tbuckley/cabot-search huggingface dataset:
Trapping of PARP1 and PARP2 by Clinical PARP Inhibitors
Authors: Junko Murai, Shar-yin N. Huang, Benu Brata Das, Amelie Renaud, Yiping Zhang, James H. Doroshow, Jiuping Ji, Shunichi Takeda, Yves Pommier
Journal: Cancer Research (2012)

Abstract Small-molecule inhibitors of PARP are thought to mediate their antitumor effects as catalytic inhibitors that block repair of DNA single-strand breaks (SSB). However, the mechanism of action of PARP inhibitors with regard to their effects in cancer cells is not fully understood. In this study, we show that PARP inhibitors trap the PARP1 and PARP2 enzymes at damaged DNA. Trapped PARP–DNA complexes were more cytotoxic than unrepaired SSBs caused by PARP inactivation, arguing that PARP inhibitors act in part as poisons that trap PARP enzyme on DNA. Moreover, the potency in trapping PARP differed markedly among inhibitors with niraparib (MK-4827) &amp;gt; olaparib (AZD-2281) &amp;gt;&amp;gt; veliparib (ABT-888), a pattern not correlated with the catalytic inhibitory properties for each drug. We also analyzed repair pathways for PARP–DNA complexes using 30 genetically altered avian DT40 cell lines with preestablished deletions in specific DNA repair genes. This analysis revealed that, in addition to homologous recombination, postreplication repair, the Fanconi anemia pathway, polymerase β, and FEN1 are critical for repairing trapped PARP–DNA complexes. In summary, our study provides a new mechanistic foundation for the rational application of PARP inhibitors in cancer therapy. Cancer Res; 72(21); 5588–99. ©2012 AACR.
Quantitative coronary angiography to measure progression and regression of coronary atherosclerosis. Value, limitations, and implications for clinical trials.
Authors: P J de Feyter, P W Serruys, M J Davies, P Richardson, J Lubsen, M F Oliver
Journal: Circulation (1991)

T here have been five primary prevention trials of which the purpose was to determine whether reducing hypercholesterolemia would also decrease the incidence of coronary heart disease (CHD).1-5Two were dietary studies, and three were pharmacological studies.Although there were inconsistencies in the findings among the trials, largely due to differences in design and method of intervention, each demonstrated significant reduc- tion in the incidence of CHD, particularly CHD morbidity, although none showed a convincing reduc- tion in total mortality.However, there is evidence to suggest that a synergistic effect occurs when interven- tions are combined, especially when one intervention is aimed at reducing hypercholesterolemia.For in- stance, the Oslo Heart Study showed an impressive reduction in CHD morbidity and mortality in previ- ously healthy men with the combined interventions of reducing cigarette smoking and lowering serum cho- lesterol levels by diet.6 Very recently, three trials showed, using repeated coronary angiography, that cholesterol lowering was associated with less progression of coronary artery disease and that the frequency of regression of lesions was increased.7-9The establishment and successful conduct of new primary prevention trials of the effectiveness of lowering hypercholesterol- emia are very expensive and complex.Therefore, one of the most important questions now facing the medical and scientific community is whether it is possible to show that significant regression of cor- onary atherosclerotic lesions can be achieved by new and more powerful interventions that reduce From the Thorax Center (P.
Omeprazole inhibits colorectal carcinogenesis induced by azoxymethane in rats.
Authors: I D Penman, E el-Omar, J R McGregor, K J Hillan, P J O'Dwyer, K E McColl
Journal: Gut (1993)

