tbuckley/cabot-search huggingface dataset:
Arterial disease of the gut.
Authors: J. K. Watt
Journal: BMJ (1968)

Knowledge of ischaemic lesions of the alimentary tract has increased in recent years owing to the technical advances of radiology and vascular surgery.Lateral aortography and selec- tive visceral angiography have facilitated the diagnosis of chronic ischaemic lesions, and vascular surgical techniques can offer restoration of normal blood flow.The intestinal tract and accessory digestive organs are sup- plied with arterial blood through the three main arteries distri- buted to the fore, mid, and hind guts-that is, the coeliac axis and the superior mesenteric and inferior mesenteric arteries.The first two anastomose via the pancreatico-duodenal anasto- mosis and the two mesenteric arteries via the marginal artery of the colon..In sudden occlusion of healthy main arteries these anastomoses may be unable to maintain viability of the bowel, but in chronic arterial lesions where ischaemia develops slowly they can hypertrophy and supply sufficient blood to prevent necrosis.The adequacy of this collateral circulation will determine whether the patient remains symptom-free or whether he develops symptoms of intestinal ischaemia.When arterial lesions lie distal to the main trunks the rich anastomosis of the arteries of the stomach, the numerous arcades in the arteries of the small intestine, and the marginal artery of the colon usually prevent ischaemia of bowel unless the lesions are widespread throughout the small arteries (e.g., thromboangiltis obliterans).At the present time radiological visualization of the small arteries is difficult even with selective catheterization techniques, and the part played by distal lesions in gut ischaemia is not yet delineated. Acute Intestinal Ischaemia Superior Mesenteric LesionsAcute occlusion of the superior mesenteric artery is due either to thrombosis or embolism.The commonest cause of thrombosis is atherosclerosis, which usually narrows the proximal 2-3 cm. of the artery, but a minority of cases have intimal thickening and stenosis extend- ing below the level of the mesocolon.Thrombosis is the final event in a long-standing degenerative process, and approxi- mately 50% of cases experience premonitory symptoms of chronic ischaemia prior to developing acute infarction.'Because of its size and the acute angle made with the abdominal aorta embolism of the superior mesenteric artery is commoner than that of the coeliac axis or the inferior mesenteric artery.The results depend mainly on the size of the embolus.If it is large extensive midgut necrosis will occur, but if it is small, if it breaks up into several fragments on impact, or if it consists of a shower of small emboli the arterial blockage may occur distally and the level and extent of ischaemic bowel will vary according to the degree of embolization and the development of a collateral blood flow.
Severe facial clefting in Insig-deficient mouse embryos caused by sterol accumulation and reversed by lovastatin
Authors: Luke J. Engelking, Bret M. Evers, James A. Richardson, Joseph L. Goldstein, Michael S. Brown, Guosheng Liang
Journal: Journal of Clinical Investigation (2006)

Insig-1 and Insig-2 are regulatory proteins that restrict the cholesterol biosynthetic pathway by preventing proteolytic activation of SREBPs and by enhancing degradation of HMG-CoA reductase. Here, we created Insig–double-knockout (Insig-DKO) mice that are homozygous for null mutations in Insig-1 and Insig-2. After 18.5 days of development, 96% of Insig-DKO embryos had defects in midline facial development, ranging from cleft palate (52%) to complete cleft face (44%). Middle and inner ear structures were abnormal, but teeth and skeletons were normal. The animals were lethargic and runted; they died within 1 day of birth. The livers and heads of Insig-DKO embryos overproduced sterols, causing a marked buildup of sterol intermediates. Treatment of pregnant mice with the HMG-CoA reductase inhibitor lovastatin reduced sterol synthesis in Insig-DKO embryos and reduced the pre-cholesterol intermediates. This treatment ameliorated the clefting syndrome so that 54% of Insig-DKO mice had normal faces, and only 7% had cleft faces. We conclude that buildup of pre-cholesterol sterol intermediates interferes with midline fusion of facial structures in mice. These findings have implications for the pathogenesis of the cleft palate component of Smith-Lemli-Opitz syndrome and other human malformation syndromes in which mutations in enzymes catalyzing steps in cholesterol biosynthesis produce a buildup of sterol intermediates.
Gatekeeper reflux repair system; a mechanistic hypothesis
Authors: P J Kahrilas
Journal: Gut (2005)

The Gatekeeper reflux repair system is the fifth endoluminal therapy for GORD to gain regulatory approval and, akin to its predecessors, still faces many questions regarding its place in clinical practice

Although there can clearly be an argument regarding the threshold at which it becomes a disease, gastro-oesophageal reflux disease (GORD) is ultimately the result of excessive gastro-oesophageal reflux and the associated consequences of that. It then seems rather straightforward that therapeutic interventions should seek to reduce or eliminate gastro-oesophageal reflux. The paradox is that the dominant medical interventions do not; rather, they alter the content of the refluxate (by inhibiting gastric acid secretion) so as to make it less noxious to the oesophageal epithelium. This, in a nutshell, summarises the decades old argument regarding the relative merits of medical verses surgical therapy for GORD. Or so it was, until the dawn of the era of endoluminal therapies for GORD a few short years ago. Now it seems that physicians have assumed some attributes of their surgical colleagues as they experiment with therapies that target the reflux itself. 

