tbuckley/cabot-search huggingface dataset:
Combination Therapy of Bortezomib with Novel Targeted Agents: An Emerging Treatment Strategy
Authors: John J. Wright
Journal: Clinical Cancer Research (2010)

Clinical trials evaluating combinations of targeted agents with bortezomib, the first-in-class proteasome inhibitor, have been initiated, with the objective of enhancing its single agent activity in hematologic malignancies (myeloma, mantle cell lymphoma), as well as expanding its efficacy in solid tumors. In most cases, preclinical studies have provided a supportive rationale for designing these doublet combination studies. Novel, small molecule-targeted agents being investigated with bortezomib in clinical trials include protein deacetylase inhibitors, kinase inhibitors, farnesyltransferase inhibitors, heat-shock protein 90 inhibitors, pan-Bcl-2 family inhibitors, and other classes of targeted inhibitors. Preliminary clinical data, available from a number of ongoing trials, suggest that most of these combinations are well tolerated and some have promising clinical efficacy that will require subsequent confirmation. Translational studies, conducted as part of the trials, may provide important insights into the putative mechanism of action delineated by preclinical studies of the combinations. The emergence of novel proteasome inhibitors may also expand the opportunities for optimizing these combination therapies. There is potential for an increasingly broad clinical trials program to investigate this therapeutic approach in a range of tumor types, as well as to consider additional agents in sequence or in combination.
Lessons learned from the initial sequencing of the pig genome: comparative analysis of an 8 Mb region of pig chromosome 17
Authors: Elizabeth A Hart, Mario Caccamo, Jennifer L Harrow, Sean J Humphray, James GR Gilbert, Steve Trevanion, Tim Hubbard, Jane Rogers, Max F Rothschild
Journal: Genome biology (2007)

Abstract Background We describe here the sequencing, annotation and comparative analysis of an 8 Mb region of pig chromosome 17, which provides a useful test region to assess coverage and quality for the pig genome sequencing project. We report our findings comparing the annotation of draft sequence assembled at different depths of coverage. Results Within this region we annotated 71 loci, of which 53 are orthologous to human known coding genes. When compared to the syntenic regions in human (20q13.13-q13.33) and mouse (chromosome 2, 167.5 Mb-178.3 Mb), this region was found to be highly conserved with respect to gene order. The most notable difference between the three species is the presence of a large expansion of zinc finger coding genes and pseudogenes on mouse chromosome 2 between Edn3 and Phactr3 that is absent from pig and human. All of our annotation has been made publicly available in the Vertebrate Genome Annotation browser, VEGA. We assessed the impact of coverage on sequence assembly across this region and found, as expected, that increased sequence depth resulted in fewer, longer contigs. One-third of our annotated loci could not be fully re-aligned back to the low coverage version of the sequence, principally because the transcripts are fragmented over several contigs. Conclusion We have demonstrated the considerable advantages of sequencing at increased read depths and discuss the implications that lower coverage sequence may have on subsequent comparative and functional studies, particularly those involving complex loci such as GNAS .
Dual Punch Tumour-Specific Transcriptional Gene Silencing Inducing Therapeutic Approach Based on Novel Tumour-Specific Promoter and Recombinant Sendai Immuno-Virosomes
Authors: I. Khan, K. Zakariya, P. Mani, P. Chattopadhyay, D.P. Sarkar, S. Sinha
Journal: Annals of Oncology (2014)
Doctors will need NICE's advice for fair drug rationing, says BMA
Authors: A. O'Dowd
Journal: BMJ (2011)

The BMA is keen on a strong role for the drug watchdog the National Institute for Health and Clinical Excellence (NICE) if doctors in England take responsibility for choosing which drugs are available on the NHS.

Doctors have been expressing concerns about unfair rationing of drugs when the new general practice commissioning consortiums take charge of deciding which drugs are to be made available to the NHS—a role currently held by NICE ( BMJ 2010;341:c6240, doi:10.1136/bmj.c6240).

