tbuckley/cabot-search huggingface dataset:
Antitumor and antimicrovascular effects of sorafenib (Soraf) in fresh human tumor culture in comparison with other putative tyrosine kinase inhibitors (TKI).
Authors: L. M. Weisenthal
Journal: Journal of Clinical Oncology (2010)

e13617 Background: Soraf is postulated to be a clinical anti-angiogenic agent (AAA). Yet preliminary clinical evidence suggests it may not be cross resistant with other AAAs, including sunitinib (Tamaskar, et al. J Urology 179:81,2008). An alternative hypothesis is that soraf has direct antitumor cell (ATC) effects. In order to determine whether antivascular (AV) or ATC effects were more important, we measured both AV and ATC effects of soraf in short term cultures of fresh human tumor biopsies and compared these activities with those of other putative TKIs. Methods: We used methods described in the following publication: Weisenthal, et al. Cell culture detection of microvascular cell death in clinical specimens of human neoplasms and peripheral blood. J Intern Med 264: 275–287, 2008. doi:10.1111/j.1365-2796.2008.01955.x Results: Utilizing methods described in Table 1 of the above publication, 2008, we determined the relative AV activity vs ATC activity of TKI and other agents. Expressed as a ratio of AV activity divided by ATC activity, the rank order (greatest to least relative AV activity) was as follows: pazopanib > bevacizumab > dasatinib > sunitinib > erlotinib > lapatinib > gefitinib > imatinib > sorafenib > cisplatin. AV activity of soraf was minimal. We also determined correlation coefficients (CC) for ATC activity of these agents (comparing activity of two agents at a time in the same specimen datasets; size of comparison TKI datasets ranging from 11 to 587, median of 247 direct activity comparisons between pairs of agents. CC are as follows: doxorubicin/epirubicin 0.88, cisplatin/carboplatin 0.86, paclitaxel/docetaxel 0.64, cisplatin/oxaliplatin 0.48, cisplatin/5FU 0.35, gefitinib/erlotinib 0.61, erlotinib/imatinib 0.51, erlotinib/lapatinib 0.46, erlotinib/dasatinib 0.41, erlotinib/sunitinib 0.28, sunitinib/imatinib 0.51, soraf/dasatinib 0.19, soraf/gefitinib 0.17, soraf/pazopanib 0.10, soraf/sunitinib 0.01, soraf/lapatinib 0.00, soraf/imatinib −0.01. Conclusions: Soraf has minimal AV activity in short term cultures of fresh human tumors, in comparison with other TKIs and has virtually non-cross resistant ATC activity. No significant financial relationships to disclose.
Gastrointestinal Carcinoma-Associated Antigen Defined by a Murine Monoclonal Antibody
Authors: John K. Chin, Guo Huang Rong, Joshua E. Scharff, William F. Sindelar
Journal: JNCI Journal of the National Cancer Institute (1986)

A murine monoclonal antibody, CHIP, has been prepared against a human pancreatic carcinoma cell line, SHAW. With the use of the avidin-biotin immunoperoxidase technique, the CHIP antibody detected an antigen found in 11 of 20 fixed tissue sections of tumors obtained from patients with pancreatic carcinoma. The antibody also detected the antigen in 25 of 26 colon carcinoma specimens, 4 of 6 gastric carcinoma specimens, and 1 of 2 esophageal adenocarcinoma specimens. The antigen was also found in normal proximal jejunum and colon and in small amounts in pancreatic islets and parathyroid. There was no reactivity with normal pancreatic ductal or acinar cells or with mesenchymal tissues.
Abstract 14029: Deletion of Rac1 in Smooth Muscle Cells Induces Hypertension in Mice by Depressing the Nitric Oxide-Dependent Signaling Pathway
Authors: Gwennan Andre, Kevin Retailleau, Laurent Loufrani, Malvyne Rolli-Derkinderen, Xose Bustelo, Gervaise Loirand, Vincent Sauzeau
Journal: Circulation (2012)

