tbuckley/cabot-search huggingface dataset:
A phase I dose-escalation and pharmacokinetic study of enzastaurin combined with capecitabine in patients with advanced cancer
Authors: S. Leong, R. Camidge, G. Eckhardt, M. Basche, L. Musib, C. Darstein, D. Thornton, C. Britten
Journal: Journal of Clinical Oncology (2006)

2048 Background: Enzastaurin (ENZ), an oral inhibitor of protein kinase C (PKC), affects signal transduction associated with angiogenesis, proliferation, and survival. The combination of ENZ and capecitabine (CAPE) has the potential for additive or synergistic anticancer effects without excessive toxicity. Methods: Patients (pts) with advanced, refractory, solid tumors received lead-in treatment with ENZ for 7–14 days (cycle 1), to achieve steady-state exposures. In subsequent 21-day cycles, ENZ was given once daily, orally, on days 1–21 and CAPE twice daily (bid), orally, on days 1–14 in 3 dose levels (L): L 1 = ENZ 350 mg + CAPE 750 mg/m 2 ; L 2 = ENZ 350 mg + CAPE 1000 mg/m 2 ; L 3 = ENZ 525 mg (some pts received 500 mg tablets) + CAPE 1000 mg/m 2 . PK for ENZ was assessed on day 1–3 and 7 in cycle 1 and day 8 in cycle 2 and for CAPE on day 1, 8 in cycle 2. Therapy continued until disease progression or unacceptable toxicity occurred. Results: 27 pts (13 males; 14 females, ECOG ≤1) with a median age of 58 yrs (range: 38–74 yrs), received a median number of 3 cycles (range: 2–14 cycles). High interpatient PK variability was noted for total ENZ analytes. Ratio of geometric mean AUC (90% CI) of ENZ with CAPE versus ENZ alone at 500/525 mg was 0.65 (0.38–1.11, n=6) and of Cmax was 0.66 (0.42–1.10, n=4). PK parameters of CAPE in the presence of ENZ were similar to those previously reported for CAPE alone. No grade (Gr) 4 toxicities occurred. Gr 3 toxicities were anemia (1 pt), headache (1 pt), intestinal perforation (1 pt with gastric carcinoma), fatigue (1 pt), hand-foot syndrome (2 pts), and cardiac ischemia (1 pt). PBMCs demonstrated PKC inhibition following exposure to ENZ. Plasma VEGF and bFGF levels did not reflect any significant changes. No objective tumor responses were seen. Five pts had stable disease (lung, breast, pancreas, head/neck, and hemangiopericytoma) for ≥ 6 months (range: 6–9.7 months). Conclusions: The recommended phase II dose is ENZ 500 mg, qd and Cape 1000 mg/m 2 bid, days 1–14 every 21 days. This regimen was well tolerated, and exposures of ENZ and CAPE did not appear to be significantly altered when given in combination. [Table: see text]
Dopamine Delivery via pH‐Sensitive Nanoparticles for Tumor Blood Vessel Normalization and an Improved Effect of Cancer Chemotherapeutic Drugs
Authors: Mohammad Taleb, Yanping Ding, Bin Wang, Na Yang, Xuexiang Han, Chong Du, Yingqiu Qi, Yinlong Zhang, Zeinab Farhadi Sabet, Hamideh Rezvani Alanagh, Ayeesha Mujeeb, Khosro Khajeh, Guangjun Nie
Journal: Advanced Healthcare Materials (2019)

