresponding to less than minimally improved) at week 2. Secondary outcomes were absent cross-sectional symptomatic remission and <20% PANSS or BPRS reduction at endpoint. Potential moderator variables were examined by meta-regression.In 34 studies (N=9,460) a <20% PANSS or BPRS reduction at week 2 predicted nonresponse at endpoint with a specificity of 86% and a positive predictive value (PPV) of 90%. Using data for observed cases (specificity=86%, PPV=85%) or lack of remission (specificity=77%, PPV=88%) yielded similar results. Conversely, using the definition of <20% reduction at endpoint yielded worse results (specificity=70%, PPV=55%). The test specificity was significantly moderated by a trial duration of <6 weeks, higher baseline illness severity, and shorter illness duration.Patients not even minimally improved by week 2 of antipsychotic treatment are unlikely to respond later and may benefit from a treatment change.
Postoperative exercise tolerance after aortic valve replacement by small-size prosthesis
Authors: Pierre Becassis, Maurice Hayot, Jean-Marc Frapier, Florence Leclercq, Lionel Beck, Jérome Brunet, Eric Arnaud, Christian Prefaut, Paul-André Chaptal, J.M Davy, Patrick Messner-Pellenc, R Grolleau
Journal: Journal of the American College of Cardiology (2000)
Variants of uncertain significance in BRCA: a harbinger of ethical and policy issues to come?
Authors: Jae Yeon Cheon, Jessica Mozersky, Robert Cook-Deegan
Journal: Genome Medicine (2014)

After two decades of genetic testing and research, the BRCA1 and BRCA2 genes are two of the most well-characterized genes in the human genome. As a result, variants of uncertain significance (VUS; also called variants of unknown significance) are reported less frequently than for genes that have been less thoroughly studied. However, VUS continue to be uncovered, even for BRCA1/2. The increasing use of multi-gene panels and whole-genome and whole-exome sequencing will lead to higher rates of VUS detection because more genes are being tested, and most genomic loci have been far less intensively characterized than BRCA1/2. In this article, we draw attention to ethical and policy-related issues that will emerge. Experience garnered from BRCA1/2 testing is a useful introduction to the challenges of detecting VUS in other genetic testing contexts, while features unique to BRCA1/2 suggest key differences between the BRCA experience and the current challenges of multi-gene panels in clinical care. We propose lines of research and policy development, emphasizing the importance of pooling data into a centralized open-access database for the storage of gene variants to improve VUS interpretation. In addition, establishing ethical norms and regulated practices for sharing and curating data, analytical algorithms, interpretive frameworks and patient re-contact are important policy areas.
Expression and function of a recombinant endothelial nitric oxide synthase gene in porcine coronary arteries
Authors: D Cable
Journal: Cardiovascular Research (1997)

Direct gene transfer of exogenous nitric oxide synthase, with the subsequent increase in nitric oxide production, could represent a potential therapeutic strategy in the treatment of vascular proliferative disorders. The goal of the present study was to determine if porcine coronary arteries could be transduced with an adenoviral vector encoding endothelial nitric oxide synthase (Ad.CMVeNOS) resulting in functional expression.Segments of porcine right coronary artery were exposed for 1 h at 37 degrees C to either replication-deficient adenovirus encoding bovine endothelial nitric oxide synthase (Ad.CMVeNOS, 5 x 10(9) pfu/ml) or control adenovirus encoding Escherichia coli beta-galactosidase (Ad.CMVLacZ, 5 x 10(9) pfu/ml). Immunohistochemistry with a monoclonal antibody specific for nitric oxide synthase (NOS) demonstrated recombinant gene expression in both the endothelial and adventitial layers of Ad.CMVeNOS transduced coronaries with only endogenous NOS confirmed in the endothelium of Ad.CMVLacZ arteries. Coronary arteries transduced with Ad.CMVeNOS yielded 517 +/- 110 (mean +/- S.E.M.) nM/ng nitrite while vessels transduced with Ad.CMVLacZ yielded 126 +/- 84 nM/ng (P < 0.05, n = 6). Isometric tension recording, following prostaglandin F2 alpha constriction, documented a reduced tension in Ad.CMVeNOS transduced coronaries, compared to matched Ad.CMVLacZ coronaries (6.10 +/- 1.08 g vs. 8.45 +/- 1.19 g, respectively, P = 0.05, n = 8). This tension differential was eliminated with prior incubation in NG-monomethyl-L-arginine (L-NMMA, 10(-4) M). The EC50 for calcium ionophore relaxation of Ad.CMVeNOS coronary arteries was reduced compared to Ad.CMVLacZ (-7.90 +/- 0.03 logM vs. -7.26 +/- 0.11 logM, respectively, P < 0.05, n = 8).These studies demonstrate successful transfer of endothelial nitric oxide synthase into porcine coronary arteries as verified by histochemical localization of recombinant protein with an increase of nitric oxide release as demonstrated by enhanced nitrite production and an alteration in vasomotor function.
Demonstration of delta rec-pseudo J alpha rearrangement with deletion of the delta locus in a human stem-cell leukemia.
Authors: C G Begley, P D Aplan, M P Davey, J P de Villartay, D I Cohen, T A Waldmann, I R Kirsch
Journal: The Journal of Experimental Medicine (1989)

