tbuckley/cabot-search huggingface dataset:
Abstract LB-60: The BRAF:MEK complex reveals new therapeutic strategies for targeting KRASMT tumors.
Authors: Jacob R. Haling, Jawahar Sudhamsu, Georgia Hatzivassiliou, Kyung Song, Marcia Belvin, Sarah Hymowitz, Shiva Malek
Journal: Cancer Research (2013)

Abstract Spatial activation and regulation of MAPK signaling is determined by genetic context. In BRAFV600E tumor models kinase activity of BRAF is insensitive to normal regulatory mechanisms, whereas in KRASMT tumor models CRAF is the primary driver of the pathway and its function is governed by RAF dimerization, translocation to the plasma membrane, and phosphorylation. Since MEK is a common downstream substrate, multiple allosteric MEK inhibitors are being tested in clinical trials in BRAFV600E and KRASMT cancer types. To date, the efficacy of MEK inhibitors has been substantially higher in BRAFV600E tumors than in KRASMT tumors suggesting that the mechanism regulating MEK activity is different in these settings. In this work, we have discovered that BRAF has a suppressive function in KRASMT tumor lines by forming a stable cytosolic complex with MEK which prevents MEK from being phosphorylated by CRAF. Enrichment of this complex in KRASMT cells results in dampened phospho-MEK levels compared to BRAFV600E cells where little cytosolic BRAF:MEK complexes are observed. Treatment of KRASMT tumor cells with particular classes of MEK inhibitors stabilize the BRAF:MEK complex and inhibit phosphorylation of MEK, while other MEK inhibitors dissociate the complex and enhance MEK phosphorylation. Further we find that the former class of MEK inhibitors selectively prefers binding to the BRAF:MEK complex compared to MEK alone based on the significantly slower off-rate for the BRAF:MEK complex. The crystal structure of a heterotetrameric BRAF:MEK complex in the presence of G-573, an allosteric MEK inhibitor, provides structural rationale for this observation and sheds light on the ability of G-573 and similar classes of MEK inhibitors to prevent RAF phosphorylation of MEK at Ser-218 and Ser-222. Although all MEK inhibitors function to inhibit ERK phosphorylation, our data explains the discrepancy of MEK activation between different classes of MEK inhibitors. Hence we conclude that more effective strategies to treat KRASMT tumors may require targeting signaling protein complexes such as BRAF:MEK as opposed to inhibiting individual components of the pathway. Importantly our work illustrates small molecule kinase inhibitors may not only affect enzymatic activity but also regulate protein-protein interactions thereby influencing pathway signaling. Citation Format: Jacob R. Haling, Jawahar Sudhamsu, Georgia Hatzivassiliou, Kyung Song, Marcia Belvin, Sarah Hymowitz, Shiva Malek. The BRAF:MEK complex reveals new therapeutic strategies for targeting KRASMT tumors. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-60. doi:10.1158/1538-7445.AM2013-LB-60
Orthostatic Hypotension, Anhidrosis, and Impotence
Authors: MARVIN ROSECAN, ROBERT J. GLASER, MELVIN L. GOLDMAN
Journal: Circulation (1952)

Anhidrosis and impotence occur frequently with idiopathic orthostatic hypotension. Two new cases of this syndrome, which occurs chiefly in males over 40 years of age, are herewith described. Postural vertigo and/or syncope, weakness, and anhidrosis or hypohidrosis are common symptoms, and a marked fall in systolic and diastolic blood pressure is noted when the patients stand. The pathologic physiology of the syndrome is discussed and various forms of therapy, none of them especially satisfactory, are reviewed.
RGS Expression Rate-Limits Recovery of Rod Photoresponses
Authors: Claudia M. Krispel, Desheng Chen, Nathan Melling, Yu-Jiun Chen, Kirill A. Martemyanov, Nidia Quillinan, Vadim Y. Arshavsky, Theodore G. Wensel, Ching-Kang Chen, Marie E. Burns
Journal: Neuron (2006)
A case of cicatricial pemphigoid with simultaneous IgG autoantibodies against the 180 kd bullous pemphigoid antigen and laminin 5
Authors: Yoshie Kawaharaa, Masayuki Amagaia, Yoshiyuki Ohataa, Ken Ishiia, Yoshinori Hasegawab, Roger Hsuc, Carole Yeec, Kim B. Yanceyc, Takeji Nishikawaa
Journal: Journal of the American Academy of Dermatology (1998)
Stevens' cure for tuberculosis
Authors: R L Maynard
Journal: Journal of the Royal Society of Medicine (2002)

