tbuckley/cabot-search huggingface dataset:
Effect of BPM31510 on radiosensitivity of temozolomide-resistant glioblastoma cell model and survival in in vivo C6 glioma rat model supporting phase I clinical investigation in GBM.
Authors: Seema Nagpal, Tulin Dadali, Taichang Jang, Milton Merchant, Anne R. Diers, Stephane Gesta, Janice Stevens, Megan Wilson, Vivek Vishnudas, Michael Kiebish, Viacheslav R Akmaev, Niven R. Narain, Rangaprasad Sarangarajan, Lawrence David Recht
Journal: Journal of Clinical Oncology (2017)

e13509 Background: Glioblastoma (GB) is characterized by dysregulated metabolism, utilizing glycolysis for energy production to support unrestricted growth. BPM 31510, an ubidecarenone containing lipid nanodispersion effectuates a switch in cancer energy sourcing from glycolysis towards mitochondrial OXPHOS, i.e. reverses Warburg effect, providing rationale for its potential utility in treatment of GB. The current study investigated utility of BPM31510 alone and in combination with temozolomide. Methods: In vitro (U251-MG human GB cell line) and in vivo (C6 glioma rat model) preclinical models of GB were used to assess the anti-cancer activity of BPM 31510 alone (100 mg/kg/d) and combination with TMZ/bevacizumab (BEV). In addition, an in vitro model of acquired TMZ chemo-resistance was established by progressive adaptation of parental U251-MG cells to increasing doses of TMZ. Parental and resistant subclones (TMZ-R) were used to define activity of BPM31510 in the TMZ-refractory setting. Results: In vitro results demonstrated that BPM 31510 has anti-cancer activity in both parental and TMZ-R U251-MG cells with EC 50 values of ~400 µM and 800 µM, respectively. Importantly, BPM 31510 treatment also resensitized TMZ-R cell lines to TMZ. In vivo, BPM 31510 treatment was associated with increasing duration of survival; one fifth of the rats treated achieved survival greater than 15 days post implantation, a response not observed in the control or irradiation arms of the study. Assessment of the combination of BPM 31510 with TMZ or BEV in the in vivoC6 glioma rat model is ongoing. A phase I open-label, non-randomized clinical trial to evaluate the safety and tolerability of BPM31510 in patients with recurrent BEV-refractory GB, as well as the changes in GB metabolism by SUV-PET imaging in response to treatment is under investigation. Conclusions: Preclinical data demonstrate that BPM 31510 has potential anti-cancer activity alone and in combination with standard therapy regimens and alleviates TMZ chemo-resistance in preclinical models of GB. These results provide support of a Phase 1 clinical study of BPM31510 in GB; this study is actively enrolling.
Association of breast cancer risk in women of African ancestry with genetic variants in the TET-related DNA demethylation pathway.
Authors: Kris M. Lee, Shengfeng Wang, Dezheng Huo, Temidayo O. Ogundiran, Oladosu Ojengbede, Wei Zheng, Katherine L. Nathanson, Barbara Nemesure, Stefan Ambs, Yonglan Zheng, Olufunmilayo I. Olopade
Journal: Journal of Clinical Oncology (2017)

e13015 Background: Imbalance in DNA methylation/demethylation cycles due to mutations in TET1, TET2, TET3, and TDG has been implicated in the onset and progression of breast cancer. However, few studies have assessed the relationship between genetic variants in the TET-related DNA demethylation pathway and breast cancer risk, particularly among women of African ancestry. Methods: We investigated 4095 single-nucleotide polymorphisms (SNPs) in four TET-related DNA demethylation pathway genes in the ROOT consortium, which includes women of African ancestry, in 1657 cases [403 estrogen receptor-positive (ER+) and 374 ER-negative (ER-)] and 2029 controls. Pathway and gene-level analyses were conducted using the adaptive rank truncated product (ARTP) test for 925 SNPs that were not highly correlated (r 2 &lt; 0.8), and SNP-level analyses were conducted with logistic regression, which was used to estimate the odds ratio (OR) and 95 % confidence intervals (CI). Results: The Tet-related DNA demethylation pathway was significantly associated with ER-negative breast cancer (pathway level P = 0.049). Gene-level analyses showed that TET1 was the candidate gene responsible for the association at the pathway level ( P = 0.008). SNP TET1 rs10998376 (OR = 1.21, 95% CI = 1.02-1.42, P adj = 0.0032) was statistically significant even after gene-level correction for multiple comparisons, and was associated with increased risk. There were no SNPs in genes with P &gt; 0.05 in the ARTP tests that were significant after Boferroni correction. Conclusions: In conclusion, specific TET-related DNA demethylation pathway genes may contribute to breast cancer risk, in particular, to risk of ER-negative tumors in women of African ancestry.
Low Dose IGFBP1, IGFBP2 and ANGPTL3 Coordinately Stimulate Ex Vivo Expansion of Human Umbilical Cord Blood (UCB) Hematopoietic Stem Cells (HSCs).
Authors: Xiubo Fan, Pak Yan Chu, Florence Gay, Sudipto Bari, Justina Ang, SaiKiang Lim, William Hwang
Journal: Blood (2010)
Closing the Medication-Assisted Treatment Gap for Youth With Opioid Use Disorder
Authors: Brendan Saloner, Kenneth A. Feder, Noa Krawczyk
Journal: JAMA Pediatrics (2017)

