tbuckley/cabot-search huggingface dataset:
Abstract 5680: Bortezomib-induced quiescence of multiple myeloma cells is associated with changes in the expression of p21(CIP/KIP) and the H3K27-methyltransferase EZH2
Authors: Alfred Adomako, Julio A. Aguirre-Ghiso
Journal: Cancer Research (2012)

Abstract Bortezomib-induced quiescence of multiple myeloma cells is associated with changes in the expression of p21CIP/KIP and the H3K27-methyltransferase EZH2. Most multiple myeloma (MM) patients respond positively to the proteasome inhibitor (PI) bortezomib (Velcade). However, there are high rates of relapse after variable remission periods. It is still unclear whether these periods of remission are due to residual cells that after bortezomib treatment enter dormancy or simply due to a small residual population that slowly proliferate until patients becoming symptomatic. It is therefore important to determine whether minimal residual disease (MRD) can be rendered quiescent by bortezomib. We had shown that in MM cells, bortezomib induced ER-stress and quiescence. However, the mechanism for the induction and maintenance of this quiescent state is unclear. We hypothesized that the prolonged quiescence might involve prototypical cell cycle inhibitors and that epigenetic mechanisms sustain the growth arrest. Quantification of viable cells using immunofluorescence microscopy showed a 6-fold increase in p21 protein after a 24-hour pulse treatment with bortezomib followed by washout. p21 and p27 were also persistently induced 2-fold and 1.5-fold respectively along with the downregulation of CDK6 3 days after the drug washout. This suggests that quiescence onset is triggered by cell cycle inhibitor induction that block the G1 to S transition. This correlated with the previously reported reduction in Rb phosphorylation in bortezomib-surviving MM cells. When we tested the levels of the histone H3 methyl-transferase EZH2 and H3K27me3, these were strongly downregulated in the quiescent MM cells. EZH2 depletion was previously linked to p21-mediated senescence in melanoma. Our results suggest that changes in histone methylation and cell cycle inhibitor induction may be a mechanism regulating bortezomib-induced quiescence. Further studies will validate whether these mechanisms are active in patients by analyzing clinical samples from MM patients. 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 5680. doi:1538-7445.AM2012-5680
A Controlled Trial of Riluzole in Amyotrophic Lateral Sclerosis
Authors: G. Bensimon, L. Lacomblez, V. Meininger
Journal: New England Journal of Medicine (1994)

Amyotrophic lateral sclerosis is a progressive motor neuron disease for which there is no adequate treatment. Some research suggests that the excitatory amino acid neurotransmitter glutamate may be involved in the pathogenesis.
760 A PHASE III CLINICAL TRIAL WITH A NASAL VACCINE CONTAINING BOTH HBsAg AND HBcAg IN PATIENTS WITH CHRONIC HEPATITIS B
Authors: M.A. Mahtab, F. Akbar, H. Uddin, S. Rahman, J.C.A. Rubido, G.E.G. Nieto, M. Onji, S. Mishiro
Journal: Journal of Hepatology (2013)
PTH-102 Treatment Of Benign Pancreatic Duct Strictures With Fully Covered Self Expandable Metal Stents (fc-sems) Is Feasible, Safe And Effective In Patients With Symptomatic Chronic Pancreatitis (cp): Abstract PTH-102 Table 1
Authors: R Rameshshanker, H Kaltsidis, P Vlavianos, N Phillips, D Westaby
Journal: Gut (2014)