Launching a consultation in December last year, the Department of Health proposed that NICE lose its power to turn down new drugs for use on the NHS after evaluating …
Propionate absorption and metabolism in the rabbit hindgut.
Authors: M Y Vernay
Journal: Gut (1987)

Propionate disappearance from the loops of the hindgut in the rabbit was evaluated by measuring variations in the concentration of propionate in caecocolonic loops and differences in the arterial and venous plasma. In vivo metabolism in gut and liver tissues was studied after introduction of (1-14C) propionate into the caecocolonic loops. The rate of disappearance from the loops was always quantitatively significant but was greater in the proximal colon. Hindgut tissue metabolised propionate and the intensity of the metabolism varied with the segment studied; the proximal colon showed by far the highest propionate consumption. Radioactivity was found in a certain number of free amino acids, organic acids, sugars, lipid soluble substances and proteins. Propionate is an efficient respiratory fuel for the colonocyte and a good precursor for gluconeogenesis.
Notch2 signaling and undifferentiated liver cancers: Evidence of hepatic stem/progenitor cell origin
Authors: Vincenzo Cardinale, Guido Carpino, Lola M. Reid, Eugenio Gaudio, Domenico Alvaro
Journal: Hepatology (2013)

Dill et al. demonstrated how aberrant activation of Notch2 signaling in albumin-expressing cells of AlbCre/N2ICD mice resulted in hepatocellular carcinomas (HCCs) associated with proliferation and expansion of immature biliary epithelial cells (BECs).1 HCC formation was enhanced by treatment with diethylnitrosamine (DEN), which induced the appearance of combined HCC-cholangiocarcinoma (CCC) and of CCC with immature BEC features.1 Expansion of the BEC compartment in AlbCre/N2ICD mice mimics activation of hepatic stem cells (HpSCs) in human diseases characterized by Notch2 up-regulation.2 Moreover, aberrant Notch2 signaling induces the formation of human liver cancers with HpSC features.3 Thus, the HpSC compartment is the most likely candidate for oncogenic events in AlbCre/N2ICD mice, supporting the concept that a spectrum of liver cancers could originate from activation of HpSCs. Alternatively, it was proposed that CCCs might originate from dedifferentiation of hepatocytes.4, 5 This provocative assumption is based on observations by genetic tracing studies that CCCs arose from albumin- or transthyretin-expressing cells.4, 5 However, albumin and transthyretin are expressed in cells undergoing liver differentiation from embryoid bodies6 and in hepatic and biliary tree stem/progenitors in intrahepatic (canals of Hering) and/or extrahepatic (peribiliary glands) niches.7, 8 In the studies by Dill et al.,1 biliary hyperplasia and large biliary cyst formation were induced, even though the albumin gene promoter was targeted to induce selective hepatic N2ICD overexpression. Therefore, albumin-expressing cells in different anatomical sites could have been targeted. Although dedifferentiation of hepatocytes in oncogenesis cannot be excluded, neoplastic transformation of a stem/progenitor cell subpopulation more easily explains oncogenesis. Identification of the cell(s) of origin and the signaling pathways involved are challenging issues in liver cancers with pivotal implications in the clinicopathological and therapeutic perspectives. VINCENZO CARDINALE, M.D.1 GUIDO CARPINO, M.D., PH.D.2,3 LOLA M. REID, PH.D.4 EUGENIO GAUDIO, M.D.2 DOMENICO ALVARO, M.D.1,5 1Department of Medico-Surgical Sciences and Biotechnologies, Polo Pontino, Italy 2Department of Anatomical, Histological, Forensic Medicine, and Orthopedics Sciences Sapienza University of Rome, Rome, Italy 3Department of Health Sciences University of Rome “Foro Italico”, Rome, Italy 4Department of Cell Biology and Physiology, Program in Molecular Biology and Biotechnology, University of North Carolina School of Medicine, Chapel Hill, NC 5Eleonora Lorillard Spencer-Cenci Foundation, Rome, Italy
Echocardiographic evaluation of long-term effects of exercise on left ventricular hypertrophy and function in professional bicyclists.
Authors: T Nishimura, Y Yamada, C Kawai
Journal: Circulation (1980)