<h3>Introduction</h3> Undernutrition is a major risk factor for tuberculosis (TB), which is estimated to be responsible for 1.9 million TB cases per year globally. The effectiveness of micronutrient supplementation on TB treatment outcomes and its prognostic markers (sputum conversion, serum zinc, retinol and haemoglobin levels) has been poorly understood. This study aimed to determine the effect of zinc and vitamin A supplementation on prognostic markers and TB treatment outcomes among adults with sputum-positive pulmonary TB. <h3>Methods</h3> A systematic literature search for randomised controlled trials (RCTs) was performed in PubMed, Embase and Scopus databases. Meta-analysis with a random effect model was performed to estimate risk ratio (RR) and mean difference (MD), with a 95% CI, for dichotomous and continuous outcomes, respectively. <h3>Results</h3> Our search identified 2195 records. Of these, nine RCTs consisting of 1375 participants were included in the final analyses. Among adults with pulmonary TB, zinc (RR: 0.94, 95% CI: 0.86 to 1.03), vitamin A (RR: 0.90, 95% CI: 0.80 to 1.01) and combined zinc and vitamin A (RR: 0.98, 95% CI: 0.89 to 1.08) supplementation were not significantly associated with TB treatment success. Combined zinc and vitamin A supplementation was significantly associated with increased sputum smear conversion at 2 months (RR: 1.16, 95% CI: 1.03 to 1.32), serum zinc levels at 2 months (MD: 0.86 μmol/L, 95% CI: 0.14 to 1.57), serum retinol levels at 2 months (MD: 0.06 μmol/L, 95% CI: 0.04 to 0.08) and 6 months (MD: 0.12 μmol/L, 95% CI: 0.10 to 0.14) and serum haemoglobin level at 6 months (MD: 0.29 μg/dL, 95% CI: 0.08 to 0.51), among adults with pulmonary TB. <h3>Conclusions</h3> Providing zinc and vitamin A supplementation to adults with sputum-positive pulmonary TB during treatment may increase early sputum smear conversion, serum zinc, retinol and haemoglobin levels. However, the use of zinc, vitamin A or both was not associated with TB treatment success. <h3>PROSPERO registration number</h3> CRD42021248548.
The very 5′ end and the constant region of Ig genes are spared from somatic mutation because AID does not access these regions
Authors: Simonne Longerich, Atsushi Tanaka, Grazyna Bozek, Dan Nicolae, Ursula Storb
Journal: The Journal of Experimental Medicine (2005)

Somatic hypermutation (SHM) is restricted to VDJ regions and their adjacent flanks in immunoglobulin (Ig) genes, whereas constant regions are spared. Mutations occur after about 100 nucleotides downstream of the promoter and extend to 1–2 kb. We have asked why the very 5′ and most of the 3′ region of Ig genes are unmutated. Does the activation-induced cytosine deaminase (AID) that initiates SHM not gain access to these regions, or does AID gain access, but the resulting uracils are repaired error-free because error-prone repair does not gain access? The distribution of mutations was compared between uracil DNA glycosylase (Ung)-deficient and wild-type mice in endogenous Ig genes and in an Ig transgene. If AID gains access to the 5′ and 3′ regions that are unmutated in wild-type mice, one would expect an “AID footprint,” namely transition mutations from C and G in Ung-deficient mice in the regions normally devoid of SHM. We find that the distribution of total mutations and transitions from C and G is indistinguishable in wild-type and Ung-deficient mice. Thus, AID does not gain access to the 5′ and constant regions of Ig genes. The implications for the role of transcription and Ung in SHM are discussed.
Overexpression of the platelet P2X1 ion channel in transgenic mice generates a novel prothrombotic phenotype
Authors: Cécile Oury, Marijke J. E. Kuijpers, Emese Toth-Zsamboki, Arnaud Bonnefoy, Sophie Danloy, Ingrid Vreys, Marion A. H. Feijge, Rita De Vos, Jos Vermylen, Johan W. M. Heemskerk, Marc F. Hoylaerts
Journal: Blood (2003)
Genome-Wide Loss of Heterozygosity and Uniparental Disomy in BRCA1/2-Associated Ovarian Carcinomas
Authors: Christine S. Walsh, Seishi Ogawa, Daniel R. Scoles, Carl W. Miller, Norihiko Kawamata, Steven A. Narod, H. Phillip Koeffler, Beth Y. Karlan
Journal: Clinical Cancer Research (2008)

The importance of the BRCA gene products in maintaining genomic stability led us to hypothesize that BRCA-associated and sporadic ovarian cancers would have distinctive genetic profiles despite similarities in histologic appearance.A whole-genome copy number analysis of fresh, frozen, papillary serous ovarian cancer DNA was done using the Affymetrix 50K Xba Mapping Array using each patient's normal genomic DNA as the matched control. Loss of heterozygosity and copy number abnormalities were summarized to define regions of amplification, deletion, or uniparental disomy (UPD), defined as loss of one allele and duplication of the remaining allele. Genomic abnormalities were compared between BRCA-associated and sporadic tumors.We compared 6 BRCA-associated with 14 sporadic papillary serous ovarian carcinomas. Genetic instability, measured by percentage of genome altered, was more pronounced in BRCA-associated tumors (median, 86.6%; range, 54-100%) than sporadic tumors (median, 43.6%; range, 2-83%; P = 0.009). We used frequency plots to show the proportion of cases affected by each type abnormality at each genomic region. BRCA-associated tumors showed genome-wide loss of heterozygosity primarily due to the occurrence of UPD rather than deletion. UPD was found in 100% of the BRCA-associated and 50% of the sporadic tumors profiled.This study reports on a previously underappreciated genetic phenomenon of UPD, which occurs frequently in ovarian cancer DNA. We observed distinct genetic patterns between BRCA-associated and sporadic ovarian cancers, suggesting that these papillary serous tumors arise from different molecular pathways.
High Titer of Autoantibodies to GAD Identifies a Specific Phenotype of Adult-Onset Autoimmune Diabetes
Authors: Raffaella Buzzetti, Sergio Di Pietro, Andrea Giaccari, Antonio Petrone, Mattia Locatelli, Concetta Suraci, Marco Capizzi, Maria Luisa Arpi, Elena Bazzigaluppi, Francesco Dotta, Emanuele Bosi
Journal: Diabetes Care (2007)