Stevens' cure for tuberculosis I was fascinated by Dr Newsom's account of Stevens' cure (September 2002 JRSM 1 ).In 1927 my father was apparently close to death in Talgarth TB sanatorium, South Wales, with severe bilateral lung disease and multiple haemoptyses.He was considered too ill for the thoracoplasty operation fashionable at the time.His father, himself dying of TB, had advised him on his deathbed to try Stevens' cure and at this stage of his illness he did.His recovery started from that date.He never had another haemoptysis and within 3-4 years was able to obtain life insurance and marry.The medical examiner was said to have flung down his stethoscope in amazement, declaring 'no sign of disease at all'.My father continued to take the umckaloabo root on and off for years but never had another attack.The distinctive pungent odour of what seemed to be an infusion would often fill the house and signal that Dad was not feeling too good for some reason.He worked as a chemistry teacher till he was 65 with never a day 'off sick' and died of heart failure at 77.When I went to Oxford to read medicine in 1958 I was found, to my surprise, to be Mantoux-test negative.My father, who possessed a lot of newspaper articles and one of the books on Stevens' cure, thought the BMA had been very unfair to Stevens (a non-medic) and very unscientific in their approach to a much needed avenue of possible TB research.Perhaps today, with the widespread resistance to TB drugs, the root should be properly evaluated.
Thermoactinomyces in Refrigerators
Authors: Benjamin Becker
Journal: JAMA (1976)

To the Editor.—  I have discovered thermophilic actinomycetes ( Thermoactinomyces ) growing in 66% of frost-free home refrigerators surveyed. Samples were taken from the drip pans of 230 refrigerators from homes in Indiana, New Jersey, and Illinois. Thermoactinomyces , which is a known cause of hypersensitivity pneumonitis (farmer's lung), readily produces millions of spores during growth.  More recently, I have isolated Thermoactinomyces from warm moist dirt at the outside bottom of a home freezer. Previously, Thermoactinomyces was found by others in overheated hay, grain, and bagasse, as well as in home heating systems and humidifiers. I suggest cleaning the drip pan with detergent once a month.
Visceral leishmaniasis with cutaneous lesions in a patient infected with human immunodeficiency virus
Authors: None Ara, None Maillo, None PEON, None Clavel, None Cuesta, None Grasa, None Carapeto
Journal: British Journal of Dermatology (1998)

We report a case of visceral leishmaniasis (VL) with cutaneous lesions in a patient infected with human immunodeficiency virus (HIV). The cutaneous lesions consisted of erythematous papules on the legs. Biopsy of one lesion showed abundant Leishmania amastigotes within epithelial cells of an eccrine sweat gland in the dermis. Leishmania organisms were also found in a blood smear. Rapid and complete clearance of the cutaneous lesions was achieved after antimony therapy. Cutaneous lesions in VL are being reported increasingly frequently in patients with HIV infection and their significance remains in discussion.
Aid workers are compromised by “war on terror,” UN official says
Authors: Peter Moszynski
Journal: BMJ (2007)

Humanitarian workers are facing unprecedented danger because of the erosion of the concept of neutrality in the wake of the war in Iraq and the “war on terror,” said the former United Nations deputy general Mark Malloch Brown.

Giving the International Rescue Committee's annual lecture at the Royal Geographical Society in London, Sir Mark said that “between 1997 and 2005 the number of relief workers lost annually had more than doubled to over 100.” Last year “60 aid workers were lost in Darfur alone.” This is partly because the number of aid workers has grown by 60% to 250 000, so “there …
Abstract 1768: Enhanced cytotoxicity and apoptosis of cisplatin by p53-reactivating small molecule RITA in head and neck cancer
Authors: Chang Hwan Ryu, In Sun Ryu, Gi Cheol Park, Jun Young Choi, Jung Je Park, Jong-Lyel Roh
Journal: Cancer Research (2012)