Echocardiographic examinations were performed in 60 professional bicyclists and control subjects to determine the effects of exercise on left ventricular hypertrophy and function. The athletes were separated by age into three groups: group 1 (n = 14), 20-29 years; group 2 (n = 17), 30-39 years; and group 3 (n = 29), 40-49 years. Echocardiograms showed enlargment of the left ventricular end-diastolic dimensions in all three groups compared with age-matched control groups (p less than 0.001). Thickness of the interventricular septum and the left ventricular posterior wall was more prominent in group 3 of the athletes than groups 1 and 2 of the athletes and control group (p less than 0.001). Resting left ventricular function evaluated with fractional shortening, ejection fraction and mean velocity of circumferential fiber shortening was significantly depressed in group 3 compared with the other groups. Moreover, 14% of group 3 subjects showed enlargement of left atrial dimension and T-wave inversion in the left precordial leads of the ECG. We conclude that left ventricular hypertrophy is an important ventricular adaptation in relatively young athletes. However, middle-aged athletes may be more susceptible to electrocardiographic abnormalities and prominent hypertrophy, and some may have slightly depressed left ventricular function.
Evaluation of Supported Upper Limb Exercise Capacity in Patients with Cystic Fibrosis
Authors: JENNIFER A. ALISON, JEFF A. REGNIS, PETER M. DONNELLY, ROGER D. ADAMS, JOHN R. SUTTON, PETER T. P. BYE
Journal: American Journal of Respiratory and Critical Care Medicine (1997)

Physiological responses to upper limb exercise have not been well documented in patients with cystic fibrosis (CF). This is the first study to quantify ventilatory responses to supported incremental upper limb exercise in this patient group. Twenty-four subjects with CF, with a wide range of pulmonary impairment, and ten normal control subjects were studied. Subjects performed pulmonary function tests and incremental arm and leg exercise to peak work capacity on an arm crank and bicycle ergometer. All subjects performed less work with the arms than legs. At an equivalent oxygen consumption, ventilation was higher for arm work than leg work. This higher ventilation was achieved mainly through a higher frequency of breathing. Only CF subjects with severe pulmonary impairment (FEV1 < 40% predicted, FEF25–75% < 20% predicted) had a reduced arm work capacity compared with control subjects. At peak arm work, these subjects had a mean ventilation to maximum voluntary ventilation ratio (V˙ e/MVV) of 106% ± 25, while maximum heart rate was less than 80% predicted. Despite the high ventilatory requirement for arm exercise, arm work capacity was well maintained in subjects with CF until severe lung disease impaired the ability to further increase ventilation.
Lenient vs. strict rate control in patients with atrial fibrillation and heart failure: a post‐hoc analysis of the RACE II study
Authors: Bart A. Mulder, Dirk J. Van Veldhuisen, Harry J.G.M. Crijns, Jan G.P. Tijssen, Hans L. Hillege, Marco Alings, Michiel Rienstra, Hessel F. Groenveld, Maarten P. Van den Berg, Isabelle C. Van Gelder
Journal: European Journal of Heart Failure (2013)
Determinants and Time Course of the Postthrombotic Syndrome after Acute Deep Venous Thrombosis
Authors: Susan R. Kahn
Journal: Annals of Internal Medicine (2008)

