tbuckley/cabot-search huggingface dataset:
Evaluation of selective inhibitors of nuclear export (SINE) CRM1 inhibitors for the treatment of renal cell carcinoma (RCC).
Authors: Hiromi Inoue, Michael Kauffman, Sharon Shacham, Yosef Landesman, Robert H Weiss
Journal: Journal of Clinical Oncology (2012)

4634 Background: For the ~30% of patients who present with RCC at the metastatic stage, multi-kinase inhibitors have been used with moderate success: progression-free survival remains at only one to two years, and thus it is imperative to discover novel therapeutic approaches for metastatic disease. We asked whether (1) SINE inhibitors of chromosome region maintenance protein 1 (CRM1) attenuate key cell cycle regulatory and apoptotic molecules and whether these compounds exert salutary effects in a human RCC xenograft mouse model. Methods: Four RCC cell lines (ACHN, Caki-1, 786-O, and A498) with distinct genotypes, and primary normal human kidney (NHK) cell lines, were used in this study. The cells were treated with the chemically related SINE CRM1 inhibitors KPT-185 or 251 and MTT assays were performed. In addition, cell cycle analyses, immunofluorescence for p53 and p21, and immunoblotting for CRM1, p53, p21, p27, and p-MDM2 were performed for all cell lines. RCC mice with Caki-1 xenografts were treated with vehicle, the orally-available CRM1 inhibitor KPT-251, or sorafenib for 26 days. Tumor volume was measured over several days. Results: Both KPT185 and 251 specifically reduced CRM1 protein levels in RCC cells. KPT-185 caused dose-dependent cytotoxicity in RCC cells, which was greater than sorafenib in RCC cell lines but less in NHK cells, suggesting a possible clinical advantage of KPT-185 over sorafenib. By FACS analysis, we showed that KPT-185 arrests the cell cycle in both G2/M and G1, and increased the sub-G0 cell population. KPT-185 and 251 both increased p53 and p21 in RCC cells, and KPT-185 confined these proteins to the nucleus. In vivo, KPT-251 inhibited Caki-1 xenografts in mice compared to both vehicle and sorafenib without obvious systemic adverse effects. Conclusions: We introduce a completely novel therapeutic approach to the treatment of RCC based on inhibition of the nuclear export of key cell cycle regulatory proteins. Inhibition of CRM1 leads to forced nuclear retention, and thereby activation, of several key p53-pathway proteins, leading to cell cycle arrest and apoptosis in RCC cell lines in vitro and tumor growth inhibition in vivo.
A <i>UGT1A1</i> *28 and *6 genotype-directed phase I study of irinotecan plus infusional leucovorin and 5-fluorouracil (sLV5FU2) in patients with previously untreated metastatic colorectal cancer (mCRC).
Authors: Yong Sang Hong, Kyu-Pyo Kim, Jae-Lyun Lee, Kyun Seop Bae, Ho-Sook Kim, Jae-Gook Shin, Jung Shin Lee, Tae Won Kim
Journal: Journal of Clinical Oncology (2012)

3592 Background: We designed a phase I study to determine maximum tolerated dose (MTD) of irinotecan when combined with sLV5FU2 in mCRC patients (pts). Methods: Pts were genotyped for UGT1A1 *28 and *6, and stratified into 3 groups according to the number of defective allele (DA), designated 0 (*1/*1), 1 (*1/*28, *1/*6), and 2 (*28/*28, *6/*6, *6/*28). Within each group, the dose of irinotecan was escalated (table) in combination with fixed dose of sLV5FU2. Plasma drug levels and dose-limiting toxicity (DLT) were evaluated at cycle 1. Results: A total of 43 pts were accrued: 19 for 0 DA, 20 for 1 DA and 4 for 2 DA group. The MTD was estimated as 300 mg/m 2 /2-week for the 1 DA group with 2 DLTs in the level 3, and the MTD was not reached for the 0 DA group with 1 DLT in the level 4 (table). The mean relative extents of glucuronidation, AUC last ratio of SN-38G to SN-38, were 