It has been hypothesized that a rearrangement between the delta recombining element (delta Rec) and a pseudo J alpha gene serves to delete the TCR-delta locus before rearrangement of the TCR-alpha genes. We have now sequenced a direct, site-specific rearrangement between the delta Rec element and a pseudo J alpha gene in a human leukemic stem-cell line. Putative "N-sequence" addition was noted at the site of recombination, suggesting that this event occurred at a time when the enzyme(s) involved in N-region addition were active in this cell. This provides support for the view that deletion of the TCR-delta locus is required before rearrangement of the TCR-alpha chain genes.
Dopamine in schizophrenia: a review and reconceptualization
Authors: K L Davis, R S Kahn, G Ko, M Davidson
Journal: American Journal of Psychiatry (1991)

The initial hypothesis that schizophrenia is a manifestation of hyperdopaminergia has recently been faulted. However, several new findings suggest that abnormal, although not necessarily excessive, dopamine activity is an important factor in schizophrenia. The authors discuss these findings and their implications.All published studies regarding dopamine and schizophrenia and all studies on the role of dopamine in cognition were reviewed. Attention has focused on post-mortem studies, positron emission tomography, neuroleptic drug actions, plasma levels of the dopamine metabolite homovanillic acid (HVA), and cerebral blood flow.Evidence, particularly from intracellular recording studies in animals and plasma HVA measurements, suggests that neuroleptics act by reducing dopamine activity in mesolimbic dopamine neurons. Post-mortem studies have shown high dopamine and HVA concentrations in various subcortical brain regions and greater than normal dopamine receptor densities in the brains of schizophrenic patients. On the other hand, the negative/deficit symptom complex of schizophrenia may be associated with low dopamine activity in the prefrontal cortex. Recent animal and human studies suggest that prefrontal dopamine neurons inhibit subcortical dopamine activity. The authors hypothesize that schizophrenia is characterized by abnormally low prefrontal dopamine activity (causing deficit symptoms) leading to excessive dopamine activity in mesolimbic dopamine neurons (causing positive symptoms).The possible co-occurrence of high and low dopamine activity in schizophrenia has implications for the conceptualization of dopamine's role in schizophrenia. It would explain the concurrent presence of negative and positive symptoms. This hypothesis is testable and has important implications for treatment of schizophrenia and schizophrenia spectrum disorders.
Rare Cancer Trial Design: Lessons from FDA Approvals
Authors: Himabindu Gaddipati, Ke Liu, Anne Pariser, Richard Pazdur
Journal: Clinical Cancer Research (2012)

A systematic analysis of clinical trials supporting rare cancer drug approvals may identify concepts and terms that can inform the effective design of prospective clinical trials for rare cancers. In this article, using annual incidence ≤6 of 100,000 individuals to define "rare cancer," we identified clinical trials for rare cancers, supporting U.S. Food and Drug Administration (FDA) drug approvals for rare cancer indications between December 1987 and May 2011. We characterized each selected trial for study design, sample size, primary efficacy endpoints, and statistical comparisons. We also profiled trials with regard to type of submission, review designation, and approval type. Our results indicated that, of 99 trials that supported the approvals of 45 drugs for 68 rare cancer indications, one third of these trials were randomized; 69% of approvals relied on objective response rate as the primary efficacy endpoint; and 63% were based on a single trial. Drugs granted accelerated approval appeared more likely to be associated with postmarketing safety findings, relative to drugs approved under the regular approval. Data collected across clinical trials were robust: Use of different lower incidence rates in analyzing these trials did not have effects on trial characteristics. The absolute number of drug approvals for rare cancer indications increased markedly over time. We concluded that one third of clinical trials supporting drug approvals for rare cancer indications were randomized, affirming the feasibility and value of randomized trial design to evaluate drugs for rare cancers. Postmarketing safety data may relate to trial design and approval type. An operational definition of "rare cancer" can be useful for the analysis of trial data and for the path toward harmonizing the terminology in the area of clinical research on rare cancers.
Intravascular lymphomatosis diagnosed by transbronchial lung biopsy
Authors: K Takamura, Y Nasuhara, T Mishina, T Matsuda, M Nishimura, Y Kawakami, M Fujita, C Mikuni, K Yamashiro
Journal: European Respiratory Journal (1997)