Background: The reason some patients with deep venous thrombosis (DVT) develop the postthrombotic syndrome is not well understood. Objective: To determine the frequency, time course, and predictors of the postthrombotic syndrome after acute DVT. Design: Prospective, multicenter cohort study. Setting: 8 Canadian hospital centers. Patients: 387 outpatients and inpatients who received an objective diagnosis of acute symptomatic DVT were recruited from 2001 to 2004. Measurements: Standardized assessments for the postthrombotic syndrome using the Villalta scale at 1, 4, 8, 12, and 24 months after enrollment. Mean postthrombotic score and severity category at each interval was calculated. Predictors of postthrombotic score profiles over time since diagnosis of DVT were identified by using linear mixed modeling. Results: At all study intervals, about 30% of patients had mild (score, 5 to 9), 10% had moderate (score, 10 to 14), and 3% had severe (score >14 or ulcer) postthrombotic syndrome. Greater postthrombotic severity category at the 1-month visit strongly predicted higher mean postthrombotic scores throughout 24 months of follow-up (1.97, 5.03, and 7.00 increase in Villalta score for mild, moderate, and severe 1-month severity categories, respectively, vs. none; P < 0.001). Additional predictors of higher scores over time were venous thrombosis of the common femoral or iliac vein (2.23 increase in score vs. distal [calf] venous thrombosis; P < 0.001), higher body mass index (0.14 increase in score per kg/m2; P < 0.001), previous ipsilateral venous thrombosis (1.78 increase in score; P= 0.001), older age (0.30 increase in score per 10-year age increase; P= 0.011), and female sex (0.79 increase in score; P= 0.020). Limitations: Decisions to prescribe compression stockings were left to treating physicians rather than by protocol. Because international normalized ratio data were unavailable, the relationship between anticoagulation quality and Villalta scores could not be assessed. Conclusion: The postthrombotic syndrome occurs frequently after DVT. Patients with extensive DVT and those with more severe postthrombotic manifestations 1 month after DVT have poorer long-term outcomes.
Chromosome Breakage Is Regulated by the Interaction of the BLM Helicase and Topoisomerase IIα
Authors: Beatriz Russell, Saumitri Bhattacharyya, Jeremy Keirsey, April Sandy, Patrick Grierson, Erin Perchiniak, Juraj Kavecansky, Samir Acharya, Joanna Groden
Journal: Cancer Research (2011)

Cells deficient in the recQ-like helicase BLM are characterized by chromosome changes that suggest the disruption of normal mechanisms needed to resolve recombination intermediates and to maintain chromosome stability. Human BLM and topoisomerase IIα interact directly via amino acids 489-587 of BLM and colocalize predominantly in late G2 and M phases of the cell cycle. Deletion of this region does not affect the inherent in vitro helicase activity of BLM but inhibits the topoisomerase IIα-dependent enhancement of its activity, based on the analysis of specific DNA substrates that represent some recombination intermediates. Deletion of the interaction domain from BLM fails to correct the elevated chromosome breakage of transfected BLM-deficient cells. Our results demonstrate that the BLM-topoisomerase IIα interaction is important for preventing chromosome breakage and elucidate a DNA repair mechanism that is critical to maintain chromosome stability in cells and to prevent tumor formation.
HEREDITARY HAEMORRHACGIC TELANGIECTASIA: WITH A NOTE ON THE AGE-INCIDENCE OF THE SKIN-LESIONS
Authors: S. ERDHEIM
Journal: British Journal of Dermatology (1929)

Journal Article HEREDITARY HÆMORRHACGIC TELANGIECTASIA: WITH A NOTE ON THE AGE‐INCIDENCE OF THE SKIN‐LESIONS Get access S. ERDHEIM, M.B., Ch.B S. ERDHEIM, M.B., Ch.B Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology and Syphilis, Volume 41, Issue 2, 1 February 1929, Pages 55–67, https://doi.org/10.1111/j.1365-2133.1929.tb09312.x Published: 01 February 1929
Eltrombopag for management of chronic immune thrombocytopenia (RAISE): a 6-month, randomised, phase 3 study
Authors: Gregory Cheng, Mansoor N Saleh, Claus Marcher, Sandra Vasey, Bhabita Mayer, Manuel Aivado, Michael Arning, Nicole L Stone, James B Bussel
Journal: The Lancet (2010)
Adjuvant Chemotherapy Was a Predictive Factor for Locally Advanced Urothelial Carcinoma Following Radical Surgery
Authors: Masaomi Ikeda, Kazumasa Matsumoto, Morihiro Nishi, Ken-ichi Tabata, Tetsuo Fujita, Toshikazu Okaneya, Masatsugu Iwamura
Journal: Annals of Oncology (2014)
Transgenic mice expressing high levels of human apolipoprotein B develop severe atherosclerotic lesions in response to a high-fat diet.
Authors: D A Purcell-Huynh, R V Farese, D F Johnson, L M Flynn, V Pierotti, D L Newland, M F Linton, D A Sanan, S G Young
Journal: Journal of Clinical Investigation (1995)