The aim of the present study was to define heterogeneity of adult-onset autoimmune diabetes based on characterization of GAD antibodies (GADAs).Patients enrolled in a nationwide survey, the Non Insulin Requiring Autoimmune Diabetes (NIRAD) Study, have been screened for GADAs and IA-2 antibodies (IA-2As) and further characterized for GADA titer, antibodies to thyroid peroxidase (TPO), and HLA DRB1-DQB1 polymorphisms.Of 4,250 consecutive type 2 diabetic patients, 4.5% had either GADAs and/or IA-2As. Patients with autoimmune diabetes showed a clinical phenotype significantly different from that of type 2 diabetes, including higher fasting glucose and A1C, lower BMI and uric acid, lower prevalence of metabolic syndrome and its components, and higher frequency of TPO antibodies. More interestingly, analysis of GADA titers showed a bimodal distribution that identified two subgroups of patients with high (>32 GADA arbitrary units) and low (< or =32 GADA arbitrary units) GADA titers. Compared with those with low GADA titers, patients with high GADA titers had more prominent traits of insulin deficiency and a profile of more severe autoimmunity resulting in higher A1C, lower BMI, a lower prevalence of metabolic syndrome and its components (P < 0.02 for all), a higher prevalence of IA-2As, TPO antibodies (P < 0.003 for both), and DRB1*03-DQB1*0201 (50 vs. 26.8%, P = 0.001), and a decreasing frequency of DQB1*0602 and DRB1*0403 (from type 2 to low and to high GADA titer autoimmune diabetes; P < 0.001 for trend for both comparisons).GADA titers identify two subgroups of patients with adult-onset autoimmune diabetes having distinct clinical, autoimmune, and genetic features.
<i>BRAF</i>mutation testing algorithm for vemurafenib treatment in melanoma: recommendations from an expert panel
Authors: D. Gonzalez, L. Fearfield, P. Nathan, P. Tanière, A. Wallace, E. Brown, C. Harwood, J. Marsden, S. Whittaker
Journal: British Journal of Dermatology (2013)

The incidence of melanoma has increased rapidly over the past 30 years, and the disease is now the sixth most common cancer among men and women in the U.K. Many patients are diagnosed with or develop metastatic disease, and survival is substantially reduced in these patients. Mutations in the BRAF gene have been identified as key drivers of melanoma cells and are found in around 50% of cutaneous melanomas. Vemurafenib (Zelboraf(®) ; Roche Molecular Systems Inc., Pleasanton, CA, U.S.A.) is the first licensed inhibitor of mutated BRAF, and offers a new first-line option for patients with unresectable or metastatic melanoma who harbour BRAF mutations. Vemurafenib was developed in conjunction with a companion diagnostic, the cobas(®) 4800 BRAF V600 Mutation Test. The purpose of this paper is to make evidence-based recommendations to facilitate the implementation of BRAF mutation testing and targeted therapy in patients with metastatic melanoma in the U.K. The recommendations are the result of a meeting of an expert panel and have been reviewed by melanoma specialists and representatives of the National Cancer Research Network Clinical Study Group on behalf of the wider melanoma community. This article is intended to be a starting point for practical advice and recommendations, which will no doubt be updated as we gain further experience in personalizing therapy for patients with melanoma.
Prisoners of war
Authors: Ian D Conache
Journal: BMJ (2006)

