tbuckley/cabot-search huggingface dataset:
Differences of cytosolic and mitochondrial 5’-nucleotidases activity in rat and mouse tissues: Implication for nucleoside analogue metabolism in animal models
Authors: Saeedeh Mirzaee, Staffan Eriksson, Freidoun Albertioni
Journal: Cancer Research (2008)

AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA

3345 

The cytosolic and mitochondrial deoxynucleoside kinases (dNK) as well as 5’deoxynucleotidases (5’-dNT): CN I, CN II and dNT1 in cytosol and dNT2 in mitochondria, are enzyme that control rate- limiting steps in intracellular and intra mitochondrial phosphorylation of natural nucleotides as well as nucleoside analogues used in antiviral and cancer chemotherapy. In order to clarify the enzymes distribution profiles in two commonly used animal models in cytostatic drug studies, the activity of 5’-dNTs were determined in 14 different mouse and rat tissues using selective measurement method by HPLC. The activity of 5’NTs (CN I, CNII and dNT1) were detected with 2-4 fold variation between mouse and rat. Mouse dNT1 activity was 2-4 fold higher than rat in all tissues except spleen and cardiac. The highest dNT1 activity was found in brain tissue of mouse which was 4 fold higher than in rat and the most active tissue in rat was spleen which was 2 fold higher than in mouse. In case of CN II also mouse tissues activity was 2-3 fold higher than rat in testis, spleen, pancreas and diaphragm, but rat lung CN II activity was 2 fold higher than mouse. Testis had the highest CN II activity but was detected 2.5 folds higher in mouse. The variation of CN I activity was negligible between rat and mouse.    The result suggest that a major difference in 5’-nucleotidases activity profiles between mouse and rat may account for discrepancies in pharmacological response of the two animals to certain nucleoside compounds.
Prospective study of dihydropyrimidine dehydrogenase (DPD) activity and DPYD IVS14+1G&gt;A mutation in patients developing FU-related toxicities: An updated analysis based on a ten-year recruitment across multiple French institutions
Authors: N. Magné, N. Renée, J.-L. Formento, M.-C. Etienne-Grimaldi, M. Francoual, G. Milano
Journal: Journal of Clinical Oncology (2005)

2003 Background: Although DPD deficiency is a well established cause of severe FU-related toxicities, relationships between the depth of the deficiency and the intensity of the toxicity is still poorly documented. We analyzed DPD activity in a large population of patients with FU-related toxicities. Methods: Blood lymphocytes from 144 consecutive cancer patients having developed FU toxicities were collected from different French institutions between January 1993 and July 2004 (53 men, 91 women; mean age 57, extremes 31–94). DPD activity was measured with a radioenzymatic HPLC assay. The IVS14+1G>A mutation was analyzed in 102 patients (RFLP assay). Results: Grade 3–4 toxicity (WHO classification) was 64% for mucositis, 58% for neutropenia, 42% for thrombopenia, 19% for diarrhea and 14% for neurotoxicity. Toxicity led to patient death in 9 cases (8 women, 1 man). DPD activity ranged from 8 to 504 pmol/min/mg (mean 200, median 188, N=144). Nine patients had an activity < 50 pmol/min/mg (severe deficiency) and 19 had an activity between 50 and 100 pmol/min/mg (partial deficiency), thus accounting for a total of 19% deficient patients. The relative risk of developing grade 3–4 toxicity in DPD deficient patients relative to non-deficient patients was 7.69 for neurotoxicity (Fisher’s Exact test, p< 0.001), 2.93 for diarrhea (p<0.001), 1.73 for thrombopenia (p=0.01), 1.63 for mucositis (p<0.001) and 1.59 for neutropenia (p=0.005). The lower the DPD activity, the higher the mucositis, neutropenia or diarrhea grading (Spearman rank correlations, p< 0.03). Toxic deaths were significantly related to low DPD activity (Mann-Whitney p=0.002), with 7 patients out of 9 exhibiting a DPD deficiency. The DPYD mutation (wt/mut) was detected in only 2 patients; both exhibited a low DPD activity (44 and 142 pmol/min/mg) and developed grade 4 mucositis, neutropenia, thrombopenia and grade 3 neurotoxicity without toxic death. Conclusions: 1- Patients with normal DPD activity may develop FU-related toxicities. 2- The intensity of the FU toxicity is related to the severity of the DPD deficiency. No significant financial relationships to disclose.
Abstract A22: CXCL12-CXCR4 chemotactic pathway modulates metastasis and perineural invasion in pancreatic cancer
Authors: Qinhong Xu, Wanxing Duan, Jianjun Lei, Jiguang Ma, Erxi Wu, Qingyong Ma
Journal: Cancer Research (2015)