Abstract Overexpression of MDM2 inactivates the tumor suppressive function of p53 and a small-molecule reactivation of p53 and induction of tumor cell apoptosis (RITA) disrupts the MDM2-p53 interaction. We evaluated whether the restoration of p53 function by RITA enhances cytotoxicity and apoptosis of cisplatin in head-and-neck cancer (HNC). RITA was tested in four human HNC cell lines differing in TP53 status. In vitro and in vivo growth suppression, cell cycle arrest, apoptosis after RITA treatment individually or in combination with cisplatin were assessed. RITA induced prominent accumulation and reactivation of p53 in a wild-type TP53-bearing tumor cell line. RITA showed maximal growth suppression in tumor cells showing MDM2-dependent p53 degradation. RITA upregulated p21, BAX, and cleavage of caspase-3 but the p53-dependent apoptosis was blocked by pifithrin-μ. Strong induction of apoptosis rather than G2-phase arrest was observed along with increased dose of RITA. In combination therapy, RITA enhanced the growth inhibition and apoptosis of HNC by cisplatin in vitro and in vivo. Our data suggest that the restoration of p53 tumor suppressive function by RITA enhances cytotoxicity and apoptosis of cisplatin, which may offer an attractive strategy for treating HNC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1768. doi:1538-7445.AM2012-1768
Chromosome 14 markers in rheumatoid arthritis.
Authors: W Ollier, W Thomson, S Welch, G G de Lange, A Silman
Journal: Annals of the Rheumatic Diseases (1988)

Phenotype frequencies for variants of the chromosome 14 markers, alpha 1 antitrypsin (protease inhibitor--Pi), and immunoglobulin heavy chain gene allotypes (Gm and Am) were examined in affected and unaffected members of multicase rheumatoid arthritis (RA) families and compared with published population data. Significantly higher frequencies of phenotypes containing Pi*Z and Pi*S were observed in unrelated index RA cases compared with UK population data. There was also a higher frequency of Pi*Z in family members without RA than in population controls but no such difference for the frequency of Pi*S. No difference in the frequency of PiM1M2 heterozygotes was seen between patients with RA and population controls. An examination of clinical data failed to show any relation between any particular feature of RA and positivity for Pi*Z or Pi*S. No significant differences in frequency of Gm phenotypes were observed between patients with RA and controls. Significant association was found, however, between Pi*Z and Gm phenotypes containing Gm(zax;g). These associations are interpreted as indicating linkage disequilibria between these alleles. No interactions between DR4 and either G1m(z), (a), or (x) allotypes were apparent in patients with RA. A significant association was seen in the index RA cases between DR4 and Pi phenotypes carrying Z or S alleles. Observations from this study provide evidence for the existence of a genetic component for RA susceptibility encoded on chromosome 14. An interactive effect of these genes with DR4 towards susceptibility appears likely.
PRODUCTION OF BCG VACCINE IN A LIQUID MEDIUM CONTAINING TWEEN 80 AND A SOLUBLE FRACTION OF HEATED HUMAN SERUM
Authors: René J. Dubos, Frank Fenner
Journal: The Journal of Experimental Medicine (1950)

Diffuse, submerged growth of BCG bacilli has been obtained in liquid media containing 0.02 per cent Tween 80 and the soluble fraction of human serum heated under acid conditions (pH 2.5) at 65 degrees C. In the absence of glucose or glycerine,-which had a detrimental effect on viability-these cultures consisted predominantly of cells that were living and that remained viable during prolonged storage at temperatures ranging from 4 to 37 degrees C.
Marfan's Syndrome
Authors: J. Douglas Lee
Journal: JAMA (1971)

<h3>To the Editor.—</h3> In a recent report (<b>217</b>:335,1971) a 26-year-old man with "Marfan's Syndrome with Complete Heart Block and Junctional Rhythm" was described. The diagnosis of Marfan's syndrome was based on arachnodactyly, dolichocephaly, congenital cataracts, high arched palate, absence of subcutaneous tissue, and arm span greater than height by 5 cm. This diagnosis must be questioned. The Marfan syndrome is a heritable disorder of connective tissue with characteristic ocular, skeletal, and vascular abnormalities. The patient described had arachnodactyly and dolichocephaly and the quoted indexes support this. Cataracts in patients with the Marfan's syndrome only occur secondary to the uveitis, retinal detachment, and glaucoma resulting from ectopia lentis. Cataract without ectopia lentis is not a part of this syndrome. A cardiac catheterization study revealed no aortic dilatation or insufficiency nor any valvular lesion to support the diagnosis in this patient of Marfan's syndrome. In the absence of a family history
Progressive fibrosis during corticosteroid therapy of autoimmune hepatitis†
Authors: Albert J. Czaja, Herschel A. Carpenter
Journal: Hepatology (2004)