The Rho family proteins (RhoA, Rac1, Cdc42) are defined as central regulators of smooth muscle cells (SMC) functions. To determine in vivo the role of Rac1 in the vascular system, we generated a conditional model of Rac1 gene inactivation in SMC (SM-Rac1-KO). SM-Rac1-KO mice display high systolic blood pressure (137±2 mmHg vs 125±3 mmHg in control mice; n≥7, p<0.05). The analysis of the contractile properties of aorta and mesenteric arteries shows no modification of the myogenic tone and minor changes in responses to vasoconstrictors in SM-Rac1-KO compared to control mice. In contrast, the nitric oxide (NO)-dependent vasorelaxation is attenuated by 14±3% (n=8, p<0.01) in aorta, and by 45±5% (n=12, p<0.01) in mesenteric arteries of SM-Rac1-KO mice. Isoproterenol- and EDHF-induced relaxations are not modified suggesting a specific alteration of the signaling pathway downstream of the NO in SM-Rac1-KO mice. This hypothesis is supported by the resistance of SM-Rac1-KO mice to the inhibition of the NO signalin...
포스터 발표 : 간이식 후 C형 간염의 Viral Dynamics와 치료 경험
Authors: 최종영, 김창욱, 장우임, 남순우, 조세현, 윤승규, 한준열, 최상욱, 한남익, 이영석, 이창돈, 차상복, 정규원, 선희식, 김동구
Journal: Clinical and Molecular Hepatology (2003)

배경/목적: 간이식후 C형 간염(HCV)은 대부분 재발하며, 5년이 되면 약 30%가 간경변으로 이행한다. 정상면역상태에 있는 C형 간염 환자와 달리 면역억제치료를 받는 간이식환자는 HCV 바이러스 인자, 숙주면역반응이 달라짐으로서 항바이러스 치료시기, 치료약제 선택이 어렵고, 치료반응율도 낮다. 이에 본병원에서 경험한 간이식후 C형 간염에서 HCV viral dynamics와 항바이러스 치료효과를 분석하였다. 대상과 방법: 1993년부터 2002년까지 간이식을 받은 120명의 환자중 원인질환이 HCV와 연관된 간경변(7) 혹은 간암 환자(3)는 총 10명이었다. 이중 남자 8 명, 여자가 2 명이었고, 평균 연령은 57세 (범위 49-64) 였다. 뇌사자 전체간이식이 5예, 생체부분간이식 5예였고 이중 1명은 간/신장 동시이식을 받았다. 간효소 수치가 상승한 경우 C형간염 재발과 급성거부반응을 감별하기 위해서 간조직검사를 하였다. 생체부분간이식 3예에서 간이식 직후 HCV viral load를 HCV Total Core Antigen ELISA Assay (Ortho Clinical Diagnostics) 방법을 사용하여 수술직전, 수술 후 1, 3, 5, 14, 21, 28일째 측정하였고, 정량적 RT-PCR 법(Amplicor HCV, Roche)으로 확인하였다. 항바이러스 치료를 받은 환자에서 serial liver biopsy, viral load를 비교하였다. 결과: 10명의 평균관찰기간은 3.2년 (범위 8 year-6 months) 이었고 생존율은 80% 였다. 간이식 전 HCV RNA 정량은 평균 204,353 IU/mL (0－458,237 IU/mL)이었다. 이식 후 황달을 동반한 심한 간염재발을 보인 2예는 이식전 viral load가 450,000 IU/mL 이상으로 다른 환자에 비교해서 높았고, 이중 1예는 이식 후 steroid pulse therapy를 받은 환자였다. 6명에서 항바이러스 치료를 받았다. 이중 1명은 HCV에 연관된 간암으로 이식 전 항바이러스 치료를 받고 HCV RNA가 음전화되었고, 이식 후 5년째 간염은 재발하지 않았다. 5명은 간이식 후 평균 3.2개월에 (범위 1-6개월) 항바이러스 치료를 시작하였고, 인터페론 단독치료를 받은 2명중 1명에서는 HCV RNA가 음전화 되었고, 다른 1명은 ALT가 정상화되었다. 인터페론/리바비린 병합치료를 받고 있는 1명은 ALT정상화 되었고, viral load도 감소되었다. 추적 조직학적인 검사를 비교하면 항바이러스 치료후 간염활성도, 간섬유화가 호전되었다. 이식직후 HCV Core Antigen을 이용해 검사한 viral load는 이식 후 1-2주 사이에 이식 전에 비교해서 10배 이상 증가하였고, 환자에 따라 바이러스 양이 증가하는 양상은 차이가 있었다. 결론: 간이식 후 C형 간염의 심한 재발은 이식 전 high viral load, 이식 후 steroid pulse therapy와 관련이 있을 수 있다. 간이식 1달 이내 viral load는 전체적으로 10배 이상 상승하며, 환자에 따라 다른 양상을 보인다. 재발한 C형간염에서 viral load 변화와 함께 주기적인 간 조직검사를 통해 간섬유화의 정도를 확인한 후 치료 여부를 결정하며, 치료 시기는 이식 후 회복정도에 따라 적절한 시기를 선택하는 것이 필요하며, 향후 많은 증례를 대상으로 연구가 있어야겠다.
The TAME adverse event summary and risk classification system: Analysis of the RTOG H&amp;N Database
Authors: A. Trotti, T. F. Pajak, C. Gwede, R. Paulus, J. Cooper, A. Forastiere, A. Garden, K. Ang
Journal: Journal of Clinical Oncology (2005)