9.36, 6.81, and 5.09 for the 0, 1, and 2 DA groups, respectively (P=0.017). Of the 43 pts, five pts showed AUC last, SN38 that exceeded 400 ng·h/mL (1.02 umol·h/L) and DLT was observed in 40% (2/5). The overall response rate was 67.4% (95% CI, 51.5-80.9) with 6 complete responses and 23 partial responses. Median progression-free and overall survival was 8.0 months (95% CI, 7.1-8.9) and 25.6 months (95% CI, 23.4-27.7), respectively. Grade 3 or 4 toxicity during all treatment cycles included neutropenia (79% [0 DA]; 90% [1 DA]; 75% [2 DA]), leucopenia (21%; 30%; 0%), febrile neutropenia (0%; 10%; 0%) and diarrhea (0; 5%; 0) per patient. Conclusions: Dose-normalized exposure of SN38 was significantly higher in the 2 DA UGT1A1 group. Higher doses of irinotecan based on UGT1A1 genotyping are feasible when combined with sLV5FU2 in mCRC pts. The recommended dose of irinotecan was 330, 270, 150 mg/m 2 /2-week for pts with 0, 1, 2 DA based on pharmacokinetic analysis. [Table: see text]
A Single-Institution Randomized Prospective Trial of Pre-Emptive Therapy with Oral Valganciclovir Compared with IV Ganciclovir for Cytomegalovirus Infection after Allogeneic Hematopoietic Stem Cell Transplant (aHSCT), Delayed until Viral Load (VL) &amp;gt;10,000 Copies/Ml or &amp;gt;5,000 Copies/Ml X 2
Authors: James C Mosley, Linda Verkruyse, Mark Fiala, Kim Trinkhaus, Camille N Abboud, Amanda F Cashen, Geoffrey L. Uy, Keith Stockerl-Goldstein, Gregory A Storch, Peter Westervelt, John F. DiPersio, Ravi Vij
Journal: Blood (2008)
Hypertension, cerebrovascular impairment, and cognitive decline in aged AβPP/PS1 mice
Authors: Maximilian Wiesmann, Valerio Zerbi, Diane Jansen, Dieter Lütjohann, Andor Veltien, Arend Heerschap, Amanda J Kiliaan
Journal: Theranostics (2017)

Cardiovascular risk factors, especially hypertension, are also major risk factors for Alzheimer's disease (AD).To elucidate the underlying vascular origin of neurodegenerative processes in AD, we investigated the relation between systolic blood pressure (SBP) cerebral blood flow (CBF) and vasoreactivity with brain structure and function in a 16-18 months old double transgenic AβPP swe /PS1 dE9 (AβPP/PS1) mouse model for AD.These aging AβPP/PS1 mice showed an increased SBP linked to a declined regional CBF.Furthermore, using advanced MRI techniques, decline of functional and structural connectivity was revealed in the AD-like mice coupled to impaired cognition, increased locomotor activity, and anxiety-related behavior.Post mortem analyses demonstrated also increased neuroinflammation, and both decreased synaptogenesis and neurogenesis in the AβPP/PS1 mice.Additionally, deviant levels of fatty acids and sterols were present in the brain tissue of the AβPP/PS1 mice indicating maladapted brain fatty acid metabolism.Our findings suggest a link between increased SBP, decreased cerebral hemodynamics and connectivity in an AD mouse model during aging, leading to behavioral and cognitive impairments.As these results mirror the complex clinical symptomatology in the prodromal phase of AD, we suggest that this AD-like murine model could be used to investigate prevention and treatment strategies for early AD patients.Moreover, this study helps to develop more efficient therapies and diagnostics for this very early stage of AD.
IMPACT OF VITAMIN D DEFICIENCY ON PATIENTS UNDERGOING CORONARY ARTERY DISEASE BETWEEN THE YEARS 2008 THROUGH 2012: NATIONWIDE INPATIENT SAMPLE DATA ANALYSIS
Authors: Yashwant Agrawal, Chris Jacob, Sourabh Aggarwal, Sidakpal Panaich, Frank Saltiel, Jagadeesh Kalavakunta, Vishal Gupta
Journal: Journal of the American College of Cardiology (2017)
Potential patient stratification by <i>TP53</i> status using a clinically derived gene expression signature.
