tbuckley/cabot-search huggingface dataset:
Abstract 4765: Drug synergies observed for antibody and toxin components of SAR3419 ADC contribute to overall conjugate efficacy and can be combination drug or tumor cell line dependent
Authors: Richard J. Rickles, Thomas P. Giordano, Shakira F. Cotard, Jill M. Grenier, Angela Romanelli, Ti Cai
Journal: Cancer Research (2014)

Abstract SAR3419, a novel antibody-drug conjugate (ADC), is composed of a humanized monoclonal IgG1 anti-CD19 antibody (huB4) attached by a cleavable linker to DM4, a derivative of cytotoxic agent maytansine (an inhibitor of microtubule polymerization). CD19 expression is restricted to B-cells and treatment of CD19-positive human lymphoma cells with SAR3419 can result in cell cycle arrest followed by apoptosis. As traditional monotherapies can rarely treat cancer effectively, particularly in non-solid tumours, a combination high throughput screen (cHTS) was performed where SAR3419 was combined with two hundred potential enhancer compounds across a panel of twenty cell lines using a 6x6 combination dose response matrix. The enhancer compounds compose a library of approved, emerging oncology drugs, and well-defined molecular probes. Robust synergies were observed between SAR3419 and PI3K inhibitors and examined further. Target/pathway inhibitor redundancy for the class of compounds served to validate PI3K inhibition as important for combination synergy. Surprisingly, for several of the cell lines, the molecular mechanism important for SAR3419-dependent combination activity is distinct. For example, for the Daudi and REC-1 tumor cell lines, PI3K inhibitor synergy can be attributed to the toxin DM4. In contrast for SU-DHL4 and SU-DHL6 cell lines, little combination activity is observed with toxin alone while the conjugate is strongly synergistic. By examining three-way combination activities (PI3K inhibitor x DM4 x huB4) using high resolution matrices, we show that the anti-CD19 antibody huB4 contributes to the synergy in the SU-DHL6 cell line and linkage of DM4 to huB4 (SAR3419) shifts both the potency and maximum activity for PI3K inhibitor combinations. The results demonstrate that the antibody component of an ADC can contribute to combination activity for specific drug pairings in a drug and cell-type specific manner and has wide ranging implications with respect to combination drug design. Citation Format: Richard J. Rickles, Thomas P. Giordano, Shakira F. Cotard, Jill M. Grenier, Angela Romanelli, Ti Cai. Drug synergies observed for antibody and toxin components of SAR3419 ADC contribute to overall conjugate efficacy and can be combination drug or tumor cell line dependent. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4765. doi:10.1158/1538-7445.AM2014-4765
Phenformin-induced Hypoglycaemia in Normal Subjects
Authors: J. Lyngsoe, J. Trap-Jensen
Journal: BMJ (1969)

Study of the effect of phenformin on the blood glucose level in normal subjects before and during 70 hours of starvation showed a statistically significant hypoglycaemic effect after 40 hours of starvation. This effect was not due to increased glucose utilization. Another finding in this study was a statistically significant decrease in total urinary nitrogen excretion during starvation in subjects given phenformin. These findings show that the hypoglycaemic effect of phenformin in starved normal subjects is due to inhibition of gluconeogenesis.
Ophthalmic Examination in Diabetes Mellitus
Authors: Stanley P. Griffith
Journal: JAMA (1994)

<h3>To the Editor.</h3> —Dr Brechner and colleagues<sup>1</sup>point out in their recent article that "about half of adults with diabetes in the United States are not receiving timely and recommended eye care to detect and treat retinopathy." Screening for retinopathy can identify early disease and prevent major vision loss. However, we have still not determined the most cost-effective screening method. Numerous articles have been published evaluating the accuracy and cost-effectiveness of various strategies of screening for diabetic retinopathy. Most have defined "accuracy" as diagnosing specific grades of diabetic retinopathy. For example, Singer et al<sup>2</sup>reviewed a previous study by Moss et al<sup>3</sup>and calculated that ophthalmoscopy had a sensitivity of 79% and a specificity of 99% for the detection of proliferative retinopathy. Of the patients known to have proliferative retinopathy by the criterion standard examination in the study by Moss et al,<sup>3</sup>screening identified proliferative retinopathy
Atrial natriuretic factor reduces cyclic adenosine monophosphate content of human fibroblasts by enhancing phosphodiesterase activity.
Authors: M A Lee, R E West, J Moss
Journal: Journal of Clinical Investigation (1988)