The Gatekeeper reflux repair system is the fifth endoluminal therapy for GORD to gain regulatory approval either in the European …
Tax impairs DNA replication forks and increases DNA breaks in specific oncogenic genome regions
Authors: Hassiba Chaib-Mezrag, Delphine Lemaçon, Hélène Fontaine, Marcia Bellon, Xue Tao Bai, Marjorie Drac, Arnaud Coquelle, Christophe Nicot
Journal: Molecular Cancer (2014)

Human T-cell leukemia virus type 1 (HTLV-I) is a human retrovirus associated with adult T-cell leukemia (ATL), an aggressive CD4 T-cell proliferative disease with dismal prognosis. The long latency preceding the development of the disease and the low incidence suggests that the virus itself is not sufficient for transformation and that genetic defects are required to create a permissive environment for leukemia. In fact, ATL cells are characterized by profound genetic modifications including structural and numerical chromosome alterations. In this study we used molecular combing techniques to study the effect of the oncoprotein Tax on DNA replication. We found that replication forks have difficulties replicating complex DNA, fork progression is slower, and they pause or stall more frequently in the presence of Tax expression. Our results also show that Tax-associated replication defects are partially compensated by an increase in the firing of back-up origins. Consistent with these effects of Tax on DNA replication, an increase in double strand DNA breaks (DDSB) was seen in Tax expressing cells. Tax-mediated increases in DDSBs were associated with the ability of Tax to activate NF-kB and to stimulate intracellular nitric oxide production. We also demonstrated a reduced expression of human translesion synthesis (TLS) DNA polymerases Pol-H and Pol-K in HTLV-I-transformed T cells and ATL cells. This was associated with an increase in DNA breaks induced by Tax at specific genome regions, such as the c-Myc and the Bcl-2 major breakpoints. Consistent with the notion that the non-homologous end joining (NHEJ) pathway is hyperactive in HTLV-I-transformed cells, we found that inhibition of the NHEJ pathway induces significant killing of HTLV-I transformed cells and patient-derived leukemic ATL cells. Our results suggest that, replication problems increase genetic instability in HTLV-I-transformed cells. As a result, abuse of NHEJ and a defective homologous repair (HR) DNA repair pathway can be targeted as a new therapeutic approach for the treatment of adult T-cell leukemia.
NSD3–NUT Fusion Oncoprotein in NUT Midline Carcinoma: Implications for a Novel Oncogenic Mechanism
Authors: Christopher A. French, Shaila Rahman, Erica M. Walsh, Simone Kühnle, Adlai R. Grayson, Madeleine E. Lemieux, Noam Grunfeld, Brian P. Rubin, Cristina R. Antonescu, Songlin Zhang, Rajkumar Venkatramani, Paola Dal Cin, Peter M. Howley
Journal: Cancer Discovery (2014)

Abstract NUT midline carcinoma (NMC) is an aggressive subtype of squamous cell carcinoma that typically harbors BRD4/3–NUT fusion oncoproteins that block differentiation and maintain tumor growth. In 20% of cases, NUT is fused to uncharacterized non-BRD gene(s). We established a new patient-derived NMC cell line (1221) and demonstrated that it harbors a novel NSD3–NUT fusion oncogene. We find that NSD3–NUT is both necessary and sufficient for the blockade of differentiation and maintenance of proliferation in NMC cells. NSD3–NUT binds to BRD4, and BRD bromodomain inhibitors induce differentiation and arrest proliferation of 1221 cells. We find further that NSD3 is required for the blockade of differentiation in BRD4–NUT-expressing NMCs. These findings identify NSD3 as a novel critical oncogenic component and potential therapeutic target in NMC. Significance: The existence of a family of fusion oncogenes in squamous cell carcinoma is unprecedented, and should lead to key insights into aberrant differentiation in NMC and possibly other squamous cell carcinomas. The involvement of the NSD3 methyltransferase as a component of the NUT fusion protein oncogenic complex identifies a new potential therapeutic target. Cancer Discov; 4(8); 928–41. ©2014 AACR. This article is highlighted in the In This Issue feature, p. 855
Reduced MLH1 Expression in Breast Tumors After Primary Chemotherapy Predicts Disease-Free Survival
Authors: H.J. Mackay, D. Cameron, M. Rahilly, M.J. Mackean, J. Paul, S.B. Kaye, R. Brown
Journal: Journal of Clinical Oncology (2000)