Hepatic fibrosis and cirrhosis are possible consequences of corticosteroid-treated autoimmune hepatitis. Our aims were to determine the frequency of progressive fibrosis and the factors associated with this progression. Two hundred seventy-seven liver tissue specimens that had been obtained from 73 patients were interpreted in batch under code by a single pathologist. Fibrosis scores and histological activity indices were determined using the Ishak scoring system, and worsening fibrosis scores were correlated with clinical features, laboratory findings, and treatment responses. Fibrosis scores increased (2.3 +/- 0.4 points to 4.2 +/- 0.4 points; P <.0001) in 18 patients (25%) during 79 +/- 13 months. Only five patients (7%) developed cirrhosis, and 55 patients (75%) had stable (16 patients) or decreased (39 patients) fibrosis scores. Human leukocyte antigen (HLA) DR3/DR4 occurred more frequently in patients with progressive fibrosis than others (23% vs. 2%; P =.03). Patients with progressive fibrosis had higher histological activity indices at last follow-up than patients with stable or reduced fibrosis (3.2 +/- 0.7 vs. 1.7 +/- 0.2; P =.01), and these indices worsened more commonly during therapy (17% vs. 2%, P =.04). Relapse, treatment failure, and incomplete response did not affect progression of fibrosis. In conclusion, fibrosis progresses in only a minority of patients during corticosteroid therapy. Progression is associated with HLA DR3/DR4 and worsening histological activity. Exacerbations or persistence of disease activity does not increase disease progression after treatment has been instituted.
Contribution of tumour necrosis factor and interleukin (IL) 1 to IL6 production, NF- B nuclear translocation, and class I MHC expression in muscle cells: in vitro regulation with specific cytokine inhibitors
Authors: G Chevrel
Journal: Annals of the Rheumatic Diseases (2005)

<b>Objective:</b> To evaluate the effect of tumour necrosis factor α (TNFα), interleukin (IL) 1β, and their respective inhibitors the p75 TNFα soluble receptor (sTNFR) and the type II sIL1βR (sIL1RII) on whole muscle and isolated myoblast activation. <b>Methods:</b> Normal muscle samples were stimulated for 7 days with TNFα alone or in combination with IL1β, and myoblasts from these samples for 48 hours. IL6 production was measured by ELISA. Nuclear translocation of NF-κB was analysed by immunofluorescent staining and class I MHC expression by FACS. <b>Results:</b> TNFα and IL1β induced IL6 production by normal muscle samples and myoblasts, the action of TNFα being more potent on muscle samples. Their soluble receptors (1 μg/ml) decreased this production. Suboptimal concentrations of TNFα and IL1β induced NF-κB translocation. sTNFR markedly down regulated TNFα-induced translocation while sIL1RII was less potent on IL1β-induced activation. NF-κB translocation induced by the combination of optimal concentrations of TNFα and IL1β was completely inhibited by their soluble receptors. TNFα and to a lesser extent IL1β induced class I MHC expression by myoblasts and this effect was completely inhibited by their respective soluble receptors. <b>Conclusion:</b> These results suggest that TNFα and IL1β should be targeted for myositis treatment.
Bandaging the Knee After Surgery
Authors: Harold M. Childress
Journal: JAMA (1969)

To the Editor:—  The article by Husni et al inThe Journal(206: 2715, 1968) on the use and abuse of pressure bandaging of the lower extremity is both timely and informative. Their statements that following surgery hemostatic compression bandages should be abandoned and that the G air splint is ideal for postoperative splinting of the kree and leg are not, however, realistic.  Admittedly, a properly inflated splint exerts a constant and uniform pressure with a minimal venous inflow obstruction. On the other hand, disadvantages make this splint objectionable. There is no ventilation to the skin of the leg and foot which becomes moist and within a few hours may become definitely wet. Despite the authors' statement to the contrary, wrinkling and creasing may occur, mostly at the knee and ankle. The immobilization produced by the splint at the foot and ankle is not desirable. Since most of these patients
MIDTERM BENEFITS OF PERIOPERATIVE STATIN THERAPY IN PATIENTS UNDERGOING ISOLATED VALVULAR HEART SURGERY: FIVE-YEAR SURGICAL EXPERIENCE
Authors: Muthiah Vaduganathan, Neil J. Stone, Satvik Ramakrishna, Eli I. Lev, Richard Lee, Edwin C. McGee, S.C. Malaisrie, Robert A. Silverberg, Patrick M. McCarthy
Journal: Journal of the American College of Cardiology (2010)
Erythema Chronicum Migrans in the United States
Authors: William E. Mast
Journal: JAMA (1976)