6026 Background: There is currently no method for concisely summarizing and comparing aggregate adverse event (AE) data among treatment options. We propose a new concept (“toxicity burden”) and new metrics to reflect treatment-related risk. Analogous to the T-N-M tumor staging system, the “T-A-M End-results system” (TAME) consolidates adverse effects data into a concise index: short-term (acute) toxicity [T], adverse long-term effects [A] and mortality risk from treatment [M]. Methods: We estimated T-scores and A-scores from published adverse event data in 13 treatment arms from 5 RTOG H&N trials (90–03, 91–11, 95–01, 97–03, 99–14) conducted between 1990–2000 (>2200 patients). Estimation of T and A scores are calculated by dividing total number of RTOG grade 3–4 events for 13 pre-specified toxic categories by the number of patients in a cohort. We also calculated scores using individual patient data (IPD) from 2 arms of the RTOG 91–11 larynx preservation trial (314 patients). Results: Estimated T-scores demonstrate more than a 500% difference in acute toxicity burden when comparing aggressive chemoradiotherapy to conventional radiotherapy (range: 0.47–3.14). Less variation was seen in estimated late effects burden (range: 0.17–0.59). Putative T-risk burden classes were designated: ≤0.6 (low), 0.7–1.0 (mod), 1.0–2.5 (high), ≥2.5 (extreme). T-values from RTOG 91–11 (see table) suggest up to 250% more toxicity burden from the use of chemotherapy. Distribution of T-scores among the concurrent PLAT-RT group revealed 22% of patients experienced 3 high-grade events, and 23% experienced 4 or more (p=<0.0001). Correlations of T-scores with KPS and selected QOL domains at 3 months were modest as expected. Conclusions: TAME scores support the feasibility of quantifying toxicity burden and may have wide applications including safety monitoring and identification of patient groups at high risk for injury in multiple oncologic disorders. No significant financial relationships to disclose.
Evidence that Microdeletions in the α Globin Gene Protect Against the Development of Sickle Cell Glomerulopathy in Humans
Authors: ANTONIO GUASCH, CARLOS F. ZAYAS, JAMES R. ECKMAN, KASINATHAN MURALIDHARAN, WEI ZHANG, LOUIS J. ELSAS
Journal: Journal of the American Society of Nephrology (1999)