PURPOSE: Loss of function or expression of the mismatch repair protein MLH1 and the tumor suppressor protein p53 have been implicated in acquired resistance to anticancer drugs. We have compared the expression of MLH1 and p53 in tumors from women with clinically node-positive breast cancer before and after primary (neoadjuvant) chemotherapy. Further, we have assessed the value of these markers as predictors of response to therapy by correlation with disease-free survival. PATIENTS AND METHODS: Immunohistochemistry scores of MLH1 and p53 expression were made on 36 tru-cut prechemotherapy biopsies and 29 paired postchemotherapy tumor samples. The significance of the change in scores and their correlation with disease-free survival were evaluated by the Wilcoxon signed rank sum test and Cox proportional hazards regression analysis, respectively. RESULTS: Primary chemotherapy results in a significant reduction in the percent of cells expressing MLH1 (P = .010). This change in MLH1 expression after chemotherapy is strongly associated with poor disease-free survival (P = .0025). Expression of p53 was not significantly altered by chemotherapy. Neither MLH1 nor p53 expression before chemotherapy predicted disease-free survival or tumor response to chemotherapy. Low MLH1 expression after chemotherapy was an independent predictor of poor disease-free survival on multivariate Cox analysis when considered with other clinicopathologic prognostic factors. CONCLUSION: Tumor cells that have reduced MLH1 expression seem to have a survival advantage during combined chemotherapy of locally advanced breast cancers, which supports the hypothesis that loss of MLH1 has a role in drug resistance. MLH1 expression after chemotherapy is an independent predictive factor for poor disease-free survival and may, therefore, define a group of patients with drug-resistant breast cancer.
Rupture of the tracheobronchial tree.
Authors: J C Roxburgh
Journal: Thorax (1987)

Eleven cases of tracheobronchial rupture are described. Nine were the result of external non-penetrating trauma and all but three had other serious injuries. The remaining two were caused by endobronchial intubation. Of the cases caused by external injury, respiratory tract injury was confined to the cervical trachea in three. Two required tracheostomy and repair and the third was managed conservatively; all made satisfactory recoveries. Intrathoracic rupture was recognised on or soon after admission in three cases. One patient died of uncontrollable pulmonary haemorrhage before he could be operated on; immediate repair gave good long term results in the other two. In three cases rupture of the main bronchus was not recognised until complete obstruction developed three, five, and 12 weeks after the accidents. The strictures were resected and the lung re-expanded. Robertshaw endobronchial tubes ruptured the left main bronchus in two patients undergoing oesophageal surgery. Uneventful recovery followed immediate repair. The difficulty of confirming rupture of a major airway is discussed and the importance of conserving the lung when the diagnosis has been missed is emphasised.
DEOXYCORTONE WITH ASCORBIC ACID IN RHEUMATOID ARTHRITIS
Authors: W.S.C. Copeman, J.J.R. Duthie, E. Fletcher, G.N. Myers, O. Savage, F. Dudley Hart, J.H. Kellgren, Philip Ellman, G.D. Kersley, H.A. Burt, E.G.L. Bywaters, S.J. Hartfall
Journal: The Lancet (1950)
Vascular Endothelial Growth Factor Induces Activation and Subcellular Translocation of Focal Adhesion Kinase (p125 <sup>FAK</sup> ) in Cultured Rat Cardiac Myocytes
Authors: Naoyuki Takahashi, Yoshinori Seko, Eisei Noiri, Kazuyuki Tobe, Takashi Kadowaki, Hisataka Sabe, Yoshio Yazaki
Journal: Circulation Research (1999)

