tbuckley/cabot-search huggingface dataset:
Phase 1 Clinical Trial of Intratumoral Reovirus Infusion for the Treatment of Recurrent Malignant Gliomas in Adults
Authors: Kimberly P Kicielinski, E Antonio Chiocca, John S Yu, George M Gill, Matt Coffey, James M Markert
Journal: Molecular Therapy (2014)

Reovirus, an oncolytic RNA virus exhibiting antiglioma activity, was shown in a previous single institution phase 1 study found that the inoculation of the virus to be well tolerated in patients with recurrent malignant glioma (MG). The goals of multicenter study reported herein were to determine the dose-limiting toxicity, maximum tolerated dose, and target lesion response rate when reovirus was administered in a novel fashion via intratumoral infusion for 72 hours in patients with recurrent malignant glioma. Fifteen adult patients were treated in a dose escalation study ranging from 1 × 108 to 1 × 1010 tissue culture infectious dose 50, tentimes the dose achieved in the previous trial. Neurological, functional examinations, and imaging studies were completed pre- and postinfusion. There was one grade 3 adverse event (convulsions) felt to be possibly related to treatment, but no grade 4 adverse events considered probably or definitely related to treatment. Dose-limiting toxicity were not identified and a maximum tolerated dose was not reached. Evidence of antiglioma activity was seen in some patients. This first report of intratumoral infusion of reovirus in patients with recurrent malignant glioma demonstrated the approach to be safe and well tolerated, warranting further studies. Reovirus, an oncolytic RNA virus exhibiting antiglioma activity, was shown in a previous single institution phase 1 study found that the inoculation of the virus to be well tolerated in patients with recurrent malignant glioma (MG). The goals of multicenter study reported herein were to determine the dose-limiting toxicity, maximum tolerated dose, and target lesion response rate when reovirus was administered in a novel fashion via intratumoral infusion for 72 hours in patients with recurrent malignant glioma. Fifteen adult patients were treated in a dose escalation study ranging from 1 × 108 to 1 × 1010 tissue culture infectious dose 50, tentimes the dose achieved in the previous trial. Neurological, functional examinations, and imaging studies were completed pre- and postinfusion. There was one grade 3 adverse event (convulsions) felt to be possibly related to treatment, but no grade 4 adverse events considered probably or definitely related to treatment. Dose-limiting toxicity were not identified and a maximum tolerated dose was not reached. Evidence of antiglioma activity was seen in some patients. This first report of intratumoral infusion of reovirus in patients with recurrent malignant glioma demonstrated the approach to be safe and well tolerated, warranting further studies.
PRIMARY ANTIBODY RESPONSE IN VITRO IN PERITONEAL CELLS
Authors: Alain E. Bussard, Melvyn Lurie
Journal: The Journal of Experimental Medicine (1967)

Peritoneal cells (PC), from nonimmunized mice, incubated in a carboxymethyl cellulose gum containing sheep red blood cells (SRBC) and guinea pig complement (following the technique of Ingraham and Bussard) start to produce plaques of hemolysis 20 hr after the beginning of incubation at 37 degrees C. In contrast, spleen cells from immunized mice complete their plaque-forming activity in 6 hr. The fact that formation of plaques by previously uncommitted cells is related to the life of the leukocytes, and is complement dependent brings evidence that we are dealing with an immunological phenomenon. Puromycin suppresses the formation of plaque. Previous incubation of the PC with SRBC in liquid medium, before incorporation in the detection system, reduces the lag in the production of plaques. This indicates that a phase of stimulation precedes the phase of expression (manifested by plaque formation). The immunological activity of the peritoneal cell suspension is highly dependent on the concentration of the suspension, which indicates that this activity results from a cooperative process. Actinomycin D, which does not suppress the production of plaques by cells from immunized animals, stops completely the in vitro induction. It is concluded that we have probably observed a primary immune response induced in vitro.
Evidence for tissue-resident mesenchymal stem cells in human adult lung from studies of transplanted allografts
Authors: Vibha N. Lama, Lisa Smith, Linda Badri, Andrew Flint, Adin-Cristian Andrei, Susan Murray, Zhuo Wang, Hui Liao, Galen B. Toews, Paul H. Krebsbach, Marc Peters-Golden, David J. Pinsky, Fernando J. Martinez, Victor J. Thannickal
Journal: Journal of Clinical Investigation (2007)