Abstract. There is a large variability in the severity of the clinical manifestations of sickle cell anemia (SSA), including renal involvement. Haplotypes in the β-globin gene cluster associated with the geographical origin of the sickle mutation, as well as microdeletions in the α-globin genes, could provide an epigenetic influence on the heterogeneous outcome in SSA. It has been determined that the cause of progressive renal insufficiency in SSA is a glomerulopathy, clinically detected by the presence of macroalbuminuria (albumin excretion rate &gt;300 mg/g creatinine). To investigate the role of the α-globin gene microdeletion and β-globin gene cluster haplotypes on the degree of glomerular involvement, 76 adult SSA patients (hemoglobin SS) were studied to determine the relationship between these genetic markers and the development of sickle cell glomerulopathy. Macroalbuminuria was present in 22 (29%) of 76 adult SSA patients. The coinheritance of microdeletions in one or two of the four α-globin genes (α-thalassemia) was associated with a lower prevalence of macroalbuminuria (13%) versus patients with intact α-globin genes (40%, P = 0.01). By contrast, there was no association between albuminuria and β-globin gene haplotypes (Central African Republic [CAR] versus non-CAR haplotypes). Patients with α-globin gene microdeletions had lower mean corpuscular volumes and mean corpuscular hemoglobin concentration than patients with all four α genes (86 ± 2 versus 99 ± 3 fl, and 33.9 ± 0.2 versus 34.9 ± 0.2%, respectively, P &lt; 0.05). There were no such hematologic differences between CAR and non-CAR β-globin haplotypes. There were no differences in duration of disease (age), hemoglobin levels, reticulocyte index, and lactate dehydrogenase levels between those with and without glomerulopathy, but the mean arterial pressure was higher (87 ± 1 mmHg) in patients with intact α gene locus versus those with microdeletions (80 ± 2 mmHg, P &lt; 0.05). It is concluded that the coinheritance of microdeletions in the α-globin gene locus in SSA patients confers “renoprotection” by mechanisms not related to the degree of anemia or the severity of hemolysis, but could be related to a reduced mean corpuscular volume or to a lower erythrocyte hemoglobin concentration.
Abstract 16882: Electrocardiographic Characteristics of Patients With Sudden Unexplained Death in Epilepsy
Authors: Janice Y Chyou, Marina Cerrone, Daniel Friedman, William Slater, Daniel Taupin, Sean O'Rourke, Orrin Devinsky, Silvia G Priori
Journal: Circulation (2013)

Introduction: Sudden unexplained death in epilepsy (SUDEP) can occur in a subset of patients with epilepsy. Animal studies and sporadic cases suggest a link between SUDEP and cardiac channelopathy....
Pulmonary function and inflammation discriminated by symptom-pattern phenotypes in preschool wheezers
Authors: Elpis Hatziagorou, Fotis Kirvassilis, Vasiliki Avramidou, Ilektra Touliou, John Tsanakas
Journal: European Respiratory Journal (2012)

Background: The discrimination of episodic and multiple-trigger wheezing is commonly used among preschoolers with wheeze. However, symptom-patterns of wheeze have not been related to pulmonary function tests or markers of airway inflammation.

Objective: We investigated whether multiple-trigger wheezers were more likely to have abnormal FEV1, increased ventilation inhomogeneity (LCI) and increased fraction of exhaled nitric oxide (FeNO) than episodic wheezers. We also investigated whether multiple-trigger wheezers were more likely to have a positive reversibility test, than episodic wheezers.

Methods: FeNO, LCI and FEV1 were measured in healthy children and those with recurrent wheeze aged 4 to 6 years.

Results: Twenty-six control subjects and 25 wheezers (11 episodic and 14 multiple-trigger wheezers) were tested. FEV1 FeNO and LCI did not differ significantly among wheezers and healthy preschoolers. On average, LCI was abnormal in 18 wheezers (72%). Multiple-trigger wheezers had an average increase of 3. 1% (P < .0001) in LCI, compared with episodic wheezers. FEV1 and FeNO did not differ significantly among episodic and multiple trigger wheezers. The presence of current atopy was associated with higher FeNO (p =0,024) but did not influence pulmonary function and LCI significantly. Eight out of the 25 (32%) wheezers showed a significant increase in FEV1 and 15 out of the 25 (60%) wheezers showed a significant decrease in LCI, after administration of inhaled salbutamol.