Authors: Mary Ellen Urick, Sean Eddy, Mark Tomilo, Emma Bowden, Daniel Rhodes
Journal: Journal of Clinical Oncology (2014)

e22048 Background: Advances in both molecular diagnostics and the understanding of cancer biology are raising the bar for clinical trial paradigms with the expectation that more effective patient stratification will improve outcome and expedite approval of effective cancer drugs. Mutational status of TP53 has been identified as a predictive biomarker of treatment response and prognosis. For example, TP53 wild-type (WT) patients have been shown to exhibit significantly increased progression-free survival following therapies including adjuvant 5-ﬂuorouracil and cetuximab combination treatments compared to patients harboring TP53 mutations. These results provide impetus for development of diagnostic products to prospectively identify TP53WT patients to match the right patient to the right drug. Methods: We developed a 204 geneTP53 WT signature using mRNA expression from 547 breast cancer samples from TCGA’s breast tumor publication. Expression of the signature was evaluated across tumor types in the Oncomine database with TP53 mutation status. Student’s t-test was used to determine the significance of differential signature expression in TP53 WT versus mutated samples. Results: Five Oncomine cancer types contained sufficient TP53 mutation status data to complete analysis. Of these, significantly increased signature expression was found in TP53 WT compared to TP53 mutated clinical samples from breast (p<0.001; n=189 WT, 37 mutant), lung (p=0.0003; n=23 WT, 18 mutated), liver (p=0.0069; n= 74 WT, 11 mutated) and ovarian (p=0.05; n=22 WT, 15 mutated) cancer patients and a trend was found within lymphoma patients (p=0.068; n=65 WT, 16 mutated). Evaluation of the signature expression with regards to specific TP53 mutations is on-going. Conclusions: Our clinically-derived expression signature effectively distinguishes TP53 WT from mutant tumor samples. Although additional development and refinement is required, we have provided initial data for proof-of-concept of this candidate diagnostic signature. Given the impact of TP53 mutation status on patient treatment response and outcome, use of this or similar TP53 diagnostics represents a potentially impactful advancement in precision medicine.
A dose-escalation phase I study of a first-in-class cancer stemness inhibitor in patients with advanced malignancies.
Authors: Adrian Langleben, Jeffrey G. Supko, Sebastien J. Hotte, Gerald Batist, Hal W. Hirte, Harry Rogoff, Youzhi Li, Wei Li, David Kerstein, David Leggett, Matthew J. Hitron, Chiang Li
Journal: Journal of Clinical Oncology (2013)

2542 Background: Cancer Stem Cells (CSC) are considered to be fundamentally responsible for malignant growth, relapse, metastasis, and resistance to conventional therapies. BBI608 is an orally-administered first-in-class cancer stemness inhibitor which blocks CSC self-renewal and induces cell death in CSC as well as non-stem cancer cells by inhibition of the Stat3, Nanog and b-catenin pathways, and has shown potent anti-tumor and anti-metastatic activities pre-clinically. Methods: A phase 1 dose escalation studyin adult patients with advanced cancer who had failed standard therapies was conducted to determine the safety, tolerability, recommended phase 2 dose (RP2D), pharmacokinetics and preliminary anti-tumor activity of BBI608. A modified Simon accelerated titration scheme was used for dose escalation, with a cycle consisting of twice-daily oral administration of BBI608 for 4 weeks. Cycles were repeated every 4 weeks (28 days) until progression of disease, unacceptable toxicity, or other discontinuation criteria were met. Results: Fourteen cohorts (N=41) were dosed from 20 mg to 2000 mg/day with adverse events being generally mild; the most common being grade 1-2 diarrhea, nausea, anorexia and fatigue. Four grade 3 events included diarrhea (n=3) and fatigue (n=1). MTD was not reached and further dose escalation was limited by pill burden. By the 400 mg/day dose level the plasma concentration of BBI608 was sustained for over 8 hours at a concentration above 1.5 uM (several fold above the IC 50 ). 17/26 patients evaluable for tumor response achieved SD, for a DCR of 65%. Prolonged TTP was observed in 12/26 evaluable patients (46%), including patients with colorectal (CRC), head and neck, gastric, ovarian, melanoma, and breast cancer. In the subset of patients with CRC (N=18), SD was seen in 8/12 evaluable (67%). A median PFS of 14 weeks and median OS of 47 weeks were observed in evaluable CRC patients. Conclusions: Dose escalation of BBI608, a first-in-class cancer stem cell pathway inhibitor, has been achieved without dose limiting toxicity. BBI608 has shown an excellent safety profile, favorable pharmacokinetics, and encouraging signs of clinical activity particularly in CRC Clinical trial information: NCT01775423.