Abstract Perineural invasion (PNI) is considered as an alternative route for metastatic spread of pancreatic cancer cells; however the molecular changes leading to PNI are still poorly understood. In this study, we show that CXCL12/CXCR4 axis, which is one of the most widely studied chemokines signaling, plays a pivotal role in the neurotropism of pancreatic cancer cells to local peripheral nerves. We conducted a co-culture model, which used newborn rat dorsal root ganglia (DRG) and pancreatic cancer cells, and a sciatic nerve invasion model by nude mice. We provide in vitro and in vivo evidence to study the function of CXCL12/CXCR4 signaling in PNI progression and pathogenesis. The results showed that the activation of CXCL12/CXCR4 axis significantly increased the invasion of pancreatic cancer cells and promoted the outgrowth of DRG. The chemotaxis migration of pancreatic cancer cells to the neurites of DRG is evidently suppressed by blocking the pathway. In vivo analyses revealed that the abrogation of the activated signaling could inhibit tumor growth and invasion of the sciatic nerve toward the spinal cord. These data indicated that CXCL12/CXCR4 axis is involved in PNI, and inhibition of the signaling pathway may be a promising new therapeutic strategy for the recurrence and metastasis of pancreatic cancer. Citation Format: Qinhong Xu, Wanxing Duan, Jianjun Lei, Jiguang Ma, Erxi Wu, Qingyong Ma. CXCL12-CXCR4 chemotactic pathway modulates metastasis and perineural invasion in pancreatic cancer. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr A22.
Abstract 55: Over-expression of FoxM1 in breast cancer can be therapeutically targeted using thiostrepton
Authors: Maqbool Ahmed, Azhar Hussain, Rafiya Begum, Saravanan Thangavel, Dahish S. Ajarim, Shaham Beg, Shahab Uddin, Khawla S. Al-Kuraya
Journal: Cancer Research (2015)