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Risk of male breast cancer in users of testosterone 5α reductase inhibitors.
Authors: Hakan Lars Olsson, Jesper Lindahl, Per Broberg
Journal: Journal of Clinical Oncology (2016)

1552 Background: Male breast cancer (MBC) is rare. Hormones have a central role in the pathogenesis of this malignancy. The possible correlation between MBC and hormone-affecting or gynecomastia-causing medicines has been sparsely studied. Studies of men with benign prostate hyperplasia (BPH) have shown an increased risk of MBC.The aim of this study is to examine if medicines known to alter the hormonal balance or cause gynecomastia may increase the risk of contracting MBC. Methods: Since July 2005 369 cases of MBC were identified from the Swedish Cancer Register and each case was matched to five controls (n = 2971) from the general population of the same age and domicile. Medicines with documented side effects of hormonal imbalance or gynecomastia were collected from the Prescribed Drug Register in operation since July 2005. Drug exposure was followed both for cases and controls until the cancer diagnosis or death of the case. Cases and controls with a diagnosis of prostate cancer were excluded. The data were mainly analyzed with conditional logistic regression and Cox regression. Results: A reduced risk was observed among users of testosterone 5α reductase inhibitors (5-ARIs) (HR 0.41, 95% CI 0.17-1.00). A statistically significant positive risk was observed among users of α-adrenergic receptor antagonists (αARAs) (HR 2.24, 95% CI 1.48-3.39). Comparing 5-ARI with αARA users gave a reduced risk of (HR = 0. 17, 95% CI 0.06-0.50). No other medication was significantly associated with an increased or decreased risk of MBC. Conclusions: The risk of MBC was statistically significantly higher among men using αARAs as has previously been shown for BPH. There was a decreased risk of MBC for users of 5-ARIs. This suggests that 5-ARI medication might protect against MBC. Research should therefore focus on the possible protecting role of 5-ARI and investigate the increased risk of MBC among users of αARAs or BPH by itself. Men with BRCA2 mutations might be candidates for prevention with 5-ARI and 5-ARI should be explored as a therapeutic agent in MBC and in androgen receptor positive female breast cancer.
A phase Ib dose escalation study of the OX40 agonist MOXR0916 and the PD-L1 inhibitor atezolizumab in patients with advanced solid tumors.
Authors: Jeffrey R. Infante, Aaron Richard Hansen, Michael J. Pishvaian, Laura Quan Man Chow, Grant A. McArthur, Todd Michael Bauer, Stephen V. Liu, Shahneen Kaur Sandhu, Frank Yung-Chin Tsai, Jeong Kim, Eric Stefanich, Chi-Chung Li, Houston Gilbert, BRUCE MCCALL, Maria S. Anderson, Mahrukh Huseni, Ina Park Rhee, Lillian L. Siu, Michael S. Gordon
Journal: Journal of Clinical Oncology (2016)