Conclusions: Multiple-trigger wheeze is associated with pulmonary function abnormalities independent of atopic status. LCI is the most sensitive indicator of abnormal pulmonary function in preschool wheezers.
Abstract 2049: Characterization of a novel BRCA1-EGR1 interaction
Authors: Naomi A. Dickson, Nyree T. Crawford, Paul B. Mullan
Journal: Cancer Research (2015)

Abstract The tumor suppressor protein BRCA1 orchestrates DNA repair and cell cycle arrest following DNA damage, with transcriptional regulation integral to these processes. We have identified a novel, DNA-damage responsive, interaction between BRCA1 and the zinc-finger transcription factor EGR1. EGR1 is rapidly and transiently expressed in response to a wide variety of stress stimuli and growth factors, and like BRCA1, decreased expression of EGR1 correlates with tumor formation in mammary cell lines and tissues. The stress response gene, NDRG1, was identified as a transcriptional target of BRCA1 by microarray analysis and subsequent RQ-PCR validation. NDRG1 is a known suppressor of breast cancer metastasis and we have observed a significant reduction of NDRG1 expression in breast cancer cell lines (relative to normal cell lines). Promoter analyses identified EGR1 binding motifs within the NDRG1 proximal promoter region, and EGR1 was confirmed as the transcription factor of interest by promoter assays. Downregulation of either BRCA1 or EGR1 (using a siRNA approach) resulted in a reduction in both basal and DNA-damage induced NDRG1 promoter activity, suggesting a co-regulatory mechanism. Indeed, recruitment of BRCA1 and EGR1 to the NDRG1 promoter was confirmed by ChIP assays. GST-fused BRCA1 deletion constructs showed that EGR1 specifically interacts with a C-terminal region of BRCA1 (which contains both BRCT domains). However, following DNA damage, we observed EGR1 interaction along the entire length of the BRCA1 protein, suggesting that both BRCA1 and EGR1 reside within a larger transcriptional complex upon DNA damage. In agreement with this, siRNA knockdown of either BRCA1 or EGR1 in breast cell lines (i) induced endogenous DNA damage signalling, (ii) increased intracellular ROS generation and (iii) upregulated numerous stress-response genes. To investigate transcriptional regulation downstream of this interaction we performed analyses of publically available ChIP-Seq data for both BRCA1 and EGR1, and identified a list of genomic locations (corresponding to gene promoters) at which both proteins localise. We will use these findings, in combination with our own ChIP-Seq experiments performed in the non-tumorigenic mammary cell line, 184A1, to investigate the roles of this novel complex in the maintenance of genomic stability and within normal breast biology. Citation Format: Naomi A. Dickson, Nyree T. Crawford, Paul B. Mullan. Characterization of a novel BRCA1-EGR1 interaction. [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 2049. doi:10.1158/1538-7445.AM2015-2049
Btn2a2, a T cell immunomodulatory molecule coregulated with MHC class II genes
Authors: Kerstin Sarter, Elisa Leimgruber, Florian Gobet, Vishal Agrawal, Isabelle Dunand-Sauthier, Emmanuèle Barras, Béatris Mastelic-Gavillet, Arun Kamath, Paola Fontannaz, Leslie Guéry, Fernanda do Valle Duraes, Carla Lippens, Ulla Ravn, Marie-Laure Santiago-Raber, Giovanni Magistrelli, Nicolas Fischer, Claire-Anne Siegrist, Stéphanie Hugues, Walter Reith
Journal: The Journal of Experimental Medicine (2016)

Evidence has recently emerged that butyrophilins, which are members of the extended B7 family of co-stimulatory molecules, have diverse functions in the immune system. We found that the human and mouse genes encoding butyrophilin-2A2 (BTN2A2) are regulated by the class II trans-activator and regulatory factor X, two transcription factors dedicated to major histocompatibility complex class II expression, suggesting a role in T cell immunity. To address this, we generated Btn2a2-deficient mice. Btn2a2−/− mice exhibited enhanced effector CD4+ and CD8+ T cell responses, impaired CD4+ regulatory T cell induction, potentiated antitumor responses, and exacerbated experimental autoimmune encephalomyelitis. Altered immune responses were attributed to Btn2a2 deficiency in antigen-presenting cells rather than T cells or nonhematopoietic cells. These results provide the first genetic evidence that BTN2A2 is a co-inhibitory molecule that modulates T cell–mediated immunity.
Complications of venous access ports in 132 patients with disseminated testicular cancer treated with polychemotherapy.
Authors: N W Lemmers, M E Gels, D T Sleijfer, J T Plukker, W T van der Graaf, Z J de Langen, J H Droste, H S Koops, H J Hoekstra
Journal: Journal of Clinical Oncology (1996)