Four cases of erythema chronicum migrans occurred within a one-month period in southeastern Connecticut. The syndrome may include advancing erythematous rash stemming from an apparent insect bite, hyperesthesias, myalgias, malaise, fever, lymphadenopathy, and, rarely, meningitis. Treatment with penicillin, the tetracycline, or, in our experience, erythromycin usually results in prompt resolution.
Abstract 1868: Response biomarkers to IGF1R and mTOR inhibitor combination therapy in ovarian carcinoma
Authors: Brian B. Haines, Michael J. Wick, Kyriakos P. Papadopoulos, Anthony W. Tolcher, Jennifer G. Tammam, Marya F. Chaney, Michael Nebozhyn, Theresa Zhang, Scot W. Ebbinghaus, Jonathan D. Cheng, Leigh Zawel, Sriram Sathyanarayanan
Journal: Cancer Research (2012)

Abstract Ovarian cancer, the sixth most frequent cause of cancer death among women in the developed world, is a heterogeneous disease characterized by a diverse set of genetic alterations. These factors underscore the need for more effective treatment options accompanied by biomarker strategies to identify patients who will have a greater likelihood to respond to novel therapy. A combination strategy to target the PI3K pathway with the mTOR inhibitor ridaforolimus and anti-IGF1R antibody dalotuzumab is currently undergoing clinical development. Previous translational work has suggested that low RAS activity, as determined by a RAS gene expression signature score, and high levels of IGF1R pathway activation may enrich for response to this combination therapy. Ranking of tumors in the Moffitt tumor database with a low RAS and high IGF profile suggested that ER+ breast and ovarian cancers are enriched for these putative response biomarkers. Consistent with these observations, clinical responses were noted for several ER+ breast or ovarian cancer patients in a Phase I trial for ridaforolimus and dalotuzumab combination therapy. To provide further support for low RAS and high IGF as response biomarkers, the anti-tumor activity of ridaforolimus and dalotuzumab was assessed in 12 patient derived primary ovarian cancer xenograft models developed at START. These models have been extensively characterized by the South Texas Accelerated Research and Therapeutics (START) group for response to standard of care drugs, and the status of many commonly mutated genes in ovarian cancer. Molecular analyses of these tumors suggest that they represent a diverse cross section of ovarian cancer. Similarly, responses to ridaforolimus and dalotuzumab combination therapy ranged from minimal to significant regression. Importantly, the responsive tumor models were associated with a low RAS gene signature and a moderate to high IGF expression level. Tumors with KRAS mutations or a high RAS gene score were generally resistant to therapy. These results support the further development of low RAS and high IGF as enrichment biomarkers for ridaforolimus and dalotuzumab combination therapy in ovarian carcinoma. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1868. doi:1538-7445.AM2012-1868
Effect of Methylcellulose on Rectal and Colonic Pressures in Treatment of Diverticular Disease
Authors: J. Hodgson
Journal: BMJ (1972)

Six patients with diverticular disorder confirmed by barium-enema examination were given a six-month course of methylcellulose (Celevac) tablets; their rectal and rectosigmoid colonic pressures were measured before and afterwards. Open-tipped, fluid-filled, narrow-bore polyethylene tubes were used for pressure measurements and care was taken to site the tubes similarly in all patients before and after treatment. After methylcellulose treatment the mean rectosigmoid pressures had fallen to the same range as the mean rectal pressures, a highly significant reduction. Methylcellulose significantly reduces rectosigmoid pressures in diverticular disease.
Reverse Radioaerosol/Radioperfusion Distribution in Pulmonary Endobronchial Obstruction
Authors: ROGELIO T. FUENTES, RICHARD A. HOLMES
Journal: Clinical Nuclear Medicine (1990)

A characteristic image pattern of diminished radioaerosol penetration and reduced radioparticle perfusion has been observed in endobronchial obstruction. This reverse mismatch has a variety of etiologies, with the most common being mucus plugging. The regional hypoxia created by the obstruction causes the blood to shunt from the affected lung. Eleven patients from a group of 178 patients referred with a working diagnosis of pulmonary embolism showed the reversed mismatch. All presented with sudden dyspnea, chest pain and hypoxia. Bronchoscopy was recommended from the image results and nine patients demonstrated mucus plugs that were subsequently aspirated, one patient had a partially obstructing endobronchial carcinoma and one patient had a traumatic fractured bronchus that became occluded with healing granulation tissue. All improved following bronchoscopy. The incompleteness of the airway obstruction accounted for the variations of the perfusion images. Because of the radioaerosol's ability to sharply image the pulmonary airway distribution in contrast to the poor resolution of the radiogases such as xenon-133, it is recommended that radioaerosol lung imaging be substituted for radiogas ventilation imaging since it can accurately detect endobronchial obstruction as well as pulmonary embolism.