The origin and turnover of connective tissue cells in adult human organs, including the lung, are not well understood. Here, studies of cells derived from human lung allografts demonstrate the presence of a multipotent mesenchymal cell population, which is locally resident in the human adult lung and has extended life span in vivo. Examination of plastic-adherent cell populations in bronchoalveolar lavage samples obtained from 76 human lung transplant recipients revealed clonal proliferation of fibroblast-like cells in 62% (106 of 172) of samples. Immunophenotyping of these isolated cells demonstrated expression of vimentin and prolyl-4-hydroxylase, indicating a mesenchymal phenotype. Multiparametric flow cytometric analyses revealed expression of cell-surface proteins, CD73, CD90, and CD105, commonly found on mesenchymal stem cells (MSCs). Hematopoietic lineage markers CD14, CD34, and CD45 were absent. Multipotency of these cells was demonstrated by their capacity to differentiate into adipocytes, chondrocytes, and osteocytes. Cytogenetic analysis of cells from 7 sex-mismatched lung transplant recipients harvested up to 11 years after transplant revealed that 97.2% ± 2.1% expressed the sex genotype of the donor. The presence of MSCs of donor sex identity in lung allografts even years after transplantation provides what we believe to be the first evidence for connective tissue cell progenitors that reside locally within a postnatal, nonhematopoietic organ.
Consensus and Controversy in Clinical Research Ethics
Authors: Baruch A. Brody, Laurence B. McCullough, Richard R. Sharp
Journal: JAMA (2005)

AN INTERNATIONAL CONSENSUS FOR PROTECTING THE rights and interests of research subjects has emerged in a process that began with the Declaration of Helsinki and continues in the development of official guidelines as well as a growing scholarly literature. Despite this consensus, legitimate ethical controversies persist. This article discusses points of consensus and controversy in clinical research ethics, focusing on substantive, rather than procedural, concerns.
Mechanisms involved in airway obstruction: the role of smooth muscle
Authors: G. Mazzarella, L. Stendardi, M. Grazzini, G. Scano
Journal: Allergy (2000)

Structural changes in the airway walls that are probably driven by mediators released as a consequence of chronic allergic inflammation are prominent features of asthma. However, it is not clear how each of the many changes that occur in the airway wall contribute to altered airway function in asthma. Collagen deposition in the subepithelial matrix, around and inside the smooth muscle, would be expected to oppose the effect of smooth-muscle contraction. Conversely, geometric factors would result in exaggerated airway narrowing for a given degree of smooth-muscle shortening; decreased airway wall stiffness and increased airway narrowing for a given amount of force generated by the smooth muscle. Degradation of the matrix may alter the coupling between muscle and lung recoil, allowing exaggerated smooth-muscle shortening. Increase in muscle mass associated with preservation of its contractile capacity could be the most important contributor to exaggerated airway narrowing.
Canada's new law strengthens drug regulatory powers but is vague on mandatory trial registration
Authors: O. Dyer
Journal: BMJ (2014)

Canada’s parliament has passed a bill enabling health ministers to compel the recall of unsafe drugs and demand labelling changes, steps that previously required lengthy negotiations with manufacturers.

Bill C-17, which has passed its final reading in the Senate and now awaits only royal assent, brings Canada’s historically weak regulatory powers into line with those in other jurisdictions in developed countries. It also empowers the health minister to disclose confidential business information in explaining decisions and to order companies to conduct post-marketing studies, whose results the national health department, Health Canada, may share with provincial and aboriginal governments.

