tbuckley/cabot-search huggingface dataset:
Abstract 2563: Identification and functional characterization of a novel UGT2A1 splice variant: Potential importance in tobacco-related cancer susceptibility .
Authors: Ryan T. Bushey, Gang Chen, Philip Lazarus
Journal: Cancer Research (2013)

Abstract UGT2A1 is a phase II enzyme highly expressed in the respiratory and aerodigestive tracts. In the present study, a novel exon 3 deletion splice variant for UGT2A1 (termed ‘UGT2A1Δexon3’) was characterized. As determined by reverse-transcription polymerase chain reaction, UGT2A1Δexon3 was shown to be co-expressed with wild-type UGT2A1 in various tissues including lung, trachea, larynx, tonsil, and colon. The mRNA expression ratio of UGT2A1Δexon3:wild-type UGT2A1 was highest in colon (0.79±0.08) and lung (0.42±0.12) as determined by real-time PCR; splice variant protein (termed ‘UGT2A1_i2’) to wild-type protein (termed ‘UGT2A1_i1’) ratios were in the range of 0.5-0.9 in these tissues as determined by Western blot analysis using an UGT2A1-specific antibody. In contrast to the UGT2A1 wild-type isoform, homogenates prepared from UGT2A1_i2-over-expressing HEK293 cells exhibited no glucuronidation activity against PAHs, including benzo(a)pyrene-7,8-dihydrodiol (B(a)P-7,8-diol). An inducible in vitro system was created to determine the effect of UGT2A1_i2 expression on UGT2A1_i1 activity. Increasing UGT2A1_i2 levels resulted in a significant (p&amp;lt;0.01) decrease in the UGT2A1_i1 Vmax against 1-hydroxy (OH)-pyrene, 3-OH-B(a)P and B(a)P-7,8-diol; no significant changes in KM were observed for any of the three substrates. Co-immunoprecipitation experiments suggested the formation of UGT2A1_i1 and UGT2A1_i2 hetero-oligomers and UGT2A1_i1 homo-oligomers; co-expression of UGT2A1_i1 or UGT2A1_i2 with other UGT1A or UGT2B enzymes caused no change in UGT1A or UGT2B glucuronidation activity. These data suggest that a novel UGT2A1 splice variant regulates UGT2A1-mediated glucuronidation activity via UGT2A1-specific protein-protein interactions, and that expression of this variant could play an important role in the detoxification of carcinogens within target tissues for tobacco carcinogenesis. Citation Format: Ryan T. Bushey, Gang Chen, Philip Lazarus. Identification and functional characterization of a novel UGT2A1 splice variant: Potential importance in tobacco-related cancer susceptibility . [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2563. doi:10.1158/1538-7445.AM2013-2563
THU0374 Articular symptoms in cryopyrin-associated periodic syndrome: A retrospective french study
Authors: L. Houx, X. Guennoc, E. Hachulla, I. Koné-Paut, P. Quartier, G. Grateau, P. Pillet, M. Hamidou, I. Lemelle, A. Pagnier, B. Neven, C. Richez, V. Devauchelle-Pensec
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> The cryopyrin-associated periodic syndrome (CAPS) is a rare inherited inflammatory disease associated with mutations in <i>NLRP3</i>.It includes disorders of increasing severity, including the familial cold autoinflammatory syndrome (FCAS), the Muckle–Wells syndrome (MW), and neonatal-onset multisystem inflammatory disorder (NOMID) (also known as he chronic infantile neurologic, cutaneous, and articular syndrome: CINCA).Articular symptoms are frequently described in CAPS but their frequency have been poorly investigated. <h3>Objectives</h3> Our objectives were to describe the type and frequency of articular symptoms in a cohort of CAPS patients follwed in adults or paediatricien departments in France. <h3>Methods</h3> We conducted a retrospective study concerning articular manifestations (joint, bone and muscle symptoms) in patients with CAPS. Paediatricians, internal medicine and rheumatologists were contacted. Medical data were collected using standardized questionnary and radiographs if available were analysed. <h3>Results</h3> 75 patients were included, (12 FCAS, 45 MW, 12 CINCA/NOMID and 6 unclassified. 53% were females (40/75).Among them, 47 are adults (mean age: 31.8±15 years) and 28 are children (11±4.5 years). Disease onset was 4.7±2 years, however the age at the diagnosis was 18±4.5 years. The first symptoms were more frequently cutaneous (61%), fever (20%) articular (17%) and neurological (10%). 56 (74%) had a familial history of CAPS. 9 (12%) patients had CAPS without mutation. During the follow-up, only 17 (23%) did not have articular symptoms. For the remaining 55 (75%) had arthralgia and 46 (60%) had synovitis. The more affected joints were respectively the ankles (66%), knees (45%), hips (33%), feet (25%) and hands (21%). Only one patient with CINCA/NOMID had typical arthropathy with bone abnormalities enlarged, deformed femora and patellae. These arthragia were considered as predominant for 20% of the patients Radiographs were rarely performed. Tendinopathies occured in 12 (16%) of the patients and myalgia in 26 (35%). <h3>Conclusions</h3> Articular symptoms are frequent in patients with CAPS and considered as invalidating in 20% but they are poorly investigated by radiographs. Bone deformities are rare. Arthralgia can affected hand and feet. <h3>Disclosure of Interest</h3> None Declared
Amyloid precursor protein–mediated endocytic pathway disruption induces axonal dysfunction and neurodegeneration
Authors: Wei Xu, April M. Weissmiller, Joseph A. White, Fang Fang, Xinyi Wang, Yiwen Wu, Matthew L. Pearn, Xiaobei Zhao, Mariko Sawa, Shengdi Chen, Shermali Gunawardena, Jianqing Ding, William C. Mobley, Chengbiao Wu
Journal: Journal of Clinical Investigation (2016)