Abstract Breast cancer incidence is increasing worldwide and is one of the most common cancers among women in Saudi Arabia. In spite of conventional treatment regimes in breast cancer, the prognosis is still poor. However, over the last decade, outcome of breast cancer has improved due to increased awareness among the population leading to early detection. Forkhead box protein 1 (FoxM1), is an important member of Forkhead family protein, plays an important role in the pathogenesis of various cancer including basal cell carcinoma. In addition, FoxM1 has also been shown to be involved in the pathogenesis of breast cancer from other regions. However, the role of FoxM1 in Saudi Arabia breast cancer has not been fully elucidated. Therefore in this study, we first evaluated the expression of FoxM1 in a panel of patients with breast cancer samples in Saudi Arabia by immuno histo chemistry. Our data showed that FoxM1 is over expressed in 79% (770/975) of breast cancer and directly associated with clinical parameters such as younger age (&amp;lt;30yrs)(p = 0.00172),high Grade(p&amp;lt;0.0001), mucinous histology (p&amp;lt;0.0001), and triple negative phenotype (p&amp;lt;0.0001). In addition, FoxM1over-expession was also significantly associated with activated AKT (p = 0.0001), as well as high Ki67 expression(p&amp;lt;0.0001),matrix metalloproteinase-9 (MMP-9) (p &amp;lt;0.0001), and XIAP (p &amp;lt;0.0001). In vitro, using breast cancer cell lines, we found that treatment with thiostrepton resulted in inhibition of cell viability and induction of apoptosis in a dose dependent manner. In addition, in these cell lines, thiostrepton treatment caused down regulation of FoxM1, in activation of AKT and decreased the expression of XIAP, and MMP-9. Furthermore pharmacological inhibition of FoxM1 triggered Caspase dependent apoptosis in breast cancer cell lines. Altogether, our results suggest that FoxM1 and its associated signaling pathway may be a potential target for therapeutic intervention in the treatment of breast cancer. Citation Format: Maqbool Ahmed, Azhar Hussain, Rafiya Begum, Saravanan Thangavel, Dahish S. Ajarim, Shaham Beg, Shahab Uddin, Khawla S. Al-Kuraya. Over-expression of FoxM1 in breast cancer can be therapeutically targeted using thiostrepton. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 55. doi:10.1158/1538-7445.AM2015-55
Abstract 536: Evaluation of Left Ventricular Outflow Tract Eccentricity in Patients With Aortic Valve Sclerosis Using 64-multidetector Computed Tomography: Comparison With Two-Dimensional Echocardiography
Authors: Hiroto Utsunomiya, Hideya Yamamoto, Eiji Kunita, Norihiko Ohashi, Toshiro Kitagawa, Toshiharu Oka, Ryo Yamazato, Takenori Okada, Tomoki Shokawa, Yukiko Nakano, Hiroki Teragawa, Futoshi Tadehara, Takafumi Ishida, Jun Horiguchi, Yasuki Kihara
Journal: Circulation (2009)

Background: Estimating the aortic valve area (AVA) using the continuity equation (CE) is routinely essential to assess severity of calcified aortic valve disease. In the CE, calculated AVA is great...
A Single Retroviral Vector Design for the Simultaneous Expression of a Mir30 Based Shrna with An Oncogene – Identification of Raf-1 but Not BRAF as a Crucial Mediator for BCR-ABL Mediated Leukemogenesis.
Authors: Corinna Albers, Anna Lena Illert, Hannes Leischner, Cornelius Miething, Richard Huss, Christian Peschel, Justus Duyster
Journal: Blood (2010)
Overseas Doctors Training Scheme Opportunities for training are limited
Authors: R M Kirk, R Kavan, G P Rao, N P O'Donnell, G Jyothi, N Gandhi, P Johari, N Purandare, F Ahmed, L Appleby, R Gater, S E Josse, J Puliyel, D G Garvie, J Rosenthal, S Singh
Journal: BMJ (1994)

Opportunities for training are limited EDIrOR,-I wish that Tessa Richards had re- considered the title of her article, "The Overseas Doctors Training Scheme: failing expectations."'IIn the article she correctly identifies that the faults lie not so much in the scheme but in the constraints within which it operates.Why can we not meet the demand for posts?The royal colleges have no power to make appointments.We have to compete with a large pool of experienced, overseas trained, doctors based in Britain who have local referees and are available for interview.British surgeons prefer to select from these rather than appoint someone arriving from abroad "sight unseen."If a single trainee from the scheme disappoints them they determine never again to employ a trainee offered by the college.Why are expectations often unfulfilled?I recently visited southern India
Prevention of Ventricular Desynchronization by Permanent Para-Hisian Pacing After Atrioventricular Node Ablation in Chronic Atrial Fibrillation
Authors: Eraldo Occhetta, Miriam Bortnik, Andrea Magnani, Gabriella Francalacci, Cristina Piccinino, Laura Plebani, Paolo Marino
Journal: Journal of the American College of Cardiology (2006)
Prediction of peritoneal recurrence by analysis of hTERT mRNA in peritoneal lavage fluid on gastric carcinoma
Authors: M. Takahashi, F. Kito, C. Kunisaki, M. Nomura, H. Akiyama, H. Shimada
Journal: Journal of Clinical Oncology (2005)