Tumor blood vessels have been reported to be abnormal in both structure and function compared with those in normal tissues, leading to a hostile microenvironment and inadequate antitumor drug delivery. Dopamine, a chemical messenger, is proven to inhibit angiogenesis and improve tumor vessel normalization. Here, a mesoporous silicon nanoparticle (MSN) is constructed that is responsive to the weakly acidic pH of the tumor extracellular matrix for steady delivery and tumor‐localized release of dopamine. Then MSNs are functionalized with amine conjugated phenylboronicacid molecules, and dopamine is loaded by reacting with phenylboronic acid. In a weakly acidic environment, MSNs intelligently release dopamine due to the hydrolysis of boronic‐ester bond between dopamine and phenylboronic acid, resulting in an evident inhibition of vascular endothelial cell migration and tubule formation. It is shown that loading of dopamine into the functional MSNs significantly prolong the circulatory half‐life of this small molecule. After intravenous injection to tumor bearing mice, this nanoformulation induce tumor blood vessel normalization, thereby improving the antitumor chemotherapeutic efficacy of doxorubicin. This study demonstrates that the pH‐responsive MSN offers great potential for delivery of dopamine in vivo and the normalization of tumor vessels by dopamine can provide an auxiliary treatment for cancer chemotherapeutic drugs.
HuR regulates phospholamban expression in isoproterenol-induced cardiac remodelling
Authors: Han Hu, Mingyang Jiang, Yangpo Cao, Zhuojun Zhang, Bin Jiang, Feng Tian, Juan Feng, Yali Dou, Myriam Gorospe, Ming Zheng, Lemin Zheng, Zhongzhou Yang, Wengong Wang
Journal: Cardiovascular Research (2019)

The elevated expression of phospholamban (PLB) has been observed in heart failure and cardiac remodelling, inhibiting the affinity of Ca2+ pump to Ca2+ thereby impairing heart relaxation. However, the mechanisms underlying the regulation of PLB remains to be further studied. The present study aims to test the role of RNA-binding protein HuR in the regulation of PLB and the impact of this regulatory process in cardiac remodelling.A mouse model specifically deleted HuR in cardiomyocytes were used for testing the role of HuR in regulating PLB during isoproterenol (ISO)-induced cardiac remodelling. HuR deficiency did not significantly influence the phenotype and function of mouse heart under static status. However, deletion of HuR in cardiomyocytes mitigated the effect of ISO in inducing PLB expression and reducing β1-AR expression, in turn aggravating ISO-induced myocardial hypertrophy and cardiac fibrosis. In H9C2 cells, association of HuR with PLB and β1-AR mRNAs stabilized PLB mRNA and destabilized β1-AR mRNA, respectively.HuR stabilizes PLB mRNA and destabilizes β1-AR mRNA. The HuR-PLB and HuR-β1-AR regulatory processes impact on ISO-induced cardiac remodelling.
A validated 34-gene signature for assessing risk of recurrence in clear cell renal cell carcinoma.
Authors: Kimryn Rathmell, Samira A Brooks, Angela Rose Brannon, Joel S Parker, Jennifer C Fisher, Oishee Sen, Matthew Edward Nielsen
Journal: Journal of Clinical Oncology (2013)