We previously generated transgenic mice expressing human apolipoprotein (apo-) B and demonstrated that the plasma of chow-fed transgenic animals contained markedly increased amounts of LDL (Linton, M. F., R. V. Farese, Jr., G. Chiesa, D. S. Grass, P. Chin, R. E. Hammer, H. H. Hobbs, and S. G. Young 1992. J. Clin. Invest. 92:3029-3037). In this study, we fed groups of transgenic and nontransgenic mice either a chow diet or a diet high in fat (16%) and cholesterol (1.25%). Lipid and lipoprotein levels were assessed, and after 18 wk of diet, the extent of aortic atherosclerotic lesions in each group of animals was quantified. Compared with the female transgenic mice on the chow diet, female transgenic mice on the high-fat diet had higher plasma levels of cholesterol (312 +/- 17 vs 144 +/- 7 mg/dl; P < 0.0001) and human apo-B (120 +/- 8 vs 84 +/- 3 mg/dl; P < 0.0001). The higher human apo-B levels were due to increased plasma levels of human apo-B48; the human apo-B100 levels did not differ in animals on the two diets. In mice on the high-fat diet, most of the human apo-B48 and apo-B100 was found in LDL-sized particles. Compared with nontransgenic mice on the high-fat diet, the transgenic animals on the high-fat diet had significantly increased levels of total cholesterol (312 +/- 17 vs 230 +/- 19 mg/dl; P < 0.0001) and non-HDL cholesterol (283 +/- 17 vs 193 +/- 19 mg/dl; P < 0.0001). The extent of atherosclerotic lesion development within the ascending aorta was quantified by measuring total lesion area in 60 progressive sections, using computer-assisted image analysis. Neither the chow-fed transgenic mice nor the chow-fed nontransgenic mice had significant atherosclerotic lesions. Nontransgenic animals on the high-fat diet had relatively small atherosclerotic lesions (< 15,000 microns 2/section), almost all of which were confined to the proximal 400 microns of the aorta near the aortic valve. In contrast, transgenic animals on the high-fat diet had extensive atherosclerotic lesions (> 160,000 microns 2/section) that were widely distributed throughout the proximal 1,200 microns of the aorta. Thus, human apo-B expression, in the setting of a diet rich in fats, causes severe atherosclerosis in mice.
Human heat shock protein 70 (hsp70) protects murine cells from injury during metabolic stress.
Authors: R S Williams, J A Thomas, M Fina, Z German, I J Benjamin
Journal: Journal of Clinical Investigation (1993)

Expression of heat shock protein 70 (hsp70) is stimulated during ischemia, but its proposed cytoprotective function during metabolic stress has remained conjectural. We introduced a human hsp70 gene into mouse 10T1/2 cells and assessed the susceptibility of these cells to injury in response to conditions that mimic ischemia. Transiently transfected cells, in the absence of stress, expressed human hsp70 to levels equal to or greater than those induced by heat shock, as assessed by RNAse protection, immunoblot, and immunohistochemical analyses. By comparison to cells transfected with a control plasmid, cells expressing the human hsp70 transgene were resistant to injury induced by glucose deprivation and inhibition of mitochondrial respiration. These results provide direct evidence for a cytoprotective function of hsp70 during metabolic stress.
Research misconduct and redundant publication
Authors: M RAJAGOPALAN
Journal: Gut (1998)