4056 Background: It is important to identify the high risk factor of peritoneal recurrence on patients with advanced gastric carcinoma. The peritoneal lavage cytology has been useful for early diagnosis of peritoneal recurrence. However, 20–30% of cytology negative patients with advanced gastric carcinoma developed peritoneal recurrence. The aim of this study were to evaluate detective method of small amount of free peritoneal malignant cells using real-time PCR techniques for human telomerase reverse transcriptase (hTERT) mRNA, to assess the prognostic significance of free peritoneal malignant cells. Methods: The study based on consecutive 106 patients undergoing surgical treatment for sT3 or sT4 gastric carcinoma. Eighty-two patients of them had no peritoneal metastasis (P0). Peritoneal lavage fluids (PLFs) were collected at operation prior to resection. Exfoliated cells from PLFs were tested for quantification (TaqMan PCR) and expression (RT-PCR) of hTERT mRNA, and cytology. Results: Positive rates of the 106 samples were 37% by expression, 19% in quantification of hTERT mRNA, and 32.5% by cytology. In comparison on P0 patients, positive percents were 22% by hTERT mRNA expression and 12% by cytology. Twenty-seven P0 patients (33%) have had peritoneal recurrence. Predictive rate of the recurrence was 57% by hTERT mRNA expression and 37% by cytology. The accuracy was 81.7% in hTERT mRNA. Multivariate analysis for peritoneal recurrence on P0 gastric cancer patients revealed hTERT mRNA expression was the most reliable predictive factor (p=0.0028), and the second was serosal invasion (p=0.0043). Quantification of hTERT mRNA correlated survival time (p=0.0018) in dead cases (n=18). Conclusions: Detection of hTERT mRNA in peritoneal lavage fluid predicted peritoneal recurrence and was useful as prognostuic factor in patients with advanced gastric carcinoma. No significant financial relationships to disclose.
Systematik der Bildanalyse/Bildmuster
Authors: Hans-Ulrich Kauczor
Journal: Thorax (2003)

Die Bildanalyse der Thoraxübersichtsaufnahme und der Computertomographie erfolgt systematisch: 1. Visuelle Kontrolle der Bildqualität. 2. Morphologische Analyse von innen nach außen oder von außen nach innen bzw. Weichteilfenster und Lungenfenster: Vorhandensein normaler anatomischer Strukturen und Verhältnisse sowie Erkennen von Abweichungen. 3. Zusammenfassen der Einzelbefunde zu Bildmustern, die auf anatomisch-pathologischen Substraten beruhen. 4. Interpretation der Bildmuster in Kenntnis der klinischen Befunde. Daraus ergeben sich Diagnose, differentialdiagnostische ÖUberlegungen und abschließende Bewertung.
20 year phase 1/2 study of single agent carboplatin in metastatic seminoma: Could it have been accelerated by 72 hr PET scan response?
Authors: T. Oliver, J. Shamash, T. Powles, U. Somasundram
Journal: Journal of Clinical Oncology (2004)