The endosome/lysosome pathway is disrupted early in the course of both Alzheimer's disease (AD) and Down syndrome (DS); however, it is not clear how dysfunction in this pathway influences the development of these diseases. Herein, we explored the cellular and molecular mechanisms by which endosomal dysfunction contributes to the pathogenesis of AD and DS. We determined that full-length amyloid precursor protein (APP) and its β-C-terminal fragment (β-CTF) act though increased activation of Rab5 to cause enlargement of early endosomes and to disrupt retrograde axonal trafficking of nerve growth factor (NGF) signals. The functional impacts of APP and its various products were investigated in PC12 cells, cultured rat basal forebrain cholinergic neurons (BFCNs), and BFCNs from a mouse model of DS. We found that the full-length wild-type APP (APPWT) and β-CTF both induced endosomal enlargement and disrupted NGF signaling and axonal trafficking. β-CTF alone induced atrophy of BFCNs that was rescued by the dominant-negative Rab5 mutant, Rab5S34N. Moreover, expression of a dominant-negative Rab5 construct markedly reduced APP-induced axonal blockage in Drosophila. Therefore, increased APP and/or β-CTF impact the endocytic pathway to disrupt NGF trafficking and signaling, resulting in trophic deficits in BFCNs. Our data strongly support the emerging concept that dysregulation of Rab5 activity contributes importantly to early pathogenesis of AD and DS.
Abstract 4816: Paleolithic and Mediterranean diet scores and risk of colorectal adenoma.
Authors: Kristine A. Whalen, Baiyu Yang, Roberd M. Bostick
Journal: Cancer Research (2013)