Predictive significance of bone sialoprotein and osteopontin for bone metastases in respectable non-small cell lung cancer: A retrospective study
Authors: L. Zhang, X. Hou, H. Rao, J. Hou, R. Luo, H. Huang, P. Huang
Journal: Journal of Clinical Oncology (2007)

7666 Background: Bone sialoprotein (BSP) and osteopontin (OPN) have been demonstrated predictive of bone metastases in breast and prostate carcinoma, consistent with the proposed role of BSP as a stimulator of bone mineralization and OPN in differentiation and activation of osteoclasts. Bone metastasis (BM) is often developed in non-small-cell lung cancer (NSCLC), but no predictive biomarker was identified for high risk of metastatic bone dissemination. Methods: 180 completely resected NSCLC patients were included in this study. 38 patients subsequently developed BM. Paraffin embedded primary tumor tissue of patients were supplied to produce a tissue microarray, and immunohistochemistry method was used for evaluation the expression of BSP and OPN. Different expressions of these two biomarkers among BM group and non-BM group were estimated by χ 2 test. Bone metastasis-free survival was analyzed by Kaplan-Meier method. The prognostic impact of clinicopathologic parameters and biomarker expression was evaluated by Cox propotional hazards model. Results: BSP expression was associated with BM (P=0.027), while OPN expression could not reach statistical significance (P=0.495). Univariate analysis demonstrated that expression of BSP (P=0.036), N stage (P=0.000) and clinical stage (P=0.001) were associated with time interval to BM. Multivariate analyses showed BSP expression (RR=1.779, P=0.012) and clinical stage (RR=1.620, P=0.005) were independent prognostic factors for BM. Conclusions: BSP protein expression in the primary resected NSCLC is strongly associated with BM and could be used to identify high-risk patients. Correlation of OPN protein expression and bone metastasis need further investigation. No significant financial relationships to disclose.
PROGNOSTIC VALUE OF MYOCARDIAL FIBROSIS ASSESSED BY CARDIAC MAGNETIC RESONANCE IN PATIENT WITH IDIOPATHIC DILATED CARDIOMYOPATHY WITH LEFT VENTRICUAL SYSTOLIC DYSFUNCTION
Authors: Laura Lupi, Davide Farina, Emanuele Gavazzi, Mariangela Piazzani, Matteo Bonavita, Roberto Maroldi, Savina Nodari
Journal: Journal of the American College of Cardiology (2017)
Conduct of an international collaborative osteosarcoma trial at centers located in a developed and developing country
Authors: G. K. Rivera
Journal: Journal of Clinical Oncology (2007)

9527 Background: We conducted a collaborative protocol (twinning program) for newly diagnosed patients with localized osteosarcoma (OS 99) at SJCRH (sponsor) and CMH (partner site), a public tertiary-care pediatric hospital and bone tumor center in Santiago, Chile. Methods: CMH was selected as the partner site because Chile has a well developed public health system including free treatment for children with cancer. SJCRH trained and financially supported specialized personnel and provided oversight of study conduct and monitoring. The study was approved by the respective Human Subjects Protection Committees and a Data Safety Monitoring Board. Treatment comprised 12 cycles of chemotherapy (with growth factor support) given every 3 weeks for a total of 35 weeks and definitive surgery after 4 cycles of chemotherapy. Pathology studies and selected imaging studies were centrally reviewed at SJCRH. Patient costs were covered by the Chilean Ministry of Health and SJCRH except for sargramostim which was donated by Berlex Oncology. Patient care and study conduct were discussed in a multidisciplinary forum on a monthly basis. The two study teams maintained close communication through videoconferencing, and site visits. Results: Of the 72 eligible patients enrolled on study, 22 were treated in Santiago (2003–2006). Rare discrepancies in interpretation of diagnostic imaging and pathology studies were addressed in a timely manner. Preliminary results demonstrated similar patient outcomes and treatment tolerance at the two sites. Limb-salvage surgery was performed in 12 Chilean patients. Median per-patient costs were lower in Chile (US $80,000) than at SJCRH ($400,000). Conclusions: It is feasible, safe, and cost-effective to simultaneously treat pediatric patients with osteosarcoma on modern protocols, through well designed and rigorously monitored twinning programs that include countries with different level of resources. No significant financial relationships to disclose.