101 Background: OX40 is a co-stimulatory receptor that is transiently expressed by T cells upon antigen recognition. In murine models, OX40 engagement by an agonist anti-OX40 antibody can promote durable tumor regression associated with co-stimulation of effector T cells and reduction of regulatory T cells. This dual mechanism of action is predicted to complement the activity of PD-L1 blockade. MOXR0916 is a humanized effector-competent agonist IgG1 monoclonal antibody (mAb) that targets OX40 and atezolizumab is an engineered humanized IgG1 mAb that targets PD-L1. Methods: A Phase I, open-label, multicenter study was conducted to evaluate the safety and pharmacokinetics (PK) of MOXR0916 and atezolizumab in patients (pts) with locally advanced or metastatic solid tumors. A 3+3 dose-escalation was conducted with a 21-day window to evaluate dose-limiting toxicity (DLT). Escalating doses of MOXR0916 in combination with a fixed 1200 mg dose of atezolizumab were administered every 3 weeks (q3w). An expansion cohort to enable immune profiling of serial tumor biopsies was also enrolled. Prior immunotherapy with adequate washout was allowed if there was no history of Grade (G) ≥ 3 immune-mediated adverse events (AEs). Results: As of 7 Jan 2016, 25 pts were treated in 7 dose escalation cohorts (dose levels 0.8 to 600 mg) and 19 additional pts were treated in a serial biopsy cohort. The median number of prior therapies for metastatic disease was 2 (range 0-7), and 5 pts had received prior PD-1/PD-L1 antibodies. No DLTs, G4/5 AEs attributed to study treatment, or related AEs leading to treatment discontinuation were reported. The majority of treatment-related AEs were G1 in severity; 1 related G3 event (pneumonitis responsive to corticosteroids) was reported. The PK of each mAb was consistent with its established single agent profile. Objective responses were observed; clinical and biomarker data will be updated. The regimen selected for dose expansion is MOXR0916 300 mg + atezolizumab 1200 mg q3w. Conclusions: The combination of MOXR0916 and atezolizumab was well-tolerated. An expansion phase, with each agent administered at its recommended monotherapy dose, is ongoing in selected tumor types. Clinical trial information: NCT02410512.
A pharmacodynamic study of pre-prostatectomy buparlisib in men with high-risk, localized prostate cancer.
Authors: Archana Anantharaman, Hao Gia Nguyen, Matthew R. Cooperberg, Maxwell V. Meng, Peter Carroll, Terence W. Friedlander, Li Zhang, Miles Thomas, Phillip G. Febbo, Felix Yi-Chung Feng, Charles J. Ryan, Won Kim
Journal: Journal of Clinical Oncology (2016)

e14110 Background: Successful targeting of driver oncogenes outside the androgen receptor (AR) pathway remains elusive in the treatment of prostate cancer (PC). The PI3K pathway is commonly dysregulated in both localized and advanced PC. Buparlisib (BU) is an oral, pan class I, direct PI3K inhibitor. This prospective phase II trial evaluated the pharmacodynamic (PD) and biologic impact of neoadjuvant PI3K inhibition in men with high-risk, localized PC. Methods: Men with high-risk localized PC (Gleason ≥ 8 or high volume 4+3) undergoing radical prostatectomy (RP) with normal baseline organ function were treated with BU 100mg daily for 14 days leading up to RP. Paired pretreatment (biopsy) and on-treatment (RP) specimens were collected for immunohistochemistry (IHC) and molecular analyses. The primary endpoint was determination of downstream PI3K inhibition, defined as ≥ 60% decrease in phosphorylated S6 (pS6) from baseline by IHC. Quickscore was used for IHC quantitation. Results: Eleven men were treated with BU prior to RP. Median age was 61 (range 53-70). Median pre-treatment PSA was 21.7ng/mL (range 5.7-146.3). Five patients had Gleason ≥ 8. The study was terminated in September 2015 for lack of accrual. One patient did not have pretreatment tissue evaluable for IHC; thus 10 men were evaluable for PD efficacy and 11 were evaluable for clinical and safety endpoints. Seven (70%) men had ≥ 60% decrease in pS6 IHC from baseline. Additionally, 7 (70%) men had ≥ 60% decline in pAKT IHC, and all 10 patients had ≥ 60% decline in p4EBP1 IHC. There were no changes in CC3 and Ki-67 IHC compared to baseline. Seven (64%) men had lymph node-positive disease on RP pathology and 8 (27%) had detectable first post-RP PSAs in this high-risk cohort. Eight (73%) men began salvage therapy within 6 months of RP. No grade 3/4 toxicities were reported. Conclusions: BU demonstrates PD efficacy, demonstrated by significant downstream target inhibition of the PI3K pathway. However, there was no significant impact on apoptosis or proliferation, which may be attributable to the short BU treatment duration prior to RP. Further analyses by DNA/RNA sequencing are ongoing to determine the molecular implications of PI3K inhibition in this high-risk cohort. Clinical trial information: NCT01695473.
Multicenter, phase II open-label trial of percutaneous laser ablation (PLA) for 61 patients (pts) with early-stage (ES) primary breast cancer: Radiographic (MRI) and pathological correlation.
Authors: Barbara Stewart Schwartzberg, Osama Abdelatif, John Lewin, Jacqueline Bernard, Hanadi Bu-Ali, Simon Cawthorn, Margaret Chen-Seeto, Sheldon M. Feldman, Sasirekha Govindarajulu, Lyn Jones, Arne Juette, Sanjay Kavia, Robert Maganini, Simon Pain, Mike Shere, Craig D. Shriver, Simon Smith, Alexandra Valencia, Eric B Whitacre, Roger Whitney
Journal: Journal of Clinical Oncology (2016)