Abstract Background: A Westernized diet and lifestyle is associated with risk for colorectal cancer and adenomas. Evolutionary discordance could explain this association. Objective: We investigated associations of scores for two proposed healthy diet patterns, the “Paleolithic” and Mediterranean diets, with risk for incident, sporadic colorectal adenomas. Methods: In the Minnesota Cancer Prevention Research Unit case-control study of colorectal polyps, 1,248 participants with no history of colorectal neoplasms completed extensive questionnaires, including a Willett food frequency questionnaire, prior to an elective, outpatient colonoscopy. Of these participants 564 were identified as cases and 684 as colonoscopy-negative controls. An additional group of 535 age and sex frequency-matched population controls were also recruited. Paleolithic and the Mediterranean diet scores were calculated and categorized into quintiles, and associations estimated using unconditional logistic regression. Results: The Paleolithic and the Mediterranean diet patterns were similarly inversely associated with colorectal adenomas. The multivariable-adjusted odds ratios [OR] comparing those in the highest relative to the lowest quintiles of the Paleolithic and Mediterranean diet scores, respectively, were 0.51 (95% confidence interval [CI] 0.35-0.76) and 0.50 (95% CI 0.33-0.75) when comparing the cases to the colonoscopy negative controls, and 0.66 (95% CI 0.45 - 0.96, ptrend = 0.03) and 0.65 (95% CI 0.44 - 0.96, ptrend = 0.03) when comparing the cases to the population controls. These findings tended to be somewhat stronger among men and those who were overweight or obese. Conclusion: These findings suggest that higher adherence to the Paleolithic or Mediterranean diet patterns may be similarly associated with lower risk for incident, sporadic colorectal adenomas. Citation Format: Kristine A. Whalen, Baiyu Yang, Roberd M. Bostick. Paleolithic and Mediterranean diet scores and risk of colorectal adenoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4816. doi:10.1158/1538-7445.AM2013-4816
P4-17-07: The Shifting Landscape of Metastatic Breast Cancer to the CNS.
Authors: MR Quigley, O Fukui, B Chew, S Bhatia, S Karlovits
Journal: Cancer Research (2011)

Abstract Introduction: Improved survival following the diagnosis of breast cancer, in conjunction with new therapies and diagnostics has potentially altered the characteristics and course of patients presenting with CNS involvement. Methods: Review of clinical and radiographic records of women presenting to a tertiary medical center with the new diagnosis of CNS metastatic disease from breast cancer. This was a retrospective review from patients identities obtained from two prospective databases Results: There were 88 women analyzed who were treated over the period 1/2003-2/2010, average age 56.9. At the time of initial presentation of CNS disease, 68% of patients had multiple brain metastases, 17% had a solitary metastasis and 15% had only leptomeningeal disease (LMD). The median survival for all patients from the time of diagnosis of breast disease was 50.0 months, and 9.7 months from diagnosis of CNS involvement. The only factor related to overall survival was estrogen receptor positive (ER+) pathology (57.6 v. 38.2 months, p=.02 log-rank); those related to survival post CNS diagnosis were presentation with LMD (p=.004, HR= 3.1, Cox regression) and triple negative hormonal/HER2 status (p=.02, HR= 2.3, Cox regression). Patients with either had a median survival of 3.1 months (no patients in common). Of the 75 patients who initially presented with metastatic brain lesions, 20 (26%) subsequently developed LMD in the course of their disease (median 10.4 months), following which survival was grim (1.8 months median). Of note was that HER2+ status was protective in regard to late development of LMD (14.7 vs. 42.3%, p=.03, Chi-square). Symptoms of LMD were most commonly lower extremity weakness (14/33), followed by cranial nerve deficits (11/33). Conclusion: Treatment of patients with metastatic brain disease from breast cancer should be tailored to the patient's hormonal status (as it markedly effects survival) and practitioners must be vigilant for the development of LMD, especially as it often presents with non-descript complaints such as back pain. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-17-07.
Abstract 2549: Chromosomal instability and DNA repair status during folic acid deficiency in breast cancer cells
Authors: Michael D. Wyatt, Katie Brady, Alexandra Litvinchuk, Virginia Noxon, Xiao-Hong Wang, Robert W. Sobol
Journal: Cancer Research (2012)