A Phase 2 Multicenter Trial of KTE-C19 (anti-CD19 CAR T Cells) in Patients With Chemorefractory Primary Mediastinal B-Cell Lymphoma (PMBCL) and Transformed Follicular Lymphoma (TFL): Interim Results From ZUMA-1
Authors: Sattva S. Neelapu, Frederick L. Locke, Nancy L Bartlett, Tanya Siddiqi, Caron A. Jacobson, Jason R. Westin, Julio C. Chavez, Armin Ghobadi, Alex F Herrera, Ann S. LaCasce, Adrian Bot, John M. Rossi, Yizhou Jiang, Jeff S. Aycock, Meg Elias, Jeff Wiezorek, William Y. Go
Journal: Blood (2016)
Analysis of a Global Registration Trial of the Efficacy and Safety of CTL019 in Pediatric and Young Adults with Relapsed/Refractory Acute Lymphoblastic Leukemia (ALL)
Authors: Stephan A. Grupp, Theodore W Laetsch, Jochen Buechner, Henrique Bittencourt, Shannon L Maude, Michael R. Verneris, Gary D Myers, Michael W Boyer, Susana Rives, Barbara De Moerloose, Eneida R. Nemecek, Krysta Schlis, Paul L. Martin, Muna Qayed, Peter Bader, Hidefumi Hiramatsu, Francoise Mechinaud, Gregory A Yanik, Christina Peters, Andrea Biondi, Andre Baruchel, Nicolas Boissel, Joerg Krueger, Carl H June, Kapildeb Sen, Yiyun Zhang, Karen E Thudium, Patricia A Wood, Tetiana Taran, Michael A Pulsipher
Journal: Blood (2016)
PROVIDER RADIATION EXPOSURE DURING TRANSCATHETER AORTIC VALVE REPLACEMENT
Authors: Alec Vishnevsky, Rady Ho, Michael Savage, David Fischman, Praveen Mehrotra, John C. Entwhistle, Jordan Goldhammer, Rebecca Marcantuono, Lisa Moss, John Keklak, Marguerite Davis, Theresa Schmitz, Paul Walinsky, Rohinton Morris, Nicholas Ruggiero
Journal: Journal of the American College of Cardiology (2017)
Characterisation of liver pathogenesis, human immune responses and drug testing in a humanised mouse model of HCV infection
Authors: Choong Tat Keng, Ching Wooen Sze, Dahai Zheng, Zhiqiang Zheng, Kylie Su Mei Yong, Shu Qi Tan, Jessica Jie Ying Ong, Sue Yee Tan, Eva Loh, Megha Haridas Upadya, Chik Hong Kuick, Hak Hotta, Seng Gee Lim, Thiam Chye Tan, Kenneth T E Chang, Wanjin Hong, Jianzhu Chen, Yee-Joo Tan, Qingfeng Chen
Journal: BMJ (2015)

Objective  HCV infection affects millions of people worldwide, and many patients develop chronic infection leading to liver cancers. For decades, the lack of a small animal model that can recapitulate HCV infection, its immunopathogenesis and disease progression has impeded the development of an effective vaccine and therapeutics. We aim to provide a humanised mouse model for the understanding of HCV-specific human immune responses and HCV-associated disease pathologies.  Design  Recently, we have established human liver cells with a matched human immune system in NOD- scid Il2rg −/−   (NSG) mice (HIL mice). These mice are infected with HCV by intravenous injection, and the pathologies are investigated.  Results  In this study, we demonstrate that HIL mouse is capable of supporting HCV infection and can present some of the clinical symptoms found in HCV-infected patients including hepatitis, robust virus-specific human immune cell and cytokine responses as well as liver fibrosis and cirrhosis. Similar to results obtained from the analysis of patient samples, the human immune cells, particularly T cells and macrophages, play critical roles during the HCV-associated liver disease development in the HIL mice. Furthermore, our model is demonstrated to be able to reproduce the therapeutic effects of human interferon alpha 2a antiviral treatment.  Conclusions  The HIL mouse provides a model for the understanding of HCV-specific human immune responses and HCV-associated disease pathologies. It could also serve as a platform for antifibrosis and immune-modulatory drug testing.