Radioligand binding studies disclosed one class of high affinity atrial natriuretic factor (ANF) receptors on human fibroblast membranes (Kd = 66 pM; maximum number of binding sites [Bmax] = 7,000 sites/cell). ANF increased cellular cyclic guanosine monophosphate (cGMP) content and suppressed isoproterenol- and PGE1-elevated, but not basal, cAMP content. Pertussis toxin pretreatment, which maximally ADP-ribosylated Gi, the guanine nucleotide-binding protein that couples inhibitory receptors to adenylate cyclase and blocks receptor-mediated inhibition of adenylate cyclase, did not interfere with ANF suppression of isoproterenol- or PGE1-elevated cellular cAMP content. Preliminary incubation of fibroblasts with 8-bromo cGMP or phosphodiesterase inhibitors, including 3-isobutyl-1-methylxanthine, Ro 20-1724, and cilostamide, however, prevented the ANF suppression of cAMP. MB 22948, an inhibitor that is partially selective for cGMP phosphodiesterase, did not block the effect of ANF. We conclude that in these cells, unlike other systems, ANF reduces cAMP content by activating a phosphodiesterase rather than by inhibiting adenylate cyclase.
From 'regeneration' to prostheses: research on spinal cord injury
Authors: P. Gunby
Journal: JAMA (1981)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Coronary Artery Syndromes After Sudden Propranolol Withdrawal
Authors: EDWIN L. ALDERMAN
Journal: Annals of Internal Medicine (1974)

Six patients with stable exertional angina pectoris immediately developed unstable angina after cessation of propranolol therapy. The character and frequency of the pain episodes were significantly worse than those that the patients had experienced either before or during propranolol treatment. Four patients had acute coronary events (myocardial infarction in three and sudden death in one) after 2 to 21 days of continuing unstable angina. Two patients returned to their usual clinical state when propranolol therapy was recommenced. All patients had moderately severe angina before treatment and had shown excellent clinical responses to propranolol therapy. In our experience propranolol withdrawal syndromes have been an uncommon problem that may occasionally be seen in patients discontinuing medication before coronary arteriography or surgery.
Fetoscopic and Open Transumbilical Fetal Cardiac Catheterization in Sheep
Authors: Thomas Kohl, Zoltan Szabo, Kenji Suda, Edwin Petrossian, Eitetsu Ko, Deniz Kececioglu, Philip Moore, Norman H. Silverman, Michael R. Harrison, Tony M. Chou, Frank L. Hanley
Journal: Circulation (1997)