4763 Background: Samuels et al (1980 Proc ASCO 21 abst 415) observed 4 of 5 bulky seminomas achieved durable CR to single agent cisplatin and Oliver 1984 Proc ASCO 3. Abst 636) reported 9 of 10 durable responses. Carboplatin proved less effective and in randomised trials involving 361 patients relapse free survival was 71% with Carbo and 91% with cisplatin-based combination. Prompted by successful dose escalation of carboplatin in ovarian cancer, the initial phase 1 study that preceded the UK randomised trial was reopened and dosage escalation to AUC 8 and then 10 was undertaken. This abstract updates this study with more prolonged follow up of the previous cases and new information on the higher dosages. Methods: Initially patients received 450mg/m2 and subsequently the dose was increased to AUC 7, 8 and 10. The treatment was repeated q21 when possible and if delayed because of toxicity blood counts were repeated every 24 hours. Results: A total of 49 metastatic seminoma patients have been treated between 1983 and 2003. 79% of 19 receiving 450mg/m2, 88% of 17 receiving AUC 7 or 8 and 92% of 12 receiving AUC 10 are relapse free. As a pilot study 7 patients with a variety of metastatic germ cell cancers have had PET scan performed before and at 72 hours after treatment. 3 achieved CR, 3 had greater than 40% response and 1 after progressing after single agent carboplatin was in complete remission after one course of BEP. Conclusion: With late events increasingly a problem with more prolonged follow up of testis cancer, minimizing treatment toxicity and finding a fast track approach to proving safety is an increasing need. The data presented demonstrates the potential of early PET scan as a surrogate marker to facilitate assessment of response and could have accelerated the phase 1/2 study reported. No significant financial relationships to disclose.
Abstract 51: Heart Rate Variability and its Association with Cognitive Decline Over 20 years: The Atherosclerosis Risk in Communities - Neurocognitive Study
Authors: Faye L Lopez, Lin Y Chen, Elsayed Z Soliman, Jennifer A Deal, Rebecca F Gottesman, Gerardo Heiss, Thomas H Mosley, Alvaro Alonso
Journal: Circulation (2015)

Background: Heart rate variability (HRV) reflects activity of the sympathetic and parasympathetic nervous systems. Low HRV is associated with an increased risk of heart disease and mortality, and risk factors for lower HRV are also linked to cognitive impairment. We assessed whether HRV measures are associated with cognitive decline in the Atherosclerosis Risk in Communities (ARIC) study. Methods: We studied 10,623 individuals (23% African-American, 57% female, mean age 54). HRV measures were obtained from 2-minute electrocardiogram rhythm strips in 1987-89 and include the standard deviation of all normal RR intervals (SDNN), root mean square of successive differences (rMSSD), low frequency (LF) and high frequency (HF) spectral power, and the LF/HF ratio. Cognitive function was measured in 1990-92, 1996-98 and 2011-2013 using 3 neuropsychological tests: Delayed Word Recall (DWR), Digit Symbol Substitution (DSS), and Word Fluency (WF). Scores were standardized and their average was used as a test of global cognitive function. HRV measures were log-transformed and we used linear regression models fit with generalized estimating equations to evaluate associations with cognitive performance over time, which was modeled as a linear spline with a knot at year 6 of follow-up. Results: At baseline, lower levels of HRV were significantly associated with reduced scores in all cognitive tests. Lower baseline levels of HRV measures of sympathetic activity (LF and LF/HF ratio) were associated with faster decline in tests evaluating executive function and language (DSST and WF) (table). We did not observe associations between parasympathetic nervous system measures (rMSSD and HF) and cognitive decline. Conclusion: In this large population-based study, markers of cardiac sympathetic dysfunction measured in mid-life were associated with a faster decline in executive function, which is more frequently affected in cognitive impairment of vascular origin. Additional research should explore the mechanism for this association.
Abstract 714: Targeting Coagulation Factor XII to Protect from Cardiac Ischemia Reperfusion Injury
Authors: Stefan Frantz, Johann Bauersachs, Anna Adamek, Nadja Blomer, Georg Ertl, Thomas Renne
Journal: Circulation (2007)