Kinetics of Response to Bortezomib/Thalidomide/Dexamethasone (VTD) in Multiple Myeloma: Implications for the Choice and Design of Pretransplantation Induction Regimens
Authors: Laura Rosiñol, Albert Oriol, Ana Isabel Teruel, Dolores Hernández, M Jesús Blanchard, Javier De La Rubia, Miquel Granell, Juan Besalduch, Luis Palomera, Yolanda Gonzalez, Etxebeste Mª Asunción, Joaquín Díaz-Mediavilla, Miguel T. Hernandez, Felipe de Arriba, Norma Carmen Gutierrez, Maria-Victoria Mateos, Joaquin Martinez-Lopez, Adrian Alegre, Huaibao Feng, Helgi van de Velde, Juan José Lahuerta, Jesus F. San Miguel, Joan Blade
Journal: Blood (2014)
Hemophilia a Clots Generated with Recombinant Factor VIIa Differed in Structure and Composition from Those Formed with Factor VIII
Authors: Lilley Leong, Irina N. Chernysh, Yifan Xu, Cornell Mallari, Billy Wong, Derek Sim, Adam Cuker, Joseph Marturano, Thomas Lowery, Katalin Kauser, John W. Weisel
Journal: Blood (2016)
Prognostic significance of differential expression of angiogenic genes in women with invasive high-grade serous ovarian carcinoma.
Authors: Sharareh Siamakpour-Reihani, Kouros Owzar, Chen Jiang, Taylor Turner, Andrew Berchuck, Jeffrey Marks, Mark Dewhirst, Angeles Alvarez Secord
Journal: Journal of Clinical Oncology (2013)

5509 Background: High-grade serous ovarian carcinoma (HGSC) is an aggressive type of epithelial ovarian cancer associated with numerous genetic alterations and poor survival. Our objective was to identify novel angiogenic biomarkers that are associated with tumor angiogenesis and clinical outcome in women with HGSC. Methods: Between 1988 and 2001, 51 snap frozen samples from women with advanced HGSC were obtained. RNA was extracted and analyzed by the Affymetrix GeneChip U133A array. A panel of 285 probe sets (features) linked to 145 genes involved in angiogenesis were screened. Microvessel density (MVD) counts, surrogates of angiogenesis, were determined using CD31 and CD105, markers of proliferating endothelial cells. The association between mRNA expression levels and overall survival (OS) were assessed using a rank score statistic. The effect size was estimated parametrically as a hazard ratio (HR) under a proportional hazards model. We accounted for multiple testing within the false-discovery rate (FDR) framework using the Storey q-value method. The associations between expression level and OS for the implicated genes were further assessed in a published HGSC cohort from the “The Cancer Genome Atlas” (TCGA) database. Results: A panel of 43 features linked to 31 angiogenic genes were significantly associated with long term OS (FDR q-value (q) &lt; 0.05). In the TCGA cohort, four genes exhibited some level of significance and concordant direction of effect as assessed by HRs: AKT1 (q = 0.018, HR = 0.44; TCGA unadjusted p-value (p) &lt;0.011, HR = 0.81), and CD44 (q &lt; 0.003, HR = 0.48; TCGA p &lt; 0.054, HR = 0.89) were associated with better survival; while EPHB2 (q &lt; 0.009, HR = 8.12; TCGA p &lt; 0.051, HR = 1.23) and ERBB2(q &lt; 0.019, HR = 2.86, TCGA p &lt; 0.055, HR = 1.19) were associated with worse survival. After adjusting for multiple comparisons, CD105-MVD and CD31-MVD were not significantly associated with angiogenic gene expression. Conclusions: Our data demonstrated that mRNA levels of 31 angiogenic genes were associated with OS in advanced HGSC. Among these 4 were externally confirmed using TCGA data. Further evaluation is warranted to verify our preliminary findings.