The …
Influence of successive vagal stimulations on contractions in esophageal smooth muscle of opossum.
Authors: J S Gidda, R K Goyal
Journal: Journal of Clinical Investigation (1983)

Studies were performed in anesthetized opossums to investigate the influence of successive vagal stimuli on esophageal contractions. Mechanical activity was recorded manometrically 5 cm above the lower esophageal sphincter. Contractions in the esophagus were evoked by electrical stimuli of 2.5 mA, and 1-ms pulse duration applied to the cervical vagi, at various train durations and frequencies. Paired or multiple stimuli of 1-s train length were also tested at different interstimulus intervals (ISI). Paired stimuli at an ISI of less than or equal to 3 s and at a frequency of less than or equal to 10 Hz showed refractoriness, i.e., the contractions to the first stimulus inhibited the contraction to the second stimulus. A frequency of 50 Hz showed initial inhibition, i.e., the second stimulus inhibited the contraction to the first stimulus. Repetitive stimuli applied at a rate of 8/min (ISI 6.5 s) evoked contractions to each stimulus. At 15/min, every second or third contraction was inhibited. With stimuli applied at 30/min, contractions occurred only in response to the first and/or the last stimulus; depending upon the frequency of vagal stimulation. The intervening stimuli did not evoke any contractions. A long train stimulus produced an initial, a terminal, or both contractions depending on the stimulation value. These studies show that (a) vagal efferent stimulation causes initial inhibition and refractoriness in the esophageal smooth muscle; (b) the degree of initial inhibition increases with increasing frequency of stimulation; (c) the occurrence of contractions only at the onset and the end of a long train stimulus may be due to the influence of initial inhibition and refractoriness.
Evaluation of bcl-2 protein expression in the normal mammary epithelium of premenopausal women treated with raloxifene.
Authors: IM Lopes, BB da Silva, AR dos Santos, PV Lopes-Costa
Journal: Cancer Research (2009)

Abstract Abstract #5087 Background: Bcl-2 is one of the most important blockers of cell death and therapeutic strategies to reduce its expression may be useful in breast cancer chemoprevention. The aim of this study was to evaluate the expression of the bcl-2 protein in the normal breast tissue of premenopausal women. Materials and Methods: Thirty ovulatory premenopausal women of 18 to 40 years of age, who had been diagnosed fibroadenoma of the breast participated of this study. This was a randomized, double-blind, placebo controlled study. Patiens were randomized into two groups: Group A (placebo, n=16) and Group B (raloxifene, n=14). The drug was administered in the dose of 60 mg/day for 22 days, beginning on the first day of menstrual cycle. Excision of fibroadenoma was carried out on the 23rd day during which a sample of normal breast tissue was collected for immunohistochemistry. Cells in which cytoplasm was intensely stained in brown by anti-bcl-2 antibody were considered positive for bcl-2. A number of 500 cells on each slide were counted using a light microscope (400x), beginning with the area in which there was the greatest expression of bcl-2. The percentage of stained cells for each case was obtained from the ratio between the number of cells with stained cytoplasm and total of cells multiplied by 100. Student's t test was used to compare the means of percentages of stained cytoplasms in the two groups (p&amp;lt;0.05). Results: There was a significant reduction in the mean percentage of bcl-2-stained cytoplasms in the group that received raloxifene compared to the placebo group, 10.90±2.11 and 19.05±2.36, respectively (p&amp;lt;0.017). Discussion: Our results indicate that raloxifene reduces the anti-apoptotic bcl-2 protein expression in the normal breast tissue of premenopausal women reinforcing the argument for its use in chemoprevention of breast cancer. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 5087.
Plasma arginine vasopressin concentrations and antidiuretic action of carbamazepine.
Authors: W P Stephens, J Y Coe, P H Baylis
Journal: BMJ (1978)

Twelve subjects given therapeutic doses of carbamazepine showed no change in their plasma electrolyte concentrations. Ten of the 12 had abnormal water metabolism, however, their ability to excrete water loads being decreased. Plasma arginine vasopressin (AVP) concentrations fell while the subjects were taking the drug, indicating that the mechanism is unlikely to be increased secretion of antidiuretic hormone. We suggest that the water-retaining property of carbamazepine is a physiological effect of the drug, mediated by increased renal sensitivity to normal plasma concentrations of AVP and resetting of osmoreceptors.
Highly efficient elimination of Philadelphia leukemic cells by exposure to bcr/abl antisense oligodeoxynucleotides combined with mafosfamide.
Authors: T Skorski, M Nieborowska-Skorska, C Barletta, L Malaguarnera, C Szcyzlik, S T Chen, B Lange, B Calabretta
Journal: Journal of Clinical Investigation (1993)