Editor,—The editorial on research misconduct ( Gut 1997; 41 :1–2) is timely. Duplicate reports, redundant publications and “salami slicing” are products of today’s environment where academics are often judged by the length of their curriculum vitae and number of publications,1-3rather than the quality of work and whether it has any impact on current medical practice. This necessity to publish may be due to institutional pressures, personal ambition, vanity, direct financial gain, or even psychiatric illness.1 The prevalence of fraud is estimated to be around 0.1–0.4% of research studies and over 70 cases have been documented.4 5 About 5% of drug trials are thought to involve misconduct of some sort.6Peer review offers little or no protection against fraud.7 

A few years ago, as assistant editor of a psychiatry journal, …
Anti-TNF antibody-induced psoriasiform skin lesions in patients with inflammatory bowel disease are characterised by interferon-γ-expressing Th1 cells and IL-17A/IL-22-expressing Th17 cells and respond to anti-IL-12/IL-23 antibody treatment
Authors: Cornelia Tillack, Laura Maximiliane Ehmann, Matthias Friedrich, Rüdiger P Laubender, Pavol Papay, Harald Vogelsang, Johannes Stallhofer, Florian Beigel, Andrea Bedynek, Martin Wetzke, Harald Maier, Maria Koburger, Johanna Wagner, Jürgen Glas, Julia Diegelmann, Sarah Koglin, Yvonne Dombrowski, Jürgen Schauber, Andreas Wollenberg, Stephan Brand
Journal: Gut (2013)

We analysed incidence, predictors, histological features and specific treatment options of anti-tumour necrosis factor α (TNF-α) antibody-induced psoriasiform skin lesions in patients with inflammatory bowel diseases (IBD).Patients with IBD were prospectively screened for anti-TNF-induced psoriasiform skin lesions. Patients were genotyped for IL23R and IL12B variants. Skin lesions were examined for infiltrating Th1 and Th17 cells. Patients with severe lesions were treated with the anti-interleukin (IL)-12/IL-23 p40 antibody ustekinumab.Among 434 anti-TNF-treated patients with IBD, 21 (4.8%) developed psoriasiform skin lesions. Multiple logistic regression revealed smoking (p=0.007; OR 4.24, 95% CI 1.55 to 13.60) and an increased body mass index (p=0.029; OR 1.12, 95% CI 1.01 to 1.24) as main predictors for these lesions. Nine patients with Crohn's disease and with severe psoriasiform lesions and/or anti-TNF antibody-induced alopecia were successfully treated with the anti-p40-IL-12/IL-23 antibody ustekinumab (response rate 100%). Skin lesions were histologically characterised by infiltrates of IL-17A/IL-22-secreting T helper 17 (Th17) cells and interferon (IFN)-γ-secreting Th1 cells and IFN-α-expressing cells. IL-17A expression was significantly stronger in patients requiring ustekinumab than in patients responding to topical therapy (p=0.001). IL23R genotyping suggests disease-modifying effects of rs11209026 (p.Arg381Gln) and rs7530511 (p.Leu310Pro) in patients requiring ustekinumab.New onset psoriasiform skin lesions develop in nearly 5% of anti-TNF-treated patients with IBD. We identified smoking as a main risk factor for developing these lesions. Anti-TNF-induced psoriasiform skin lesions are characterised by Th17 and Th1 cell infiltrates. The number of IL-17A-expressing T cells correlates with the severity of skin lesions. Anti-IL-12/IL-23 antibody therapy is a highly effective therapy for these lesions.
T-cell-replete haploidentical HSCT with low-dose anti-T-lymphocyte globulin compared with matched sibling HSCT and unrelated HSCT
Authors: Yi Luo, Haowen Xiao, Xiaoyu Lai, Jimin Shi, Yamin Tan, Jingsong He, Wanzhuo Xie, Weiyan Zheng, Yuanyuan Zhu, Xiujin Ye, Xiaohong Yu, Zhen Cai, Maofang Lin, He Huang
Journal: Blood (2014)