Intravascular lymphomatosis is a rare lymphoma presenting a variety of symptoms due to proliferation of tumour cells within blood vessels in the brain, the skin and other organs. This disease is generally considered to be highly malignant, but to be relatively susceptible to combined chemotherapy, when diagnosed in the early stage. We describe a case of intravascular lymphomatosis, presenting with diffuse interstitial shadows on chest radiographic image, which could be diagnosed by transbronchial lung biopsy. The patient showed a good response to combined chemotherapy. We propose that transbronchial lung biopsy is a useful procedure for the diagnosis of intravascular lymphomatosis.
Elective operations for post-infarction left ventricular aneurysms.
Authors: C G Sbokos, J L Monro, J K Ross
Journal: Thorax (1976)

During a two-year period (February 1973 to February 1975) 20 consecutive patients with post-infarction left ventricular aneurysm, seen at the Wessex Cardiac and Thoracic Centre, underwent aneurysmectomy with or without aorta-to-coronary artery saphenous vein bypass grafts, ventricular septal defect closure, or valve replacement. The diagnoses were established by clinical means, plain chest radiographs, left ventriculography, and selective coronary arteriography. The indications for surgery were uncontrollable congestive heart failure and angina, ventricular arrhythmias, or a rapidly growing aneurysm. Low cardiac indices or high left ventricular end-diastolic pressure were not considered to be contraindications to operation. Resection of the left ventricular aneurysm was performed with the use of normothermic cardiopulmonary bypass with haemodilution. In addition to the aneurysmectomy, four of these patients had concomitant closure of post-infarction ventricular septal defects; four had valve replacements; two had grafts to coronary arteries; and one had both replacement of the mitral valve and a right coronary vein graft. There were two hospital deaths (10%) and two late deaths (10%), making an overall mortality of 20%. All but one of the deaths were related to coronary artery disease. The survivors are active, and their rehabilitation was satisfactory. The longest survivor is doing well two years after left ventricular aneurysmectomy, ventricular defect closure, and tricuspid valve replacement. It is evident from our experience and from the reports of others that surgery has an established place in the management of post-infarction left ventricular aneurysm.
MMPI Profiles of Disability Insurance Claimants
Authors: JOHN W. SHAFFER, KURT NUSSBAUM, JOHN M. LITTLE
Journal: American Journal of Psychiatry (1972)

MMPI profiles from a random sample of 1,064 physical (nonpsychiatric) disability insurance claimants were compared with those of 14,306 general medical patients, matched for age and sex, seen at the Mayo Clinic. In contrast with the latter, the disability insurance claimants produced mean profiles in the clinically significant range. These results confirm earlier clinical findings that between 35 and 44 percent of the physical disability sample suffered from moderate to severe psychoneuroses or personality disorders.
Fasting C-Peptide Levels and Death Resulting From All Causes and Breast Cancer: The Health, Eating, Activity, and Lifestyle Study
Authors: Melinda L. Irwin, Catherine Duggan, Ching-Yun Wang, Ashley Wilder Smith, Anne McTiernan, Richard N. Baumgartner, Kathy B. Baumgartner, Leslie Bernstein, Rachel Ballard-Barbash
Journal: Journal of Clinical Oncology (2010)

Purpose To examine the association between serum C-peptide, a marker of insulin secretion, measured 3 years after a breast cancer diagnosis, and death resulting from all causes and breast cancer. Patients and Methods This was a prospective, observational study of 604 women enrolled onto the Health, Eating, Activity, and Lifestyle (HEAL) Study who were diagnosed with local or regional breast cancer between 1995 and 1998 and observed until death or December 31, 2006, whichever came first. The hazard ratio (HR) for all deaths and deaths owing to breast cancer and 95% CIs for the HR were estimated using multivariable stratified Cox regression analyses. Results Among women without type 2 diabetes, fasting C-peptide levels were associated with an increased risk of death resulting from all causes and from breast cancer. A 1-ng/mL increase in C-peptide was associated with a 31% increased risk of any death (HR = 1.31; 95% CI, 1.06 to 1.63; P = .013) and a 35% increased risk of death as a result of breast cancer (HR = 1.35; 95% CI, 1.02 to 1.87, P = .048). Associations between C-peptide levels and death as a result of breast cancer were stronger in certain subgroups, including women with type 2 diabetes, women with a body mass index less than 25 kg/m 2 , women diagnosed with a higher stage of disease, and women whose tumors were estrogen receptor positive. Conclusion Treatment strategies to reduce C-peptide levels in patients with breast cancer, including dietary-induced weight loss, physical activity, and/or use of insulin-lowering medications, should be explored.
Bisphosphonates and glucocorticoid-induced osteoporosis: implications for patients with respiratory diseases
Authors: S. COWAN, S. MORIN, P. ERNST
Journal: Thorax (1998)