4522 Background: The objective of this study is to create a molecular tool that can be applied widely to clinical specimens using existing transcript signatures for use in clinical risk prediction of clear cell Renal Cell Carcinoma (ccRCC) to improve personalized disease management. Methods: We developed a 34-gene subtype predictor to classify clear cell tumors according to two subtypes, clear cell A (ccA) or B (ccB). The training set consisted of 72 ccRCC microarray-analyzed tumor samples that had previously been classified by unsupervised clustering and logical analysis of data (LAD). The predictor was developed from a panel of genes significantly expressed in ccA and ccB tumors and associated with prognosis. The prognostic value of the algorithm was corroborated in RNA-sequencing data from 379 ccRCC samples from The Cancer Genome Atlas (TCGA) and further validated using the NanoString platform with a cohort of 163 archival fixed samples collected at the University of North Carolina. Results: Risk associated molecular subtypes, ccA and ccB, were classified in TCGA and NanoString cohorts. Subtype classification showed significant prognostic outcomes for overall survival (p&lt;.001), cancer-specific survival (p=.003), and recurrence-free survival (p&lt;.05) and remained significant in multivariate analyses that included age at diagnosis, gender, ethnicity, pathologic stage, and histologic grade. A prognostic model was built for overall and recurrence-free survival for non-metastatic ccRCC patients within the context of subtype and clinical characteristics. Conclusions: The ccA and ccB subtypes significantly added prognostic information to clinical parameters, particularly for non-metastatic ccRCC patients.The subtypes can be used for future analyses involving risk for developing metastatic disease and cancer-specific outcomes. This research was supported with a grant from the American Association for Cancer Research, and the UNC Lineberger Comprehensive Cancer Center Cancer Cell Biology Training Grant.
TP-0903, a Novel Axl Inhibitor with Activity in Drug Resistant FLT3-ITD+ AML through a Mechanism That Includes FLT3 Inhibition
Authors: Jae Yoon Jeon, Il-Kyoo Park, Daelynn R Buelow, Clifford Whatcott, Steven L. Warner, William Blum, Sharyn Baker
Journal: Blood (2017)
Ribonucleotide reductase subunit-2 (RRM2) and thymidylate synthase (TS) to predict shorter survival in patients (pts) with resected stage I-III non-small cell lung cancer (NSCLC).
Authors: Francesco Grossi, Maria Giovanna Dal Bello, Graziana Savarino, Sandra Salvi, Roberto Puzone, Ulrich Pfeffer, Vincenzo Fontana, Erika Rijavec, Giulia Barletta, Carlo Genova, Claudio Sini, Giovanni Battista Ratto, Mauro Truini, Domenico Franco Merlo
Journal: Journal of Clinical Oncology (2013)

11063 Background: Tumor biomarkers can help to identify pts with early-stage NSCLC with high risk of relapse and poor prognosis. The aim of this study was to investigate the prognostic value of 7 biomarkers involved in DNA synthesis and repair. Methods: Tumour tissues from 82 radically resected, stage I-III NSCLC pts were consecutively collected to investigate the following biomarkers: excision repair cross-complementation group 1 (ERCC1), breast cancer 1 (BRCA1), ribonucleotide reductase subunit 1 (RRM1), ribonucleotide reductase subunit 2 (RRM2), subunit p53R2, thymidylate synthase (TS) and class III beta-tubulin (TUBB3) using immunohistochemistry (IHC) and quantitative real time-polymerase chain reaction (qRT-PCR). Expression levels of these genes were also investigated in a large publicly available NSCLC microarray dataset (Director Challenge Consortium, DCC). Results: RRM2 expression (p=0.031), TS expression (p=0.023), and pathologic stage (p&lt;0.001) were found as independent prognostic factors for shorter survival. The expression of ERCC1, RRM1, p53R2, TUBB3, BRCA1, as well as other clinical characteristics, failed to show any statistically significant association with the survival. Despite the lack of statistical significance, patients with lower RRM2 expression (i.e., ≤ 140) survived longer than pts with higher RRM2 levels (p=0.069). There was a trend towards longer survival for BRCA1-, ERCC1-, RRM1- and TS-negative pts and for p53R2- and TUBB3-positive pts. For all of the biomarkers except TUBB3, the OS trends relative to the protein expression levels were in agreement with those relative to the respective gene expression levels, although the differences were not statistically significant. In the larger DCC dataset, TS (p=0.005), and BRCA1 (p=0.021) were identified as prognostic markers for OS, independent of tumour stage. Conclusions: This study has shown that high RRM2 and TS protein levels are negative prognostic factors for resected, stage I-III NSCLC pts. The data obtained by qRT-PCR confirmed these results. Analysis of the DCC microarray dataset detected TS and BRCA1 as independent prognostic markers of OS.
Investigation of tumor biomarkers as response predictors in a monotherapy study with lapatinib (L) as a first line treatment in ErbB2 amplified women with breast cancer
Authors: H. L. Gomez, M. A. Chavez, D. C. Doval, S. Franco, M. Arbushites, M. S. Berger, M. A. Casey, S. Stein, T. Zaks, A. M. Martin
Journal: Journal of Clinical Oncology (2007)