Background Shortening the prenatal disease course of severe aortic and pulmonary stenoses by balloon valvuloplasty may diminish their postnatal expression. The purpose of this study in fetal sheep was to assess the feasibility of fetoscopic and open transumbilical fetal cardiac catheterization guided by fetal transesophageal echocardiography to provide alternative approaches for human fetal cardiac intervention. Methods and Results We studied a total of nine fetal sheep (95 to 103 days of gestation; term=145 to 150 days) and performed transumbilical fetal cardiac catheterization by a minimally invasive fetoscopic (n=6) or an open fetal surgical approach (n=3). Monitored by fetal transesophageal echocardiography, with an 8F or 10F, 10-MHz intravascular ultrasound catheter we placed guidewires and interventional catheters via the umbilical arterial route into the fetal heart. In three of the fetuses, we created supravalvar pulmonary artery stenosis by open fetal cardiac surgery. After fetal and maternal recovery, we exteriorized these fetuses and performed open transumbilical fetal cardiac catheterization with successful pulmonary arterial angioplasty in two. Three fetuses survived fetoscopic transumbilical catheterization for 1 or 2 days and died most likely of blood loss after sheath dislodgment (n=1) or removal (n=2). By securing the sheath insertion site with a suture, we prevented sheath dislodgment and minimized bleeding during sheath removal in three fetuses. These fetuses then survived fetoscopic transumbilical fetal cardiac catheterization for 1 to 2 weeks before being killed. Conclusions This study in fetal sheep demonstrates that fetoscopic and open transumbilical fetal cardiac catheterization are feasible and, guided by fetal transesophageal echocardiography, provide potential alternative approaches for human fetal cardiac intervention.
UVA solarium versus UVB phototherapy of atopic dermatitis: a paired-comparison study
Authors: J. JEKLER, O. LARKO
Journal: British Journal of Dermatology (1991)

In a paired-comparison study, 21 patients suffering from atopic dermatitis were treated with fluorescent tubes radiating mainly ultraviolet A (UVA) on one half of the body and with tubes radiating mainly UVB on the other. Treatment was given three times a week for up to 8 weeks. Eight variables reflecting disease status were recorded and the sum of these comprised the total score. The total score and the overall evaluation score were better with UVA therapy (P less than 0.02 and P = 0.01, respectively). No statistically significant difference for the pruritus score was found. The reduction in extent of dermatitis, seen with both therapies, was more pronounced with UVA (P less than 0.05). Differences in the healing score were not statistically significant. Treatment with UVA resulted in healing or considerable improvement in 15 patients and 13 patients showed improvement when treated with UVB. A better result was found with UVA in 10 subjects and with UVB in two subjects. Equal results occurred with both UVA and UVB in nine of the patients although most preferred UVA treatment.
Fatal Spontaneous Rupture of an Aortic Aneurysm in a Young Adult
Authors: A. W. McCracken, D. J. Stoker
Journal: Thorax (1961)

AIMS: To determine at what stage there is increased expression of transforming growth factor alpha (TGF alpha) in preneoplastic diseases of the breast and to determine if this would assist in the histological diagnosis of different intraduct epithelial proliferations. METHODS: Specimens were retrieved from the archives of 17 cases of ductal hyperplasia, six cases of atypical ductal hyperplasia and 13 cases of ductal carcinoma in situ together with 12 9normal9 breast biopsy specimens. Sections were stained immunohistochemically for TGF alpha. The staining was assessed semi-quantitatively taking into account both the staining intensity and the proportion of cells stained. RESULTS: Minimal expression of TGF alpha was observed in normal breast tissue. Increased levels of expression were seen in ductal hyperplasia, atypical ductal hyperplasia, and ductal carcinoma in situ. Increased levels of expression of TGF alpha were also found in morphologically normal ducts immediately adjacent to areas of intraduct epithelial proliferation. CONCLUSION: Increased expression of TGF alpha occurs in the early stages of intraduct epithelial proliferation and will not help the histopathologist distinguish atypical ductal hyperplasia from either ductal hyperplasia or ductal carcinoma in situ. The molecular changes within a cell may precede the morphological changes observed by light microscopy thereby reflecting the biological potential of the epithelium.
Cystic fibrosis. 2. Lung injury in cystic fibrosis.
Authors: J S Elborn, D J Shale
Journal: Thorax (1990)