Venous access ports (VAPs) can be used to administer polychemotherapy to patients with malignancies. The purpose of this study was to evaluate perioperative and late complications related to VAP implantations and to analyze factors that may predict the development of complications.During the period 1983 to 1994, 135 VAPs were implanted in 132 patients with disseminated testicular tumors. In a retrospective study, the perioperative and late complications were recorded in this homogeneous patient group. Multivariate analysis was performed to detect factors that may predict the development of complications.The median age of the patients was 28 years (range, 16 to 55). Perioperative complications were recorded in five patients (3.7%): pneumothorax in two (1.5%), blood loss in two (1.5%), and mediastinal bleeding in one (0.7%). The ports remained in situ for a total of 55,247 days (median, 413; range, 7 to 1,607). In 31 patients (23%), 42 late complications developed (31%): system obstruction in 13 (9.6%), thrombosis in 11 (8.1%), infection in six (4.4%), catheter defect in six (4.4%), extravasation in four (3.0%), and local skin necrosis in two (1.5%). Late complications were significantly more common in patients who had received chemotherapy before VAP implantation (P < .001). Univariate analysis showed that there were significantly more complications after VAP implantation under local anesthesia than under general anesthesia (P < .05).Polychemotherapy could be administered in an adequate manner using a VAP. Complications occurred in 26.7% of a homogeneous group of patients who received a VAP implantation for polychemotherapy for disseminated testicular cancer. Chemotherapy treatment before VAP implantation was the only independent risk factor for late complications.
Abstract 69: Angiotensin II- Canonical TGF-β Signaling Downregulates Apelinergic Pathway in Hypertension
Authors: Rahul Rai, Varun Nagpal, Amanda E Boe, Douglas E Vaughan
Journal: Circulation Research (2014)

Background: Apelin is a novel peptide which along with its receptor, APJ, mediates apelinergic signaling. Apelinergic signaling plays a critical role in cardiovascular homeostasis, including regulation of blood pressure. While exogenous apelin blocks Angiotensin II (AngII) mediated nuclear signaling, the role and regulation of endogenous apelin in hypertension (HTN) remains obscure. We hypothesize that apelinergic pathway is downregulated in HTN, which is primarily mediated by aberrant AngII signaling. Approach: To test our hypothesis we utilized two mouse models of HTN, including AngII infusion and oral administration of N (ω)-nitro-l-arginine methyl ester (L-NAME). Blood pressure was monitored via noninvasive tail-cuff device. To determine the signaling involved we investigated the effect of AngII on apelinergic pathway in vitro. Results: Cardiac apelin was decreased significantly in both murine models of HTN. Downregulated apelin also corresponded with increased deposition of collagen, and up-regulation of senescence markers including PAI-1. Meanwhile, APJ levels were unaffected in both these hypertensive models. In our in vitro studies AngII downregulated apelin expression in human aortic endothelial cells (HAECs) and human cardiac fibroblasts (HCFs). Furthermore, our studies in AngII infused mice and in HCFs highlight the role of TGF-β-pSMAD signaling, independent of MEK involvement, in AngII induced apelin downregulation. Conclusion and Significance: Our studies demonstrate that aberrant AngII signaling downregulates apelin in HTN. This downregulation involves canonical Tgf-β1 signaling and affects apelin transcription. Importantly, we propose that AngII mediates its hypertensive pathology by decreasing apelinergic regulation. Since exogenous apelin blocks AngII signaling, further knowledge and negation of AngII induced apelin downregulation could result in the development of novel anti-hypertensive therapies.