10562 Background: Lapatinib is a potent inhibitor of both EGFR and HER2 tyrosine kinase activity. Results of the phase II trial EGF20009 in advanced or metastatic breast cancer (MBC) indicated an overall response rate of 24% to monotherapy L as first line (1L) treatment in 138 patients. In an effort to better define predictive biomarkers of response, we evaluated correlations between baseline tumor biomarker expression levels and clinical response to L. Methods: Response rate (RR) was defined as either complete response (CR) or partial response (PR). Tumor blocks were available on 118 patients from the time of most recent biopsy, and mRNA was extracted from 65 individual patient blocks for this preliminary analysis. Using qRT-PCR Taqman analysis, tumors were evaluated for expression of ERBB1- 4, PTEN, c-MYC, as well as two comparator genes for normalization. DecisionTree analysis using SpotFire software was performed to determine the genes most significantly associated with RR. Results: For the initial 65 patient samples analyzed, an elevation of ERBB2 expression was significantly associated with response to treatment with L (p=0.02) and a longer time to progression following treatment with L (p&lt;0.0025). Furthermore, of the 17/65 responders in this preliminary study, SpotFire Decision Tree Analysis demonstrated that 16/17 (94%) who responded to L had a gene expression signature combining ERBB1, 2, and 3, which is currently being confirmed. No association was observed with ERBB4, PTEN and c-MYC in this preliminary analysis. Conclusion: This analysis suggests a correlation between elevated ERBB2 mRNA levels and both RR and TTP in patients treated with L as a 1L treatment. Analysis of the full set of samples (including genome-wide microarray analysis) is ongoing in an effort to determine biomarkers predictive of clinical activity beyond HER2. No significant financial relationships to disclose.
Phase I study of concurrent motexafin gadolinium (MGd) with radiation therapy for children with newly diagnosed brain stem gliomas (BSG): A Children’s Oncology Group study
Authors: K. Bradley, M. Mehta, P. Adamson, M. Ames, R. Jakacki, G. Vezina, A. Ingle, P. Ivy, S. Blaney, I. Pollack
Journal: Journal of Clinical Oncology (2006)

9014 Background: MGd, a radiosensitizer that selectively accumulates in tumors, generates reactive oxygen species intracellularly. In preclinical experiments, MGd enhances RT-induced apoptosis. Methods: A multi-institutional Phase I dose escalation and pharmacokinetic (PK) study was performed in children with newly diagnosed BSG to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT) of MGd administered i.v. 2 to 5 hours prior to involved field radiotherapy (RT) (1.8 Gy/day, total 54 Gy). Cohort 1 received MGd, 1.7 mg/kg/dose M-F × 3 wks and cohort 2 received the same dose M, W and F × 6 wks. The 6 subsequent cohorts of 3 to 6 pts received MGd M-F × 6 weeks at doses of 1.9, 3.4, 4.4, 5.5, 7.1 and 9.2 mg/kg/dose. Serum for PK analysis, and MRI scans (MGd is detectable by MR), were obtained for analysis of drug accumulation and responses. Results: 44 pts (42 fully evaluable for toxicity) with a median age of 6 years (range 2–20) were enrolled. At the 9.2 mg/kg/dose, 2/2 pts experienced DLT. During subsequent expansion of the 7.1 and 5.5 mg/kg/dose cohorts, DLTs, including transaminitis, hypertension and urticaria, were observed in 2/5 and 2/6 pts. At the MTD of 4.4 mg/kg/dose, 1/6 pts had reversible grade 3 serum transaminase elevations. PK analysis showed biphasic elimination with a terminal t 1/2 of 6.4 h. At the MTD, serum MGd concentrations were &gt;250 ng/ml for 24 h. Serum clearance and steady-state volume of distribution were 0.0243 L/h/kg and 0.162 L/kg. MRI for intra-tumoral MGd distribution is ongoing. One patient had a CR and 4 had a PR. The estimated median survival is 10.3 months (95% confidence interval: 8.1 months-11.5 months). Conclusions: The recommended phase II dose of MGd for children with BSG is 4.4 mg/kg/d administered M-F × 6 weeks with involved field RT. A COG phase II trial is planned. [Table: see text]
Sodium–Glucose Cotransporter-2 Inhibitors and the Risk for Severe Urinary Tract Infections
Authors: Chintan V. Dave, Sebastian Schneeweiss, Dae Kim, Michael Fralick, Angela Tong, Elisabetta Patorno
Journal: Annals of Internal Medicine (2019)