The major cause of death in cystic fibrosis is respiratory failure associated with pulmonary hypertension and cor pulmonale.This follows a variable period of chronic pulmonary infec- tion and progressive lung injury associated with a considerable morbidity.Lung injury is caused mainly by a continuous and exuberant host inflammatory response to chronic endobronchial bacterial infection.The initia- tion of infection and the regulation of the inflammatory response are poorly defined and greater understanding of both might indicate ways of protecting the lungs and prolonging survival.Pathology of the lung in cystic fibrosis Histological abnormalities of the lung are detectable within the first few days of life.'Before any infective episodes submucosal gland hypertrophy, duct obstruction, and mucus cell hyperplasia occur.These abnor- malities are probably related to the underlying genetic defect and encourage colonisation of the respiratory tract with microorganisms.Repeated pulmonary infection causes bron- chiolitis, mucus impaction, cyst formation, and ultimately bronchiectasis, which has been observed in children as young as 2 months.2This leads to a vicious circle of endobronchial and endobronchiolar infection and inflamma- tion with impaired ciliary function and reduced clearance of mucus.5Further bron- chial and bronchiolar damage occurs, leading to obstruction, bronchial compression, and secondary alveolar injury with atelectasis.
Congenital malignant melanoma: a case report
Authors: J. Asai, H. Takenaka, S. Ikada, F. Soga, S. Kishimoto
Journal: British Journal of Dermatology (2004)

Congenital malignant melanoma (MM) is an uncommon condition that is defined as MM recognized at birth. Its incidence is difficult to determine because of the small number of reported cases and because of problems associated with diagnosis. Generally, Spitz naevus and melanoma have many clinical and histopathological similarities, so it is difficult to differentiate between the two. We describe a rare case of congenital MM in which differential diagnosis from Spitz naevus was problematic. In addition, we review the literature and comment on the prognostic differences among the three types of congenital and infantile MM.
A typical case of pemphigoid gestationis with a unique pattern of intercellular immunofluorescence
Authors: S.A.VAUGHAN JONES, B.S. BHOGAL, M.M. BLACK, M. CLEMENT, T. HASHIMOTO, T. NISHIKAWA
Journal: British Journal of Dermatology (1997)

Pemphigoid gestationis is an autoimmune bullous disorder affecting pregnant women which typically presents in the second and third trimester of pregnancy with an itchy bullous eruption on the abdomen and limbs. The diagnosis is confirmed by the presence of complement-binding IgG antibasement membrane zone (BMZ) antibodies, which bind to the roof of salt-split skin. We describe a case of clinically typical pemphigoid gestationis with the combination of intercellular IgG and BMZ IgG and C3 staining on immunofluorescence, a pattern which is unique for this condition.
Monocyte tethering by P-selectin regulates monocyte chemotactic protein-1 and tumor necrosis factor-alpha secretion. Signal integration and NF-kappa B translocation.
Authors: A S Weyrich, T M McIntyre, R P McEver, S M Prescott, G A Zimmerman
Journal: Journal of Clinical Investigation (1995)

Adhesion molecules that tether circulating leukocytes to endothelial cells may also transduce or modulate outside-in signals for cellular activation, providing an initial regulatory point in the inflammatory response.Adhesion of human monocytes to P-selectin, the most rapidly expressed endothe- lial tethering factor, increased the secretion of monocyte chemotactic protein-i (MCP-1) and tumor necrosis factor- a (TNF-a) by the leukocytes when they were stimulated with platelet-activating factor.Increased cytokine secretion was specifically inhibited by G1, an anti-P-selectin mAb that prevents P-selectin from binding to its ligand (P-selectin glycoprotein ligand-1) on myeloid cells.Moreover, tethering by P-selectin specifically enhanced nuclear translocation of nuclear factor-KB (NF-cB), a transcription factor required for expression of MCP-1, TNF-a, and other immediate-early genes.These results demonstrate that P-selectin, through its ligands on monocytes, may locally regulate cytokine secretion in inflamed tissues.(
Hyponatraemia and severity and outcome of myocardial infarction.
Authors: C T Flear, P Hilton
Journal: BMJ (1979)