Abstract —Vascular endothelial growth factor (VEGF) has been proposed to be among the candidate factors with the most potential to play a role in ischemia-induced collateral vessel formation. Recently, we found that VEGF activated the mitogen-activated protein kinase cascade in cultured rat cardiac myocytes. To elucidate how VEGF affects adhesive interaction of cardiac myocytes with the extracellular matrix (ECM), one of the important cell functions, we investigated the molecular mechanism of activation of focal adhesion-related proteins, especially focal adhesion kinase (p125 FAK ), in cultured rat cardiac myocytes. We found that the 2 VEGF receptors, KDR/Flk-1 and Flt-1, were expressed in cardiac myocytes and that KDR/Flk-1 was significantly tyrosine phosphorylated on VEGF stimulation. VEGF induced tyrosine phosphorylation and activation of p125 FAK as well as tyrosine phosphorylation of paxillin; this was accompanied by subcellular translocation of p125 FAK from perinuclear sites to the focal adhesions. This VEGF-induced activation of p125 FAK was inhibited partially by the tyrosine kinase inhibitors genistein and tyrphostin. Activation of p125 FAK was accompanied by its increased association with adapter proteins GRB2, Shc, and nonreceptor type tyrosine kinase p60 c-src . Furthermore, we confirmed that VEGF induced a significant increase in adhesive interaction between cardiac myocytes and ECM using an electric cell-substrate impedance sensor. These results strongly suggest that p125 FAK is one of the most important components in VEGF-induced signaling in cardiac myocytes, playing a critical role in adhesive interaction between cardiac myocytes and ECM.
EGFR Signaling Regulates Tumor Cell Migration in Craniopharyngiomas
Authors: Annett Hölsken, Matthias Gebhardt, Michael Buchfelder, Rudolf Fahlbusch, Ingmar Blümcke, Rolf Buslei
Journal: Clinical Cancer Research (2011)

Constitutive Wnt signaling caused by mutations in the β-catenin gene is a molecular hallmark of adamantinomatous craniopharyngiomas (adaCP) and promotes infiltration into adjacent brain tissue. Herein, we studied the pathogenic role of epidermal growth factor receptor (EGFR) activation in adaCP and whether tumor cell migration can be inhibited by the tyrosine kinase inhibitor gefitinib.EGFR expression and activation [phosphorylated EGFR (EGFR-P)] was examined in a cohort of 25 surgical adaCP samples by PCR and Western blotting. Regional and cellular localization patterns of EGFR-P, β-catenin, and its target gene product Fascin were determined by immunofluorescence microscopy. Mutation analysis and gene copy number assay were carried out to examine genetic alterations in the EGFR gene. The impact of EGFR signaling on tumor cell migration was studied in vitro by using 11 primary human adaCP cultures treated with the EGFR ligand EGF and its inhibitor gefitinib.Neither mutations nor amplifications in the EGFR gene were detected in our adaCP series. However, EGFR-P was detectable in tumor cell clusters located at the brain infiltration border and colocalized with nuclear β-catenin and Fascin. Activated EGFR significantly promoted tumor cell migration in vitro, whereas gefitinib reduced both tumor cell motility and Fascin expression.Our data suggest EGFR signaling to play a role in cell migration and brain infiltration of adaCP. Targeting the EGFR signaling pathway by gefitinib may present a promising pharmacologic option in the treatment of this challenging tumor disease.
Conversion from daily to alternate daily corticosteroids in rheumatoid arthritis.
Authors: M A Fitzcharles, J Halsey, H L Currey
Journal: Annals of the Rheumatic Diseases (1982)

An attempt was made to convert 24 patients on corticosteroid treatment from a daily to an alternate daily regimen. Ten patients were successfully converted, 11 failed to convert, and 3 had to be withdrawn for irrelevant reasons. A simple tetracosactrin stimulation test gave some indication of which patients were more likely to convert successfully. Success was not influenced by severity or duration of disease, nor by dose of duration of steroid therapy. Conversion did not influence various clinical and laboratory measures of undesirable steroid side effects, but the follow-up period was probably too short to judge this. The evidence of others suggests that conversion is worth attempting.
National Clinical Guideline Centre Cost-Effectiveness Assessment for the National Institute for Health and Clinical Excellence
Authors: David Wonderling, Laura Sawyer, Elisabetta Fenu, Kate Lovibond, Philippe Laramée
Journal: Annals of Internal Medicine (2011)

The National Clinical Guideline Centre (NCGC) develops evidence-based clinical guidelines on behalf of the National Institute for Health and Clinical Excellence (NICE) in the United Kingdom. The U.K. Department of Health has commissioned NICE to make recommendations on the basis of both clinical effectiveness and cost-effectiveness. This article describes how cost-effectiveness is evaluated and accounted for in NCGC guidelines. Six recent case studies are presented, in which consideration of cost-effectiveness has informed recommendations in various ways for clinical guidelines on alcohol use disorders, chronic obstructive pulmonary disease, glaucoma, lower urinary tract symptoms, non–ST-segment elevation myocardial infarction and unstable angina, and venous thromboembolism prophylaxis. Some of the challenges faced in trying to account for cost-effectiveness in clinical guidelines are outlined, as well as some of the difficulties in adapting cost-effectiveness guidelines for other settings.
Treatment patterns, outcomes, and resource utilization of patients with metastatic melanoma in the U.K.: the MELODY study
Authors: P. Lorigan, M. Marples, M. Harries, J. Wagstaff, A.G. Dalgleish, R. Osborne, A. Maraveyas, S. Nicholson, N. Davidson, Q. Wang, L. Pericleous, U. Bapat, M.R. Middleton
Journal: British Journal of Dermatology (2013)