67 As long term treatment with oral glucocorticoids is a common practice in the management of patients with chronic respiratory diseases, strategies to decrease the burden of glucocorticoid-induced osteoporosis are needed. Glucocorticoid-induced bone loss results from a decrease in bone formation due to reduced intestinal calcium absorption, increased urinary calcium excretion, and reduced osteoblast formation and function. 1248 The bisphosphonates, a class of drugs structurally similar to pyrophosphate, alter the bone remodelling process. By binding to hydroxyapatite these agents structurally inhibit osteoclastic activity and prevent bone resorption. 9 This significantly increases bone mineral density in the lumbar spine and femur and decreases the rate of fracture at these sites. 10‐13 For this reason, bisphosphonates such as etidronate and alendronate have received oYcial approval for the treatment and prevention of postmenopausal osteoporosis in many countries. The bisphosphonates have also been studied in the prevention and treatment of glucocorticoidinduced osteoporosis. In this issue of Thorax Pitt et al shed further light on the use of etidronate for the treatment of glucocorticoidinduced osteoporosis. 14 Using a double blind, placebo controlled design, patients receiving oral glucocorticoids for at least six months were randomised to receive etidronate 400 mg daily or placebo for 14 days followed by 76 days of calcium and vitamin D supplementation.This three month cycle was repeated eight times over a two year period. In the primary measure of outcome a significant diVerence between etidronate and placebo was found in the mean percentage change from baseline in the lumbar spine after two years. Specifically, after six months there was a mean increase of 4.33% in the bone mineral density of the lumbar spine for the etidronate group which increased to 5.12% at two years. In contrast, no clinically important changes were reported in patients receiving placebo. 14
The inflammatory and proliferative response of normal skin in a model for acute chemical injury: ornithine decarboxylase induction as a common feature in various models for acute skin injury
Authors: W.M.G.VAN DUIJNHOVEN-AVONTUUR, J.A.C. ALKEMADE, J. SCHALKWIJK, P.D. MIER, P.G.M. VALK
Journal: British Journal of Dermatology (1994)

Journal Article The inflammatory and proliferative response of normal skin in a model for acute chemical injury: ornithine decarboxylase induction as a common feature in various models for acute skin injury Get access W.M.G.VAN DUIJNHOVEN‐AVONTUUR, W.M.G.VAN DUIJNHOVEN‐AVONTUUR Department of Dermatology, University Hospital, Nijmeyen, the Netherlands Search for other works by this author on: Oxford Academic Google Scholar J.A.C. ALKEMADE, J.A.C. ALKEMADE Department of Dermatology, University Hospital, Nijmeyen, the Netherlands Search for other works by this author on: Oxford Academic Google Scholar J. SCHALKWIJK, J. SCHALKWIJK Department of Dermatology, University Hospital, Nijmeyen, the Netherlands Search for other works by this author on: Oxford Academic Google Scholar P.D. MIER, P.D. MIER Department of Dermatology, University Hospital, Nijmeyen, the Netherlands Search for other works by this author on: Oxford Academic Google Scholar P.G.M. VAN DER VALK P.G.M. VAN DER VALK Department of Dermatology, University Hospital, Nijmeyen, the Netherlands P.G.M.van der Valk, Department of Dermatology, University Hospital Nijmegen, Postbus 9101, 6500 HB Nijmegen, the Netherlands. Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 130, Issue 6, 1 June 1994, Pages 725–730, https://doi.org/10.1111/j.1365-2133.1994.tb03409.x Published: 01 June 1994 Article history Accepted: 20 October 1993 Published: 01 June 1994
Prostate Cancer Screening: Facts, Statistics, and Interpretation in Response to the US Preventive Services Task Force Review
Authors: Sigrid Carlsson, Andrew J. Vickers, Monique Roobol, James Eastham, Peter Scardino, Hans Lilja, Jonas Hugosson
Journal: Journal of Clinical Oncology (2012)

Recently, the US Preventive Services Task Force (USPSTF) published a review of the evidence for screening for prostate cancer1 and made a clear recommendation against screening. By giving a grade of “D” in the recommendation statement that was based on this review, the USPSTF concluded that “there is moderate or high certainty that this service has no net benefit or that the harms outweigh the benefits.” 2(p3)