Abstract Folic acid deficiency is thought to be procarcinogenic because it promotes the incorporation of genomic uracil. Base excision repair (BER) normally prevents genomic instability by removing procarcinogenic base lesions. However, BER might paradoxically contribute to folate deficient-carcinogenesis if the pathway is initiated but cannot be completed, resulting in the accumulation of BER intermediates (DNA strand breaks). DNA polymerase ≤ (POLα) performs two key steps in BER and so we utilized human metastatic breast cancer cells in which the expression of POLα has been eliminated or transgenically expressed to determine the influence of POLα on chromosomal stability. We found that folic acid deficiency induced premature chromatin condensation (PCC) and strand breaks in POLα deficient cells, demonstrating that folic acid deficiency and BER deficiency induce chromosomal instability. We also examined the expression and localization of PARP1, a key component of BER and strand break repair. PARP1 was not cleaved during folic acid deficiency, suggesting that apoptosis was not occurring under these conditions. More interestingly, PARP1 was dramatically re-localized within the nucleus in POLα deficient cells. We are currently examining the effect of PARP inhibitors and the activation of PARP under these conditions. Collectively, the data suggests that folic acid deficiency in combination with deficiency in POLα is capable of inducing gross chromosomal instability that invokes DSB repair pathways. 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 2549. doi:1538-7445.AM2012-2549
Safety of the colonoscope magnetic imaging device (ScopeGuide) in patients with implantable cardiac devices
Authors: Gareth Corbett, Yean Lim, James Lee, Alexey Chernolesskiy, Peter Pugh, Ewen Cameron
Journal: Endoscopy (2014)

<b>Background and study aims:</b> Use of the colonoscope magnetic imaging device (ScopeGuide, Olympus Medical Systems, Tokyo, Japan) is currently contraindicated by the manufacturer for patients with implantable cardiac devices, a group of patients that is increasing annually along with the number of colonoscopies performed in the era of colorectal cancer screening. This is the first study to examine the safety of ScopeGuide in patients with permanent pacemakers, implantable cardioverter defibrillators, and cardiac resynchronization therapy. <b>Patients and methods: </b>Nonimplanted cardiac devices were exposed to the electromagnetic field of ScopeGuide ex vivo and assessed for evidence of interference or change in device settings. Following this, consecutive patients attending device check clinics were prospectively recruited and exposed to the ScopeGuide electromagnetic field. After an initial device check, patients underwent continuous external cardiac monitoring and device interrogation while a colonoscope was placed on the abdomen over clothing and connected to ScopeGuide to simulate colonoscopy. Patients were monitored for 2 minutes to assess for any interference. ScopeGuide was then disconnected and devices were checked for any change in settings. <b>Results:</b> A total of 230 patients were invited to participate and 100 were recruited to the study. There was no evidence of interference on device leads or change in programming following exposure to the electromagnetic field generated by ScopeGuide. <b>Conclusion: </b>ScopeGuide does not appear to cause interference or change in settings and is therefore likely to be safe for use in patients with implantable cardiac devices.
Infection with<i>Mycobacterium avium</i>Complex in Patients without Predisposing Conditions
Authors: D S Prince, D D Peterson, R M Steiner, J E Gottlieb, R Scott, H L Israel, W G Figueroa, J E Fish
Journal: New England Journal of Medicine (1989)

Pulmonary disease caused by Mycobacterium avium complex usually occurs in patients with chronic lung disease or deficient cellular immunity, and its prevalence is increasing. We describe 21 patients (mean age, 66 years) with such infection without the usual predisposing factors, representing 18 percent of the 119 patients surveyed. Seventeen women and 4 men were given a diagnosis of M. avium complex from 1978 to 1987, with a stable incidence over the decade, on the basis of pulmonary symptoms, abnormalities on chest films, positive cultures, and in 14, biopsy evidence of invasive disease. Most of the patients (86 percent) presented with persistent cough and purulent sputum, usually without fever or weight loss. The cough was present for a mean of 25 weeks before the correct diagnosis was made. Radiographic patterns of slowly progressive nodular opacities predominated (71 percent); only five patients had cavitary disease at presentation. All patients responded initially to antimycobacterial therapy, but eight eventually relapsed when it was stopped. Four patients died of progressive pulmonary infection caused by M. avium complex. The extent of the initial pulmonary involvement was greater in patients with progressive disease than in those whose condition improved. We conclude that pulmonary disease caused by the M. avium complex can affect persons without predisposing conditions, particularly elderly women, and that recognition of this disease is often delayed because of its indolent nature.
Malignant Pleural Mesothelioma: Phase II Pilot Study of Ifosfamide and Mesna*
Authors: A. S. ALBERTS, G. FALKSON, L. VAN ZYL
Journal: JNCI Journal of the National Cancer Institute (1988)