A total of 235 consecutive patients admitted to a coronary care unit were investigated for serum electrolyte and urea concentrations; activities of aspartate amino-transferase, lactate dehydrogenase, and lactate dehydrogenase isoenzymes; electrocardiographic changes; clinical state; and outcome. Hyponatraemia, hypochloraemia, and uraemia were common in patients with confirmed myocardial infarctions, the degree of infarction correlating well with all the above indices of severity. The day-to-day variability of plasma sodium, chloride, and potassium concentrations was often increased above normal. Disturbances were greater in patients given diuretics. It is concluded that plasma sodium concentration fall after infarction and that the extent and duration of the fall are indices of the severity of the infarction.
Drug Trials—the Dark Side: This World
Authors: Ike Iheanacho
Journal: BMJ (2006)

An advert posted inside some London buses shrieks, “Drop by today—it could be a beneficial visit!” Placed by the pharmaceutical services company PAREXEL, it seeks volunteers for research—at Northwick Park Hospital. The recent disastrous trial of the monoclonal antibody TGN 1412 at that venue has heightened the public's interest in clinical drug studies. And the long term result may be increased scepticism, such that fewer people in the United Kingdom will be willing to participate in clinical research, no matter how upbeat the recruitment messages.

In addressing this problem, the pharmaceutical industry is, predictably, well ahead of the game. For instance, clinical trials are increasingly being conducted in developing countries that offer a rich source of suitable and apparently willing patients. Drug Trials—the Dark Side was a compelling documentary on how drug companies are targeting India for this purpose.

The scene was set by the comments of a patient-recruitment agent, who boasted how much quicker and cheaper it was to enrol patients for trials in India, compared with, for example, the United States and countries in …
IgA1 is the major IgA subclass in cutaneous blood vessels in Henoch-Schonlein purpura
Authors: C.A. Egan, T.B. Taylor, L.J. Meyer, M.J. Petersen, J.J. Zone
Journal: British Journal of Dermatology (1999)

Henoch–Schönlein purpura (HSP) is characterized by palpable purpura predominantly involving the lower extremities. On direct immunofluorescence IgA can be seen deposited in the blood vessel walls of the superficial dermis. The subclass distribution of antibodies to this IgA was studied in the biopsies of 28 patients with HSP by direct immunofluorescence using anti‐IgA1 and anti‐IgA2 specific monoclonal antibodies. All 28 patients' biopsies demonstrated deposition of IgA1 while only one patient had IgA2 deposition. Positive and negative controls stained appropriately. This demonstrates that IgA1 is the dominant IgA subclass found in the skin in Henoch–Schönlein purpura.
More than just a simple fracture
Authors: M. Monem, A. Trompeter
Journal: BMJ (2014)

A 10 year old white girl presented to our emergency department after falling on to her left arm while cart wheeling in her garden. After the fall, she had pain and was reluctant to move her arm. She had no symptoms before the fall and no other injuries at the time. She was otherwise fit and well with no medical history of note.

On examination, she had mild swelling of her left upper arm, which was tender. The skin was intact with no bruising or other external signs of injury. No deformity of the upper limb was noted, and her distal neurological and vascular status was normal on examination. This was an isolated injury. Basic observations including heart rate, blood pressure, and temperature were all normal. She was otherwise well.

Plain anterioposterior (fig 1⇓) and lateral radiographs of the left shoulder were requested.





### 1 What does the radiograph show?

#### Short answer

This anterioposterior radiograph of the left proximal humerus shows a fracture in the proximal metaphysis. Minimal displacement is seen and there is no intra-articular involvement. However the bone has a lytic appearance. This is a pathological fracture.

#### Long answer

In patients who have experienced trauma to the humerus, it is important to request both anterioposterior and lateral radiographs. The anterioposterior radiograph shows an underlying expansile metaphyseal lytic “bubble” lesion (fig 2⇓), which is spreading distally to the diaphysis and is accompanied by cortical thinning. This lesion abuts but does not affect the physis (growth plate), and no periosteal reaction is seen. There is no associated soft tissue lesion. The zone of transition from normal to pathological bone …