Introduction FC-SEMS have been used for treatment of benigh biliary strictures (BBS) with excellent results. Pancreatic duct strictures (PDS) of CP vary in length and complexity and associated with upstream dilatation and/or stones. Limited data on aggressive endotherapy (ET) with insertion of the repeated plastic stents (PS) showed good response. Experience with FC-SEMS in pancreatic strictures is limited. Methods Aim:To assess feasibility and safety of smaller diameter (8 mm) FC-SEMS for treatment of CP with dominant downstream strictures either de novo or as resque (failed previous ET). Methods All patients referred to our tertiary institution for pancreatic intervention and successfully underwent SEMS were included. Response (i.e. pain control) was assessed at 3 months by using a 1–10 visual analogue scale to compare pre- and post-intervention symptoms (a score <2 is complete, 3 or above is partial response). Results A total of 15 patients (8 male and 7 female, mean age 52) received FC - SEMS 10 in main PD and 5 in the accessory duct (Santorini). 13 had previous endotherapy while for 2 patients this was the first attempt at endotherapy. 4 individuals with PD stones had ESWL prior to ERCP. [Table 1][1] summarises the data on this patient group. View this table: Abstract PTH-102 Table 1 Placement of stents was feasible in all individuals. All had their stents removed at 4 months or earlier if they were symptomatic. One stent migrated proximally and associated with formation of an accessory duct abscess treated with antibiotics and stent removal. At 3 months, a total of 9 patients (60%) reported complete resolution of pain whereas in another 2 (13%) the response was parial. In the remaiing 4 individuals (27%) there was no improvement after placement of FC-SEMS and those were subsequently removed; these individuals are considered for surgical drainage. 3 patients (2 complete responders and 1 partial responder) developed new strictures at the proximal end of the stents. Conclusion Placement of FC-SEMS for treatment of BPS is feasible with an acceptable safety profile. Stent migration occured in one. New strictures seen in 3 patients and warrant further assessment. Future FC-SEMS designed for use in the pancreas may overcome this problem. Disclosure of Interest None Declared. [1]: #T1
Abstract 1996: Chronic arsenic exposure and changes in global levels of histone modifications in a human population in Bangladesh
Authors: Yana Chervona, Adriana Arita, Fen Wu, Hong Sun, Kathrine Kiok, Thomas Kluz, Hsiang-Chi Tseng, Jiri Zavadil, Gary Leroy, Mary Gamble, Max Costa
Journal: Cancer Research (2011)

Abstract Arsenic and arsenic compounds have been classified as group 1 human carcinogens by IARC. Naturally occurring inorganic arsenic, in particular, has been implicated in the development of human skin, lung, and bladder cancers and has also been associated with the development of liver and prostate cancers. However, despite being a formidable carcinogen, arsenic is a poor mutagen and it has been suggested that arsenic-induced carcinogenesis maybe governed by epigenetic mechanisms. We have detected differences in the levels of several histone epigenetic marks, such as H3K9acetylation, H3K9dimethylation and H3K27trimethylation in human peripheral mononuclear cell collected from individuals exposed to varying levels of inorganic arsenic in their drinking water. The changes in the global levels of these epigenetic marks were primarily measured using a novel ELISA method, while changes of arsenic-induced histone modifications in peripheral blood lymphocytes treated in vitro have also been examined via Mass Spectrometry and Western Blotting. Furthermore, we have also found a profound increase in the expression of histone genes after in vitro treatment of peripheral blood lymphocytes with sodium arsenite and will be examining this finding further. To the best of our knowledge, this study is the first in its class to measure arsenic-induced epigenetic modifications in humans and how they relate to changes in gene expression in a human population. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1996. doi:10.1158/1538-7445.AM2011-1996
Abstract 1856: Sustained release curcumin microparticles delay mammary tumorigenesis in BALB-neuT transgenic mice
Authors: Alex Grill, Jayanth Panyam
Journal: Cancer Research (2011)

Abstract This work examined the chemopreventive efficacy of curcumin delivered by poly(lactide-co-glycolide) (PLGA) microparticles in a HER-2 transgenic mouse mammary tumor model. HER-2 positive breast cancers have a high incidence of metastasis to the brain and are not well treated by conventional means. Curcumin, a dietary polyphenol derived from turmeric, is a powerful antioxidant and has shown chemopreventive activity in vitro. Curcumin suffers from poor oral bioavailability, requiring the need for a controlled release system that could maintain steady plasma levels over a long period of time. Our lab has formulated a curcumin loaded microparticle formulation using the FDA approved polymer, PLGA. Previously published data using this system showed steady curcumin plasma concentrations for a month and efficacy against MDA-MB-231 tumor xenografts (Shahani et al, Cancer Res. 70(11):4443-52). In the present study, Balb-neuT +/- mice were injected subcutaneously with curcumin loaded or empty microparticles at 4, 7 or 12 weeks of age and then once a month thereafter until all mammary pads developed palpable tumors. Mice that started receiving curcumin microparticles at 4 weeks of age showed a difference in age to 50% tumor multiplicity (16 vs 18.5 weeks) and 100% tumor multiplicity (20 vs 22 weeks) compared to those that received control microparticles. No difference was seen in tumor multiplicity when the treatments were started at 7 or 12 weeks of age. Mammary pads from mice that started receiving curcumin treatment at 4 weeks of age showed a significant decrease in Ki-67 expression compared to those from control mice. Curcumin treated mice also showed a decrease in overall percent area of tissue showing abnormal morphology (lobular hyperplasia and carcinoma in situ). These data suggest that curcumin delays tumorigenesis in this model through inhibition of cell proliferation. In summary, sustained release curcumin microparticles show promise as a chemopreventive against Her-2 positive breast cancer. Future studies will examine the effect of starting curcumin treatment at 2 weeks of age (prior to induction of hyperplasia) and determine other potential mechanisms of action of curcumin including inhibition of angiogenesis and induction of apoptosis in this transgenic model. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1856. doi:10.1158/1538-7445.AM2011-1856
SP0101 Case 2 discussion: Calcinosis CUTIS
Authors: C.P. Denton
Journal: Annals of the Rheumatic Diseases (2013)