The patient should stop smoking, and control of diabetes, hypertension, and hyperlipidaemia should be optimised.Patients may find benefits from sleeping in a bed raised at the head end.Patients should follow simple advice on foot and leg care.Walking is beneficial.Infection can cause rapid deterioration in an arterial ulcer, and treatment with systemic antibiotics (along the lines for venous ulceration outlined above) should be started.Patients with rest pain or worsening claudication, or both, and a non-healing ulcer should be referred to a vascular surgeon; opioid analgesia may be necessary during the wait for surgery.It is not appropriate to debride arterial ulcers as this may promote further ischaemia and lead to the formation of a larger ulcer.Choice of wound dressings will be dictated by the nature of the wound.Vasoconstrictive drugs such as non-selective blockers should be avoided.(See 11th article in this series for more information on drug treatment.)Ulceration of mixed aetiology is not uncommon: patients may have a combination of venous and arterial diseases, resulting in ulcers of mixed aetiologies, which will limit the degree of compression (if any) that can be used.
Reduced wound contraction and scar formation in punch biopsy wounds. Native collagen dermal substitutes. A clinical study
Authors: H.J.C. VRIES, J.E. ZEEGELAAR, E. MIDDELKOOP, G. GIJSBERS, J. MARLE, C.H.R. WILDEVUUR, W. WESTERHOF
Journal: British Journal of Dermatology (2006)

In full-thickness skin wounds dermal regeneration usually fails, resulting in scar formation and wound contraction. We studied dermal regeneration by implantation of collagenous matrices in a human punch biopsy wound model. Matrices were made of native bovine collagen 1 fibres, and either hyaluronic acid, fibronectin, or elastin was added. Matrices were placed in 6-mm punch biopsy holes in seven patients (biopsies were used for the grafting of leg ulcers), and covered with a protective semi-permeable polyether urethane membrane. Histology, wound contraction and dermal architecture were studied. Dermal architecture was evaluated using a recently developed laser scatter technique. All collagen matrices showed a tendency to reduce wound contraction, compared with control wounds; elastin- and fibronectin-treated matrices showed significantly less contraction than control wounds. Only the addition of elastin had a clear beneficial effect on dermal architecture; collagen bundles were more randomly organized, compared with control wounds, and wounds treated with collagen matrices coated with fibronectin or hyaluronic acid, or without coating. We conclude that the punch biopsy wound model provides important information on dermal regeneration in humans. Native collagen matrices with elastin contributed to dermal regeneration and reduced wound contraction, in contrast with matrices coated with fibronectin or hyaluronic acid, or without coating. Future clinical studies of large-area, full-thickness wounds will be required to establish their clinical relevance for leg ulcer and burn treatment.
Clinical and aetiological aspects in urticaria and angio-oedema
Authors: E. Nettis, A. Pannofino, C. D'Aprile, A. Ferrannini, A. Tursi
Journal: British Journal of Dermatology (2003)

Urticaria is a common disorder that affects as many as 20% of all people at some time during their lifetime.To analyse the prevalence of various forms of urticaria according to an aetiological and clinical classification, we carried out a 4-year study in an outpatient clinic.The study was carried out on 562 consecutive patients (178 males and 384 females; mean age 35.4 +/- 16), who had been referred to our unit for the study of urticaria and angio-oedema. Baseline investigations included: the patient's family and personal history of allergy; duration of symptoms, presence of associated symptoms and objective signs of the current episode; clinical, laboratory and instrumental investigations; assessment of response to antihistamine treatment.A family history of atopy was present in 35% of patients and a personal history of allergy in 24%. We subdivided urticaria and angio-oedema into several groups on the basis of their clinical and aetiological aspects. Of the 562 patients, 424 (76%) presented with ordinary urticaria (43 acute urticaria, 311 chronic urticaria, 70 episodic urticaria), 80 (14%) physical urticaria, 49 (9%) angio-oedema without weals, six (1%) IgE-mediated contact urticaria and three (0.5%) urticarial vasculitis. In 64 cases (11%) urticaria/angio-oedema was associated with one or more symptoms. We identified 394 cases (82%) of idiopathic urticaria, 42 (9%) of immunological urticaria, 29 (6%) of non-immunological urticaria and 17 (3%) of urticaria secondary to infections. Of the treated subjects, 54% showed a good response to treatment with antihistamines.Our data provide an overview of urticaria/angio-oedema in a large series of patients, based on clinical-aetiological aspects, and related to recent diagnostic guidelines.
Executive Dysfunction in Geriatric Depression
Authors: Kathryn A. Lockwood, George S. Alexopoulos, Wilfred G. van Gorp
Journal: American Journal of Psychiatry (2002)