Prior studies evaluating risk for severe urinary tract infections (UTIs) with sodium-glucose cotransporter-2 (SGLT-2) inhibitors have reported conflicting findings.To assess whether patients initiating use of SGLT-2 inhibitors were at increased risk for severe UTI events compared with those initiating use of dipeptidyl peptidase-4 (DPP-4) inhibitors or glucagon-like peptide-1 receptor (GLP-1) agonists.Population-based cohort study.2 large, U.S.-based databases of commercial claims (March 2013 to September 2015).Within each database, 2 cohorts were created and matched 1:1 on propensity score. Patients were aged 18 years or older, had type 2 diabetes mellitus, and were initiating use of SGLT-2 inhibitors versus DPP-4 inhibitors (cohort 1) or GLP-1 agonists (cohort 2).The primary outcome was a severe UTI event, defined as a hospitalization for primary UTI, sepsis with UTI, or pyelonephritis; the secondary outcome was outpatient UTI treated with antibiotics. Hazard ratios (HRs) were estimated in each propensity score-matched cohort, with adjustment for more than 90 baseline characteristics.After 1:1 matching on propensity score, 123 752 patients were identified in cohort 1 and 111 978 in cohort 2 in the 2 databases. In cohort 1, persons newly receiving SGLT-2 inhibitors had 61 severe UTI events (incidence rate [IR] per 1000 person-years, 1.76), compared with 57 events in the DPP-4 inhibitor group (IR, 1.77) (HR, 0.98 [95% CI, 0.68 to 1.41]). In cohort 2, those receiving SGLT-2 inhibitors had 73 events (IR, 2.15), compared with 87 events in the GLP-1 agonist group (IR, 2.96) (HR, 0.72 [CI, 0.53 to 0.99]). Findings were robust across sensitivity analyses; within several subgroups of age, sex, and frailty; and for canagliflozin and dapagliflozin individually. In addition, SGLT-2 inhibitors were not associated with increased risk for outpatient UTIs (cohort 1: HR, 0.96 [CI, 0.89 to 1.04]; cohort 2: HR, 0.91 [CI, 0.84 to 0.99]).Generalizability of the study findings may be limited to patients with commercial insurance.In a large cohort of patients seen in routine clinical practice, risk for severe and nonsevere UTI events among those initiating SGLT-2 inhibitor therapy was similar to that among patients initiating treatment with other second-line antidiabetic medications.Brigham and Women's Hospital, Division of Pharmacoepidemiology and Pharmacoeconomics.
Radiotherapy plus concomitant and adjuvant temozolamide for newly diagnosed pediatric high-grade astrocytoma
Authors: M. M. Abdel Wahab, H. El-Hosseini, L. R. Eezz El-Arab
Journal: Journal of Clinical Oncology (2006)