Calcinosis cutis represents a major clinical problem in a number of rheumatic diseases but is especially recognised in dermatomyositis and systemic sclerosis. In dermatomyositis it is especially a feature of childhood onset disease and can be very disabling. In systemic sclerosis calcinosis occurs in several distinct contexts and these may require different approaches to management. The commonest form is that which is seen in limited cutaneous systemic sclerosis, previously termed CREST syndrome. This is most often seen in the fingers and at sites of local pressure or trauma. However calcinosis cutis also occurs in diffuse cutaneous systemic sclerosis and may have a more widespread distribution. It can occur very diffusely in fascial layers of the limbs and trunk. Another form of calcinosis occurs around joints and can lead to very severe restriction of movement. Finally there can be specific foci of more severe calcinosis in the soft tissue at sites of co-existent trauma. The mechanism underlying calcinosis is poorly understood but may reflect aberrant mesenchymal tissue repair. Biochemical analysis conforms that calcinosis deposits are formed from calcium hydroxyapatite. Treatment is challenging. There has been anecdotal benefit from some medical approaches including minocylcine as well as warfarin, calcium channel blockers and bisphosphonates. In addition anti-TNF agents and methotrexate have been reported as helpful especially in cases associated with significant local inflammation. Surgical removal can be effective bit deposits often recur. The natural history, frequency and patterns of calcinosis cutis need to be better defined so that more systematic approaches to treatment can be developed. Calcinosis cutis remains one of the most difficult and potentially disabling manifestations of the connective tissue disease in which it occurs. <h3>Disclosure of Interest</h3> C. Denton Consultant for: Actelion, GSK, Pfizer, Sanofi-Aventis, Serono
Increased aortic cyclic guanosine monophosphate concentration in experimental cirrhosis in rats: Evidence for a role of nitric oxide in the pathogenesis of arterial vasodilation in cirrhosis*1
Authors: M NIEDERBERGER
Journal: Hepatology (1995)

Arterial vasodilation is considered to be the key factor in the development of sodium and water retention leading to ascites formation in cirrhosis. To determine if nitric oxide (NO) is involved in the pathogenesis of arterial vasodilation in cirrhosis, we measured the concentration of cyclic guanosine monophosphate (cGMP), the second messenger of NO, in arterial tissue from rats with carbon tetrachloride-induced cirrhosis. Aortic cGMP concentration was markedly increased in cirrhotic rats, particularly in those with ascites (ascites, 826 ± 70; no ascites, 597 ± 48; controls, 331 ± 25 fmol/mg, ANOVA F = 23.1, P < .0001), and correlated inversely with arterial pressure (r = −.56, P < .0001) and systemic vascular resistance (r = −.69, P = .014) and directly with cardiac index (r = .74, P < .01). The chronic administration of the NO synthesis inhibitor NG-nitro-l-arginine-methylester (l-NAME) (10 mg/kg/day for 7 days) induced a marked reduction in aortic cGMP concentration in cirrhotic rats with ascites to similar values obtained in l-NAME-treated control rats (86 ± 14 vs. 89 ± 8 fmol/mg, respectively, NS), indicating that the high-aortic cGMP content in cirrhotic rats was caused by an increased NO synthesis. Mean arterial pressure after l-NAME treatment increased to similar values in both groups of animals. These results suggest that in cirrhosis there is an increased vascular production of NO that may play a role in the pathogenesis of arterial vasodilation.
Abstract 4787: MMP-2 RNA interference leads to decreased NF-κB activation and induced JNK-mediated apoptosis by modulating TRADD-TRAF2-FADD interactions in glioma
Authors: Divya Kesanakurti, Chandramu Chetty, Praveen Bhoopathi, Sajani S. Lakka, Bharathi Gorantla, Andrew J. Tsung, Jasti S. Rao
Journal: Cancer Research (2011)