e12525 Background: PLA of ES primary breast cancer remains investigational. An IRB- approved international multicenter (11 sites) trial (NCT01478438) was completed to determine feasibility of this technique. Methods: Pts with a single focus of infiltrating ductal carcinoma ≤ 20 mm by preablation MRI were treated with image-guided PLA following informed consent (June 25, 2012 – May 1, 2015). Thermal ablation was performed with local anesthesia using a laser diode source (805 nominal nm wavelength). Successful ablation was determined by thermal sensors placed at the periphery of the tumor, measuring achievement of predefined temperature levels. Pts were evaluated by mammogram, ultrasound, and MRI preablation and again at 4 weeks postablation, after which they had surgical excision. Pathology specimens were evaluated by H&E, CK 8/18, Ki-67, and estrogen-receptor (ER) staining and compared to preablation tumor biopsies for postablation cell viability. Results: Results from 61 (60 evaluable) women (aged 42-77, mean 64 yrs) undergoing PLA are reported. Mean tumor size was 11.3 mm. Mean laser time was 15.8 min. No serious adverse events were reported. Successful ablation was best determined by CK 8/18, Ki-67 and ER changes in staining patterns. Complete ablation was confirmed in 45 pts (75%) when evaluated by postablation MRI and pathologic analysis (“true negative” TN), while 7 pts (11%) had residual invasive cancer by both postablation MRI and pathologic analysis (“true positive” TP). Four pts (7%) had a postablation residual tumor burden < 2mm not detected by MRI (“false negative” FN); 4 pts (7 %) had complete pathologic ablation but positive MRI (“false positive” FP). MRI had a negative predictive value (NPV) of 92%. Forty of the 44 pts (91%) treated according to protocol guidelines had complete ablation of their cancer. Conclusions: PLA appears to be a viable alternative to lumpectomy in the treatment of pts with ES breast cancer, with a strong correlation between findings on postablation MRI and changes in CK 8/18, Ki-67 and ER staining. Clinical trial information: NCT01478438.MRI-Pathology Correlation Subjects TN 45 (75%) TP 7 (11%) FN 4 (7%) FP 4 (7%) TOTAL 60 (100%) MRI NPV 92%
ADAM28 Enhanced the Growth and Dissemination of AML and Identified a Subgroup of AML Patients with a High Risk of Relapse in a Prospective Clinical Study
Authors: Jia-Min Zhang, Chen-Cong Wang, Qian-Ming Wang, Xiao-Lu Zhu, Hao Jiang, Qian Jiang, Yu Wang, Meng Lv, Feng-Rong Wang, Jin Lu, Huan Chen, Wei Han, Lan-Ping Xu, Kai-Yan Liu, Xiao-Jun Huang, Xiao-Hui Zhang
Journal: Blood (2016)
Phosphoproteomic portraits of triple-negative breast cancer (TNBC).
Authors: Miguel Quintela-Fandino, Ivana Zagorac, Jose Francisco Lopez-Acosta, Gonzalo Gomez, David G Pisano, Javier Munoz, Luis Manso, Soledad Alonso, Renske Penning, Maarten Altelaar, Albert JR Heck
Journal: Journal of Clinical Oncology (2016)