Synthetic oligodeoxynucleotides complementary to the break-point junction of bcr-abl transcripts selectively inhibit the proliferation of Philadelphia-positive leukemic cells, but residual leukemic cells persist in antisense oligodeoxynucleotides-treated cultures. Cyclophosphamide derivatives such as mafosfamide and 4-hydroperoxycyclophosphamide are used at high doses for purging of Philadelphia leukemic cells from marrows but such treatment can be associated with delayed engraftment and prolonged cytopenias. To develop a more effective procedure that might optimize the killing of leukemia cells and the sparing of normal hematopoietic progenitor cells, a 1:1 mixture of Philadelphia leukemic cells and normal bone marrow cells was exposed to a combination of a low dose of mafosfamide and bcr-abl antisense oligodeoxynucleotides and assayed for growth ability in clonogenic assays and in immunodeficient mice. Bcr-abl transcripts were not detected in residual colonies, and cytogenetic analysis of individual colonies revealed a normal karyotype. Normal but not leukemic hematopoietic colonies of human origin were also detected in marrows of immunodeficient mice 1 mo after injection of the treated cells. Our results indicate that a combination of a conventional chemotherapeutic agent and a tumor-specific antisense oligodeoxynucleotide is highly effective in killing leukemic cells and in sparing a much higher number of normal progenitor cells as compared with high-dose mafosfamide treatment. This offers the prospect of a novel and more selective ex vivo treatment of chronic myelogenous leukemia.
Combined exposure to ozone and nitrogen dioxide.
Authors: B D Goldstein
Journal: Environmental Health Perspectives (1979)

A study of rats acutely exposed to ozone (0.5--2.0 ppm) or nitrogen dioxide (2--20 ppm) for 2 hr and sacrificed immediately thereafter shows little similarity in the individual biochemical effects of these pollutants. No evidence of nitrogen dioxide-induced lipid peroxidation was observed. Of interest is the finding that inhalation of nitrogen dioxide increases the extent to which concanavalin A agglutinates alveolar macrophages while ozone has exactly the opposite effect.
Case 30-1976
Authors: Richard C. Cabot, Robert E. Scully, James J. Galdabini, Betty U. McNeely, Ronald A. Malt, Austin L. Vickery
Journal: New England Journal of Medicine (1976)

Presentation of CaseA 62-year-old man was admitted to the hospital because of a diagnosis of an abdominal aortic aneurysm.He was well until several months previously, when there was the onset of weight loss in an amount of 4 kg, with vague discomfort in the lower portion of the abdomen. A physician found an abdominal mass and referred him to this hospital.There was a history of hypertension, which had been treated only briefly, and of impaired potency. There was no history of back pain, intermittent claudication, rest pain, nausea, vomiting, hematemesis, melena, diarrhea or constipation.The temperature was . . .
Fulminant necrotising fasciitis developing during long term corticosteroid treatment of systemic lupus erythematosus
Authors: N Hashimoto, H Sugiyama, K Asagoe, K Hara, O Yamasaki, Y Yamasaki, H Makino
Journal: Annals of the Rheumatic Diseases (2002)

Skin manifestations are some of the most common clinical symptoms and signs seen in patients with systemic lupus erythematosus (SLE). However, necrotising subcutaneous infection, in particular necrotising fasciitis, is rarely encountered. It is a rapidly progressive and destructive infection of the subcutaneous tissue, associated with mortality and long term morbidity of the affected patients.1 We describe a patient with SLE and liver cirrhosis complicated by severe necrotising fasciitis who had been receiving corticosteroid treatment for 20 years. Necrotic skin tissue cultures grew both Staphylococcus aureus and Serratia marcescens . Despite aggressive treatment, including administration of antibiotics, emergency debridement, and total plasma exchange for severe liver damage, she died of disseminated intravascular coagulation and multiple organ failure owing to serious bacterial infection after two months in hospital. This case suggests that severe necrotising fasciitis may occur in SLE without lupus flare up during long term treatment with low dose corticosteroids.