Abstract MMP-2 belongs to a family of extracellular matrix metalloproteinases (MMPs) that play a pivotal role in the degradation of the ECM, thereby enhancing the invasive and metastatic potential of cancer cells. Our study unveiled a new mechanism of how MMP-2 RNA interference inhibits NF-κB activation. Essentially, siRNA against MMP-2 (pM) modulated the interactions between the adaptor protein TRADD-TRAF2 and TRADD-FADD, which consequently hindered the nuclear localization and DNA binding activity of NF-κB. This, in turn, led to apoptosis. Furthermore, pM treatment led to RIP cleavage and remarkable increases in the expression levels of FADD and activated MAP kinases, p38 MAPK and JNK. The prolonged activation of JNK resulted in phosphorylation of c-Jun. Treatments with specific JNK1 inhibitor (SP600125) reduced and significantly reversed the pro-apoptotic effect of pM, thereby suggesting a role of JNK in pM-induced cell death. Supplementation of recombinant human MMP-2 to pM-transfected cells restored the inhibited DNA binding activity of NF-κB and rescued cells from the pro-apoptotic effect of pM. Here, we demonstrate that the simultaneous inhibition of NF-κB activation and sustained activation of JNK play significant roles in pM-mediated apoptosis in human xenograft glioma cells. In addition, our results show that the specific downregulation of MMP-2 diminished intracranial tumor growth in vivo. The inhibition of tumor growth after pM treatment was associated with decreased MMP-2 expression, inhibited NF-κB activation, and enhanced phospho-JNK levels. In conclusion, the present study elucidates an underlying mechanism of pM-induced cell death in vitro as well as decreased tumor development in vivo. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4787. doi:10.1158/1538-7445.AM2011-4787
Searching the Evolutionary Origin of Epithelial Mucus Protein Components—Mucins and FCGBP
Authors: Tiange Lang, Sofia Klasson, Erik Larsson, Malin E. V. Johansson, Gunnar C. Hansson, Tore Samuelsson
Journal: Molecular Biology and Evolution (2016)

The gel-forming mucins are large glycosylated proteins that are essential components of the mucus layers covering epithelial cells. Using novel methods of identifying mucins based on profile hidden Markov models, we have found a large number of such proteins in Metazoa, aiding in their classification and allowing evolutionary studies. Most vertebrates have 5–6 gel-forming mucin genes and the genomic arrangement of these genes is well conserved throughout vertebrates. An exception is the frog Xenopus tropicalis with an expanded repertoire of at least 26 mucins of this type. Furthermore, we found that the ovomucin protein, originally identified in chicken, is characteristic of reptiles, birds, and amphibians. Muc6 is absent in teleost fish, but we now show that it is present in animals such as ghost sharks, demonstrating an early origin in vertebrate evolution. Public RNA-Seq data were analyzed with respect to mucins in zebrafish, frog, and chicken, thus allowing comparison in regard of tissue and developmental specificity. Analyses of invertebrate proteins reveal that gel-forming-mucin type of proteins is widely distributed also in this group. Their presence in Cnidaria, Porifera, and in Ctenophora (comb jellies) shows that these proteins were present early in metazoan evolution. Finally, we examined the evolution of the FCGBP protein, abundant in mucus and related to gel-forming mucins in terms of structure and localization. We demonstrate that FCGBP, ubiquitous in vertebrates, has a conserved N-terminal domain. Interestingly, this domain is also present as an N-terminal sequence in a number of bacterial proteins.
Spontanpneumothorax während der Laparoskopie
Authors: G. Hilt
Journal: Endoscopy (1970)