OBJECTIVE: The purpose of this study was to characterize the neuropsychological presentation of geriatric depression and to determine whether depression-related executive dysfunction is more pronounced during advanced age. METHOD: The attention and executive functioning of 40 adults with major depression were compared with those of 40 healthy comparison subjects; 20 subjects were 20–60 years old, and 20 were ≥61 years. It was hypothesized that depressed subjects, regardless of age, would perform more poorly than comparison subjects on both attention and executive tasks but that the older depressed adults would evidence significantly greater impairment on executive measures. RESULTS: A significant interaction between age and depressive status was noted for tasks of executive functioning, while no age-depression interaction was found for tasks of selective or sustained attention. Older depressed adults demonstrated the slowest psychomotor speed and the poorest performance on tasks requiring set shifting, problem solving, and initiation of novel responses. CONCLUSIONS: Patients with late-life depression have significant impairment in executive functioning. These findings can guide the development of stimulated functional neuroimaging paradigms that may clarify the pathophysiology of geriatric depression. Timely identification of attentional and executive processes fundamental to the daily functioning of depressed older adults may lead to compensatory strategies that will improve the outcomes of late-life depression.
C. elegans Slit Acts in Midline, Dorsal-Ventral, and Anterior-Posterior Guidance via the SAX-3/Robo Receptor
Authors: Joe C Hao, Timothy W Yu, Kazuko Fujisawa, Joseph G Culotti, Keiko Gengyo-Ando, Shohei Mitani, Gary Moulder, Robert Barstead, Marc Tessier-Lavigne, Cornelia I Bargmann
Journal: Neuron (2001)
Paclitaxel for anthracycline-resistant AIDS-related Kaposi’s sarcoma: clinical and angiogenic correlations
Authors: J. Stebbing, A. Wildfire, S. Portsmouth, T. Powles, C. Thirlwell, P. Hewitt, M. Nelson, S. Patterson, S. Mandalia, F. Gotch, B.G. Gazzard, M. Bower
Journal: Annals of Oncology (2003)
Clinical response to the long acting somatostatin analogue SMS 201-995 in a child with congenital microvillus atrophy.
Authors: R T Couper, A Berzen, G Berall, P M Sherman
Journal: Gut (1989)

A 27 month old girl with congenital microvillus atrophy received two courses of SMS 201-995, a synthetic long acting analogue of native somatostatin, in an attempt to decrease profuse secretory diarrhoea. During the first trial at 13 months of age fluid and electrolytes administered by parenteral infusion were decreased as measured by water and faecal electrolyte losses. During the second trial of SMS 201-995 at 19 months fluid and electrolyte input were held constant for 14 days. Stool volume declined from 275 ml/kg to 161 ml/kg. Reductions in output of stool electrolytes (Na+, K+, Cl-) were accompanied by an increase in urine fluid output and increased excretion of urinary Na+. Subsequent administration of SMS 201-995 for a nine month period was not associated with adverse side effects or an impairment of growth velocity. These findings suggest that SMS 201-995 may be useful therapy in infants with high output diarrhoea as a result of congenital microvillus atrophy.
Endothelial Progenitor Cells
Authors: Carmen Urbich, Stefanie Dimmeler
Journal: Circulation Research (2004)

Infusion of different hematopoietic stem cell populations and ex vivo expanded endothelial progenitor cells augments neovascularization of tissue after ischemia and contributes to reendothelialization after endothelial injury, thereby, providing a novel therapeutic option. However, controversy exists with respect to the identification and the origin of endothelial progenitor cells. Overall, there is consensus that endothelial progenitor cells can derive from the bone marrow and that CD133/VEGFR2 cells represent a population with endothelial progenitor capacity. However, increasing evidence suggests that there are additional bone marrow-derived cell populations (eg, myeloid cells, “side population” cells, and mesenchymal cells) and non-bone marrow-derived cells, which also can give rise to endothelial cells. The characterization of the different progenitor cell populations and their functional properties are discussed. Mobilization and endothelial progenitor cell-mediated neovascularization is critically regulated. Stimulatory (eg, statins and exercise) or inhibitory factors (risk factors for coronary artery disease) modulate progenitor cell levels and, thereby, affect the vascular repair capacity. Moreover, recruitment and incorporation of endothelial progenitor cells requires a coordinated sequence of multistep adhesive and signaling events including adhesion and migration (eg, by integrins), chemoattraction (eg, by SDF-1/CXCR4), and finally the differentiation to endothelial cells. This review summarizes the mechanisms regulating endothelial progenitor cell-mediated neovascularization and reendothelialization.