9042 Background: to evaluate the potential survival advantage of adding temozolamide (TMZ) concomitantly and adjuvant to radiotherapy (RT) as regard time to progression (TTP) and overall survival in addition to its safety and tolerability in pediatric high grade astrocytomas. Methods: A total of 29 pediatric patients newly diagnosed, histologically proven glioblastoma multiforme (GBM) or anaplastic astreocytoma (AA) were randomized, to radiotherapy alone (14 patients) or radiotherapy and concomitant (TMZ) 150mg/m 2 /d for 5 days every 28 days followed by up to 6 cycels of adjuvant TMZ (15 patients). Results: The median time to progression was significantly prolonged in patients treated with RT/TMZ compared to those treated with RT alone (14 months Vs 7 months respectively) (P&lt;0.05). The median overall survival in the combined treatment Vs monotherapy was 23 months and 13 months respectively (P&lt;0.01). Non hematologic adverse events were similar between both groups while grade 3 &amp; 4 hematologic toxicities occurred in 20% only of the RT/TMZ arm (2 patients experienced grade 3 thrombocytopenia and 1 patient developed grade 4 neutropenia). Conclusions: This study demonstrate a significant survival benefit for the addition of TMZ to treatment of pediatric patients with high grade astrocytpoma and it’s safety, well tolerability which allows it to be given concurrently with RT, followed by additional adjuvant cycles. No significant financial relationships to disclose.
A phase II study of oral gimatecan (ST1481) in women with progressing or recurring advanced epithelial ovarian, fallopian tube and peritoneal cancers
Authors: S. Pecorelli, I. Ray-Coquard, N. Colombo, D. Katsaros, C. Lhomme, A. Lissoni, J. B. Vermorken, A. Du Bois, A. Poveda, L. Frigerio
Journal: Journal of Clinical Oncology (2006)

5088 Background: Gimatecan, a new camptothecin derivative, is a potent topoisomerase I inhibitor, active by oral route. Methods: A multicenter two stage Simon design phase II study was performed to evaluate the single agent antitumor activity of gimatecan. Secondary objectives were safety, time to event/time related parameters, and translational medicine evaluations. Women with advanced epithelial ovarian, fallopian tube or peritoneal cancer who had progressed or recurred after prior treatment with platinum and taxanes, had a progression-free interval from last platinum-based therapy &lt; 12 months, had measurable disease by RECIST or assessable by CA 125 (GCIG criteria) and a ECOG performance status ≤ 1 were eligible. Gimatecan 0.8 mg/m 2 was administrated orally for five consecutive days every four weeks. Radiological response was assessed every two cycles. Results: From June to December 2005, 70 women [median age 61 years (range 37–79)] were treated in 10 European sites. Number of prior chemotherapy regimens was: 1 in 20, 2 in 35, 3 in 15 patients, respectively. Progression-free interval from last platinum-based therapy was 0–6 months in 51 patients and 6–12 months in 19 patients. The study is still ongoing, and to date 40 consecutive patients are assessable. Preliminary response analysis indicated a 23.5% response rate based on CA 125 (8/34) and a 10% response rate based on RECIST (3/29). Main toxicity was hematological, namely thrombocytopenia and neutropenia. Conclusions: Preliminary results suggest that oral gimatecan administered as single agent is active, with bone marrow suppression resulting at present as the main toxicity in these patients previously treated with platinum and taxanes. However, many patients are still on treatment and data need to mature to have a broader picture of activity and safety. [Table: see text]
Deep-learning based detection of gastric precancerous conditions
Authors: Pedro Guimarães, Andreas Keller, Tobias Fehlmann, Frank Lammert, Markus Casper
Journal: Gut (2019)

Conventional white-light endoscopy has high interobserver variability for the diagnosis of gastric precancerous conditions.Here we present a deeplearning (DL) approach for the diagnosis of atrophic gastritis developed and trained using real-world endoscopic images from the proximal stomach.The model achieved an accuracy of 93% (area under the curve (AUC): 0.98; F-score 0.93) in an independent data set, outperforming expert endoscopists.DL may overcome conventional appraisal of white-light endoscopy and support human decision making.The algorithm is available free of charge via a web-based interface (https://www.ccb.unisaarland.de/ atrophy). In MorE dETaIl