The occurence of a right sided pneumothorax in a 58-year-old male patient as a complication of a pneumoperitoneum during peritoneoscopy is described in detail. The possible causes of this complication are discussed, whereby etiologically either a congenitally present fissure or a rupture of the right hemidiaphragm from a previous accident in 1955 could have been responsible for this event.
Soundings: Be alert
Authors: Liam Farrell
Journal: BMJ (2005)

The more things change, the more they stay the same—cynical old men suckering gullible and vulnerable young men into doing their dirty work for them. You've just experienced it in London, I saw it for years in Northern Ireland, and Siegfried Sassoon wrote about it in 1918: “If I were fierce and bald and short of breath, I'd sit with scarlet Majors at the Base, And speed glum heroes up the line to death.”

You'll get used to it. More visible security, regular searches, frequent false alarms, delays on trains and buses—all these things will gradually soften like music into the background. Life has to go on, the anxiety will fade as you adjust to a different dynamic, you'll go back to talking about football and the weather, and patients will still want antibiotics for colds and sore throats even as the sirens wail. Humans aren't genetically designed for absolute tranquillity, and a bit of uncertainty is probably good for us.


Humans aren't designed for absolute tranquillity


Statistically the chances of being involved are slight. During the Troubles about 3000 people were killed, and in that same period the death toll on the roads was over 6000. But the increased threat does make you more alert to small things, a little bit more cautious and thoughtful.

I remember once driving to a house call when I noticed a cardboard box at the side of the road. I stopped the car and sat for a while, pondering. It was just a cardboard box on a small country road, almost certainly just a piece of stray litter; no wires, no traditional whiff of cordite, no sound of merry gunfire in the distance, no sign of any “insurgents,” nothing at all suspicious.

I got out of the car at a prudent distance, and looked sternly at the box; I consider myself an alpha male. It looked back at me, unblinking. Observing the conventions, it exuded a faint air of menace: “You're alive, you're dead,” it seemed to be saying, “it really doesn't matter to me.” For a long moment neither of us moved.

Then I turned around and made a detour which cost me 10 miles; fortune may favour the brave, but the devil hates a coward.
Abstract P3-01-06: Ultrasound as single mode of imaging may miss significant pathology in symptomatic women aged 35–39
Authors: EL Baker, T Masudi, A Waterworth
Journal: Cancer Research (2012)

Abstract Recent guidelines in the UK stipulate that symptomatic women aged under 40 with clinically benign disease do not need mammography as a standard part of their assessment.1 Previous practice at the Calderdale and Huddersfield NHS Trust has been to perform mammography on all women over 35 years old. This study was undertaken to determine if there would be an increase in false negative assessment under the new guidelines. All female patients 35–39 years old attending symptomatic breast clinic with benign clinical examination and undergoing both ultrasound and mammogram evaluation were eligible. Patients with previous breast cancer or a clinically suspicious lump mandating mammography were excluded. The information was gathered retrospectively using patient records. 96 women were included. Mammography and ultrasound results (including M and U valves) were compared for any discrepancy. If performed, biopsy results were also reviewed. In 70% of patients there was no discrepancy between mammographic and ultrasonic evaluation (M = U). In 25% U score was one higher than M score. On further analysis this group mainly comprised of those with fibroadenomas or fibrocystic breast changes seen on ultrasound (U2) with a normal mammogram (M1). In the remaining 5%, 3 patients had U score 2 greater than M score, 1 had M&amp;gt;U by 1 and 1 had M&amp;gt;U by 2. On further analysis of these discrepancies most patients had benign disease. In two patients with U5 scores and lower M scores malignancy was confirmed on biopsy. In one patient ultrasound showed benign disease (U2) but mammogram demonstrated suspicious calcifications (M4) that were confirmed as high grade DCIS on stereo-core biopsy. In conclusion for the vast majority of patients in this group mammography does not add to the evaluation on presentation at symptomatic breast clinic. However this study identified a case (1 patient in 96) where significant disease could have been missed had a mammogram not been undertaken. The acceptable level of such false negative assessments with ultrasound only imaging in women under 40 must be further evaluated. 1Best practice diagnostic guidelines for patients presenting with breast symptoms Alexis M Willett, Michael J Michell, Martin J R Lee, November 2010 Printed by Breakthrough Breast Cancer, www.dh.gov.uk/publications Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P3-01-06.