Formation of fibrin is critical for limiting blood loss at a site of blood vessel injury (hemostasis), but may also contribute to vascular thrombosis and thus exaggerate myocardial ischemia/reperfusion injury. Hereditary deficiency of factor XII (FXII), the protease that triggers the intrinsic pathway of coagulation in vitro, is not associated with spontaneous or excessive injury-related bleeding, but can reduce thrombus formation. Therefore, we studied the contribution of FXII for myocardial ischemia reperfusion injury. Following 30 minutes of ischemia and 24 hours of reperfusion infarct size in FXII deficient mice was significantly reduced as compared to wild type controls (infarct/area at risk, WT vs. FXII−/−, 73.5%±4.4% vs. 42.3±1.6%, p&lt;0.001) despite similar area at risk (WT vs. FXII−/−, 28.3%±1.7% vs. 29.9±1.0%, p=n.s.). There was no difference in bleeding complications and bleeding time. Mice deficient in the FXII substrate factor XI were similarly protected from ischemia reperfusion injury (infarct/area at risk, FXI−/−, 16.9%±4.1%, vs. WT p&lt;0.001). The phenotype of FXII−/−mice could be rescued by intravenous application of human FXII (infarct/area at risk, FXII−/−+FXII, 77.3%±8.4%, p&lt;0.001 vs. FXIIKO). WT mice treated with the FXII inhibitor PCK (Pro-Phe-Arg-chloromethylketone) were similarly protected from myocardial ischemia/reperfusion injury (infarct/area at risk, 46.5% ±3.7%, vs. WT p&lt;0.001). The data suggest that the intrinsic pathway is crucial for pathological clotting in myocardial ischemia reperfusion injury. FXII inhibition may offer a selective and safe strategy to reduce ischemic injury.
Abstract #5569: Characterization of an orally bioavailable homologue of MPC-6827 (MPI-0443803) that maintains high brain penetration and is not a substrate for multidrug resistance pumps
Authors: Christopher Pleiman, Adam Willardsen, In Chul Kim, Warren Weiner, Robert Halter, Patrick McConville, Jeni Baranski, Gary Mather, Kenton Zavitz, Mark Anderson, Margaret Yu, Joshu Jones
Journal: Cancer Research (2009)

AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO

MPI-0443803 was developed in an extensive medicinal chemistry effort to produce an orally bioavailable homolog of MPC-6827 (Azixa\#8482;, Myriad Pharmaceuticals, Inc.). Like MPC-6827, MPI-04438303 is a potent inducer of apoptosis that binds at or near the colchicine binding site on \#946;-tubulin and prevents the polymerization of tubulin into microtubules. MPC-6827 is an investigational new drug that has shown anti-cancer activity in two completed phase I studies and is currently being studied in the Phase Ib/II setting for the treatment of patients with recurrent high grade gliomas and in the Phase Ib setting for the treatment of patients with metastatic melanoma to the brain. Here we report that MPI-0443803 displays pro-apoptotic activity, with potency at low nanomolar concentrations in multiple cancer types including pancreatic, breast, colorectal, non-small cell lung, melanoma, ovarian and leukemia. MPI-0443803 was equipotent for induction of apoptosis in cancer cell lines, regardless of the expression levels for the multidrug resistance ABC transporters MDR-1 (Pgp-1), MRP-1, and BCRP-1. Unlike the vinca alkaloids (e.g., vinblastine, vincristine and vinorelbine), MPI-0443803 has excellent oral bioavailability that approaches 100% at a 60 mg/kg dose in mice when formulated in 5% dextrose:water with a half life (t1/2) of approximately 10 hours. MPI-0443803 crosses the blood brain barrier and distributes rapidly into the CNS with exposure in the brain approximately 7 times higher than in plasma after oral or intravenous dosing. Statistically significant (\#961; < 0.00005) inhibition of tumor growth was observed in melanoma (B16-F) allografts in nude mice dosed with oral MPI-0443803 relative to vehicle. Preliminary evidence suggests that MPI-0443803 also inhibits the growth of brain tumors derived from the D54 human glioblastoma cell line implanted orthotopically in nude mice. These studies demonstrate that MPI-0443803 has potent and broad spectrum in vitro and in vivo antitumor activity with high oral bioavailability. Therefore, MPI-0443803 is a promising candidate for development as an oral alternative to MPC-6827.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 5569.