A 58 year old Japanese woman, who had been receiving oral prednisolone treatment for SLE for 20 years, was admitted to our hospital because of a swollen …
On Encountering Hopelessness
Authors: Theodore Nadelson
Journal: JAMA (1977)

Lisa Shulman's commentary (p 2149) is a pause or a time-out by a student (now Lisa Shulman, MD) in the midst of a demanding medical clerkship. As such, she shares with us a rare experience in clinical medicine. Caught up in the process of doing, there is usually little energy or time left to pull back and integrate experience.  One realizes that there is something in this episode that touches a shared experience for all physicians. We are reluctant to acknowledge it, so the author does it for us. Our treatment of patients is greatly influenced by unexamined factors present within ourselves and is shaped by recent events in  lives and within the hospital. We are often confronted by the fact that our reach exceeds  grasp, and in medical practice, given the intensity of expectations on all sides, this becomes a painful acknowledgment. Such disappointment often leads to
First report of IMI-1-producing colistin-resistant Enterobacter clinical isolate in Ireland, March 2013
Authors: T W Boo, N O’Connell, L Power, M O’Connor, J King, E McGrath, R Hill, K L Hopkins, N Woodford
Journal: Eurosurveillance (2013)

We report the first case in Ireland of an IMI-1 carbapenemase-producing Enterobacter asburiae, which was resistant to both colistin and fosfomycin. The circumstances under which this isolate was acquired were unclear. Several reports of IMI-producing Enterobacter spp. have emerged in recent years, and colistin resistance in Enterobacteriaceae is also increasingly reported. Laboratories should be aware of the unusual antibiograms of IMI-producing isolates.
1233 GS-6620: A LIVER TARGETED NUCLEOTIDE PRODRUG WITH POTENT PAN-GENOTYPE ANTI-HEPATITIS C VIRUS ACTIVITY IN VITRO
Authors: A.S. Ray, J.Y. Feng, T. Wang, K. Wong, L. Zhang, D. Babusis, J. Vela, T. Butler, J. Xu, V. Aktoudianakis, R. Lee, D. Sauer, I. Henne, M. Fenaux, H. Mo, W. Zhong, S. Metobo, J. Perry, C. Kim, A. Cho
Journal: Journal of Hepatology (2011)
Abstract PD02-07: Impact of Mesenchymal Stem Cells on Radiation Therapy Response
Authors: L Lacerda, A Gupta, BG Debeb, W Xu, R Meyn, F Marini, M Andreeff, WA Woodward, AH. Klopp
Journal: Cancer Research (2010)

Abstract Background: Radiation increases engraftment of human bone-marrow derived mesenchymal stem cells (MSC) in tumors and this effect is augmented following repeated doses of radiation. We have recently demonstrated that MSC increase formation of mammospheres, which are enriched with radiation resistant tumor-initiating cells. Thus, we hypothesized that MSC may impact radiation therapy response through enhanced survival of tumor-initiating cells. Materials &amp; Methods: To evaluate the impact of MSC on radiation response we performed in vitro clonogenic survival assays using 2D and 3D clonogenic assays. Colony (2D) and sphere (3D) formation was quantified following irradiation of different cell lines (breast, lung, head and neck and cervix) at 2, 4 and 6 Gy in the presence of MSC conditioned media. In vivo, MSC were co-injected subcutaneously at increasing percentages with 4T1 murine breast cancer cells in BALB/c mice. The effects of MSC on radiation response were evaluated by examination of tumor size and weight following tumor irradiation at 2 and 5 Gy. Results: In vitro 2D clonogenic cell survival assays demonstrated that MSC conditioned media increased survival of breast (MDA231), lung (H460), head and neck (HN5), and cervical (SiHa) cancer cells following irradiation with 2 and 4 Gy as compared to control fibroblast conditioned media. Moreover, MSC conditioned media increased the number of HMLE (breast normal ephitelial cells) and SUM149 (breast cancer cells) mammospheres formed (55 vs 195and 263 vs 1054, respectively) and increased clonogenic survival of mammospheres after 2, 4 and 6 Gy compared to serum-free media. In vivo, irradiation with 5 Gy reduced murine breast 4T1tumors weight by 75% as compared to control untreated tumors. However, tumors co-injected with MSC did not significantly respond to 5 Gy. Discussion: MSC increase tumor resistance to radiation therapy in vivo and in vitro in 2D and 3D cultures. This effect is mediated at least in part by paracrine factors secreted by MSC. Our results here described suggest that MSC secrete factors which activate survival pathways on cancer cells exposed to sub-lethal radiation doses. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr PD02-07.