Journal Article Malignant Pleural Mesothelioma: Phase II Pilot Study of Ifosfamide and Mesna Get access ALBERT S. ALBERTS, ALBERT S. ALBERTS Department of Medical Oncology, University of PretoriaPrivate Bag x 169 Pretoria 0001 Republic of South Africa *Correspondence to Dr. Geoffrey Falkson. Search for other works by this author on: Oxford Academic PubMed Google Scholar GEOFFREY FALKSON, GEOFFREY FALKSON Department of Medical Oncology, University of PretoriaPrivate Bag x 169 Pretoria 0001 Republic of South Africa Search for other works by this author on: Oxford Academic PubMed Google Scholar LEONIE VAN ZYL LEONIE VAN ZYL Department of Medical Oncology, University of PretoriaPrivate Bag x 169 Pretoria 0001 Republic of South Africa Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 80, Issue 9, 6 July 1988, Pages 698–700, https://doi.org/10.1093/jnci/80.9.698-a Published: 06 July 1988
Olanzapine for the prevention of chemotherapy-induced nausea and vomiting (CINV) in patients receiving highly emetogenic chemotherapy (HEC): Alliance A221301, a randomized, double-blind, placebo-controlled trial.
Authors: Rudolph M. Navari, Rui Qin, Kathryn Jean Ruddy, Heshan Liu, Steven Francis Powell, Madhuri Bajaj, Leah L. Dietrich, Jacqueline M. Lafky, Charles L. Loprinzi
Journal: Journal of Clinical Oncology (2015)

176 Background: The purpose of the study was to determine the effectiveness of olanzapine (OLN) for the prevention of nausea and vomiting in patients receiving highly emetogenic chemotherapy (HEC). Methods: A randomized, double-blind, phase III trial was performed in chemotherapy-naïve patients receiving cisplatin, &gt; 70 mg/m 2 , or cyclophosphamide-anthracycline-based chemotherapy, comparing OLN to placebo in combination with aprepitant (APR), a 5-HT 3 receptor antagonist (5-HT 3 ), and dexamethasone (DEX). The OLN regimen was 10 mg of oral OLN, 125 mg APR, a 5-HT 3 , and oral DEX 12 mg pre-chemotherapy, day 1, and 10 mg/day of oral OLN and 8 mg DEX on days 2-4 post-chemotherapy plus 80 mg APR on days 2, 3 post-chemotherapy. The placebo (PLA) regimen was oral placebo, pre-chemotherapy, day 1, and on days 2-4 post-chemotherapy; the APR, 5-HT 3, and DEX pre- and post-chemotherapy were identical to that used in the OLN regimen. Fosaprepitant (150 mg IV), day 1 was allowed for substitution for the oral aprepitant. Palonosetron, ondansetron, or granisetron were the permitted 5-HT 3 options. Nausea was measured on a 0-10 visual analogue scale, with 0 being “no nausea at all” and 10 being “nausea as bad as it can be”. No nausea was the primary endpoint and, complete response (no emesis and no use of rescue medications) was a secondary endpoint. Results: 401 patients (202 OLN, 199 PLA) were enrolled in the study. The proportion of patients who had no nausea was significantly greater for the OLN regimen compared to the PLA regimen for the acute period (24h post-chemotherapy) (74% vs. 45%, p &lt; 0.0006), for the delayed period ( 24-120 h post-chemotherapy) (43% vs. 26%, p &lt; 0.0006), and for the overall period (0-120 h) (39% vs. 22%, p &lt; 0.0006). Complete response was significantly improved for the OLN patients compared to PLA patients for the acute (85% vs. 65%, p &lt; 0.0001), the delayed (67% vs. 53%, p &lt; 0.0078), and the overall periods (64% vs. 41%, p &lt; 0.0001). There were no grade 3 or 4 toxicities. Conclusions: No nausea, the primary endpoint, and complete response, a secondary endpoint, were significantly improved with OLN, compared to PLA. Clinical trial information: NCT02116530.