Advanced melanoma is an aggressive disease with a poor prognosis. Approved therapy is limited in the U.K. and, until recently, no treatment had improved survival over best supportive care. A deeper understanding of current clinical practice will help new agents find a place in future treatment pathways.To document U.K. clinical practice for the treatment of patients with unresectable stage III/IV (advanced) melanoma.MELODY (melanoma treatment patterns and outcomes among patients with unresectable stage III/IV disease: a retrospective longitudinal survey) compiled registries of consecutive patients with malignant melanoma (any stage) between 1 July 2005 and 30 June 2006 from France, Italy and the U.K. Patients with advanced melanoma and ≥ 2 months of follow-up were eligible for analysis.There were 220 eligible patients identified in the U.K., of whom 117 (53.2%) received systemic therapy outside of clinical trials. Over half of these patients received dacarbazine as first- or second-line therapy. Healthcare-resource utilization was extensive and patients had short survival times: 1- and 2-year survival rates after first-line systemic treatment were 45.5% [95% confidence interval (CI) 37.1-53.6] and 24.7% (95% CI 17.7-32.3), respectively.Systemic and palliative treatments used to manage advanced melanoma in the U.K. are associated with considerable healthcare resource utilization and poor short-term survival.
Reduced-intensity conditioning followed by allografting of hematopoietic cells can produce clinical and molecular remissions in patients with poor-risk hematologic malignancies
Authors: Paolo Corradini, Corrado Tarella, Attilio Olivieri, Alessandro M. Gianni, Claudia Voena, Francesco Zallio, Marco Ladetto, Michele Falda, Moira Lucesole, Anna Dodero, Fabio Ciceri, Fabio Benedetti, Alessandro Rambaldi, Maria R. Sajeva, Moreno Tresoldi, Alessandro Pileri, Claudio Bordignon, Marco Bregni
Journal: Blood (2002)
Phase I Pharmacokinetic and Pharmacodynamic Study of Temozolomide in Pediatric Patients With Refractory or Recurrent Leukemia: A Children's Oncology Group Study
Authors: Terzah M. Horton, Patrick A. Thompson, Stacey L. Berg, Peter C. Adamson, Ashish M. Ingle, M. Eileen Dolan, Shannon M. Delaney, Madhuri Hedge, Heidi L. Weiss, Meng-Fen Wu, Susan M. Blaney
Journal: Journal of Clinical Oncology (2007)

To determine the tolerability, pharmacokinetics, and mechanisms of temozolomide resistance in children with relapsed or refractory leukemia.Cohorts of three to six patients received 200 or 260 mg/m2/d of temozolomide by mouth daily for 5 days every 28 days. Toxicities, clinical response, and pharmacokinetics were evaluated. Pretreatment leukemia cell O6-methylguanine-DNA methyltransferase (MGMT) activity, tumor and plasma MGMT promoter methylation, and microsatellite instability (MSI) were examined in 14 of 16 study patients and in tissue bank samples from children with acute leukemia not treated with temozolomide (MGMT, n = 67; MSI, n = 65).Sixteen patients (nine female, seven male; acute lymphoblastic leukemia [ALL], n = 8; acute myeloid leukemia [AML], n = 8), median age 11 years (range, 1 to 19 years), received either 200 mg/m2/d (nine enrolled, three assessable for toxicity) or 260 mg/m2/d (seven enrolled, three assessable for toxicity) of temozolomide. Temozolomide was well tolerated and no dose-limiting toxicities occurred. The mean clearance of temozolomide was 107 mL/min/m2, with a volume of distribution of 20 L/m2 and half-life of 109 minutes. MGMT activity in leukemia cells was quite variable and was highest in patients with relapsed ALL. Only one patient had MSI. Two patients had a partial response. Both of these patients had no detectable MGMT activity; both also had methylated MGMT promoters and were MSI stable.Temozolomide was well tolerated at doses as high as 260 mg/m2/d for 5 days in children with relapsed or refractory leukemia. Increased MGMT activity may account for the temozolomide resistance in children with relapsed leukemia. Leukemia cell MGMT activity was higher in pediatric ALL than AML (P < .0001).