1071 Background: Next-gen sequencing studies demonstrate that each TNBC case harbors a unique set of mutations. We hypothesized that all the different genetic aberrations would converge in discrete patterns of activation of signaling nodes. Pinpointing these nodes would be a parsimonious solution for functional classification. Such nodes (kinases) would also constitute targets. Methods: Training set (n = 34): two groups of early TNBC paired by T, N, G: (A) relapsed in < 4 years; (B) relapse-free > 12 years. Cell lines: 3 TNBC cell lines that develop metastases and kill recipient mice in < 4 months; 7 TNBC indolent cell lines (no metastases in 60 weeks). 250 ug of protein from frozen tumors or cell pellets were purified by Ti+4-IMAC and run in triplicate in an Orbitrap Elite mass spectrometer. Software: Maxquant for peptide identification, PHOSIDA for kinase prediction, Gene-E for clustering. Validation set: phosphohits and hyperactive kinases identified were validated in 113 consecutive early TNBC cases. Mass spectra were translated into H-Scores with an in-house built algorithm and an Ariol scanner. Top hits were pharmacologically targeted on metastatic xenograft models. Results: > 15000 unique phosphopeptides (pPs)were identified and quantified in the training set. 161 and 541 pPs were up-regulated in the A vs B and B vs A groups, respectively. The hyperactivity of 13 kinases (enrichment FDR < 0.1 all) accounted for the pPs upregulated in A. Three of them (PAK2, PIM1, PRKCE) were shared with those driving pPs of aggressive cell lines. The top 40 hits (13 kinases and 27 pPs) enriched in A were validated. A signature characterized by positivity of either STAT3, CYCB, CDK6, P70S6K and/or PRKCE identified 93% of the relapsing cases. RFS of patients positive vs. negative for the signature: 6.7 vs. 11.9 years, LogRank P < 0.001; Cox´s hazard > 550% increase in relapse risk, adjusted by T, N, G, age; P < 0.001. Compared to vehicle, pharmacological blockade of CDK6, STAT3, and P70S6K induced > 2-fold increase in tumor growth control and animal survival in graft models of metastatic TNBC (P < 0.01 all. Conclusions: an unbiased interrogation of the phosphoproteome identifies kinases driving relapsing vs. non-relapsing TNBC. Such nodes constitute targets.
Efficacy of Recombinant Influenza Vaccine in Adults 50 Years of Age or Older
Authors: Lisa M. Dunkle, Ruvim Izikson, Peter Patriarca, Karen L. Goldenthal, Derek Muse, Janice Callahan, Manon M.J. Cox
Journal: New England Journal of Medicine (2017)

Improved influenza vaccines are needed to control seasonal epidemics. This trial compared the protective efficacy in older adults of a quadrivalent, recombinant influenza vaccine (RIV4) with a standard-dose, egg-grown, quadrivalent, inactivated influenza vaccine (IIV4) during the A/H3N2-predominant 2014-2015 influenza season, when antigenic mismatch between circulating and vaccine influenza strains resulted in the reduced effectiveness of many licensed vaccines.We conducted a randomized, double-blind, multicenter trial of RIV4 (45 μg of recombinant hemagglutinin [HA] per strain, 180 μg of protein per dose) versus standard-dose IIV4 (15 μg of HA per strain, 60 μg of protein per dose) to compare the relative vaccine efficacy against reverse-transcriptase polymerase-chain-reaction (RT-PCR)-confirmed, protocol-defined, influenza-like illness caused by any influenza strain starting 14 days or more after vaccination in adults who were 50 years of age or older. The diagnosis of influenza infection was confirmed by means of RT-PCR assay and culture of nasopharyngeal swabs obtained from participants with symptoms of an influenza-like illness. The primary end point was RT-PCR-confirmed, protocol defined, influenza-like illness between 14 days or more after vaccination and the end of the influenza season.A total of 9003 participants were enrolled and underwent randomization; 8855 (98.4%) received a trial vaccine and underwent an efficacy follow-up (the modified intention-to-treat population), and 8604 (95.6%) completed the per-protocol follow-up (the modified per-protocol population). Among RIV4 recipients, the RT-PCR-confirmed influenza attack rate was 2.2% (96 cases among 4303 participants) in the modified per-protocol population and 2.2% (96 cases among 4427 participants) in the modified intention-to-treat population. Among IIV4 recipients, the attack rate was 3.2% (138 cases among 4301 participants) in the modified per-protocol population and 3.1% (138 cases among 4428 participants) in the modified intention-to-treat population. A total of 181 cases of influenza A/H3N2, 47 cases of influenza B, and 6 cases of nonsubtypeable influenza A were detected. The probability of influenza-like illness was 30% lower with RIV4 than with IIV4 (95% confidence interval, 10 to 47; P=0.006) and satisfied prespecified criteria for the primary noninferiority analysis and an exploratory superiority analysis of RIV4 over IIV4. The safety profiles of the vaccines were similar.RIV4 provided better protection than standard-dose IIV4 against confirmed influenza-like illness among older adults. (Funded by Protein Sciences; ClinicalTrials.gov number, NCT02285998 .).
Abstract 11554: Integrating Intracellular Calcium Leak and Mitochondrial Dysfunction in Heart Failure
Authors: Gaetano Santulli, De Yu Mao, Wenjun Xie, Steven Reiken, Andrew R Marks
Journal: Circulation (2013)

Growing evidence indicates that mitochondrial function is impaired in heart failure (HF). However, the molecular mechanisms involved remain relatively obscure. It is widely recognized that increase...