tbuckley/cabot-search huggingface dataset:
Programmed cell death‐1 (PD‐1) checkpoint blockade in combination with a mammalian target of rapamycin inhibitor restrains hepatocellular carcinoma growth induced by hepatoma cell–intrinsic PD‐1
Authors: Hui Li, Xiaoqiang Li, Shuang Liu, Lei Guo, Bo Zhang, Jubo Zhang, Qinghai Ye
Journal: Hepatology (2017)

Inhibitors of programmed cell death 1 (PD-1) administered as single agents have resulted in durable tumor regression in advanced cancer patients. However, only a minority of cancer patients respond to anti-PD-1 immunotherapy. Here, we show that PD-1 expression in hepatocellular carcinoma promotes tumor growth independently of adaptive immunity. Knockdown of PD-1 suppresses tumor growth, whereas PD-1 overexpression enhances tumorigenesis in immunodeficient xenografted mice. Mechanistically, PD-1 binds the downstream mammalian target of rapamycin effectors eukaryotic initiation factor 4E and ribosomal protein S6, thus promoting their phosphorylation. Moreover, combining mammalian target of rapamycin inhibition with anti-PD-1 antibody treatment results in more durable and synergistic tumor regression than either single agent alone, each of which presents only modest efficacy.Targeting mammalian target of rapamycin pathways in combination with PD-1 may result in increased antitumor efficacy in cancer patients. (Hepatology 2017;66:1920-1933).
Preclinical investigation of combined gene-mediated cytotoxic immunotherapy and immune checkpoint blockade in glioblastoma
Authors: Maria-Carmela Speranza, Carmela Passaro, Franz Ricklefs, Kazue Kasai, Sarah R Klein, Hiroshi Nakashima, Johanna K Kaufmann, Abdul-Kareem Ahmed, Michal O Nowicki, Prisca Obi, Agnieszka Bronisz, Estuardo Aguilar-Cordova, Laura K Aguilar, Brian W Guzik, Xandra Breakefield, Ralph Weissleder, Gordon J Freeman, David A Reardon, Patrick Y Wen, E Antonio Chiocca, Sean E Lawler
Journal: Neuro-Oncology (2017)

Combined immunotherapy approaches are promising cancer treatments. We evaluated anti–programmed cell death protein 1 (PD-1) treatment combined with gene-mediated cytotoxic immunotherapy (GMCI) performed by intratumoral injection of a prodrug metabolizing nonreplicating adenovirus (AdV-tk), providing in situ chemotherapy and immune stimulation. The effects of GMCI on PD ligand 1 (PD-L1) expression in glioblastoma were investigated in vitro and in vivo. The efficacy of the combination was investigated in 2 syngeneic mouse glioblastoma models (GL261 and CT-2A). Immune infiltrates were analyzed by flow cytometry. GMCI upregulated PD-L1 expression in vitro and in vivo. Both GMCI and anti–PD-1 increased intratumoral T-cell infiltration. A higher percentage of long-term survivors was observed in mice treated with combined GMCI/anti–PD-1 relative to single treatments. Long-term survivors were protected from tumor rechallenge, demonstrating durable memory antitumor immunity. GMCI led to elevated interferon gamma positive T cells and a lower proportion of exhausted double positive PD1+TIM+CD8+ T cells. GMCI also increased PD-L1 levels on tumor cells and infiltrating macrophages/microglia. Our data suggest that anti–PD-1 treatment improves the effectiveness of GMCI by overcoming interferon-induced PD-L1–mediated inhibitory signals, and GMCI improves anti–PD-1 efficacy by increasing tumor-infiltrating T-cell activation. Our data show that the GMCI/anti–PD-1 combination is well tolerated and effective in glioblastoma mouse models. These results support evaluation of this combination in glioblastoma patients.
Abstract 152: In vitro Modeling of the Pacemaker/working Myocardial Fate Decision by the Shox2-nkx2-5 Antagonistic Mechanism
Authors: Yingnan Song, Wenduo Ye, Yiping Chen
Journal: Circulation Research (2015)

Our recent studies have identified a Shox2-Nkx2-5 antagonistic mechanism that regulates pacemaker/working myocardial cell fate decision in the developing venous pole in mice, particularly in the junction domain of the sinoatrial node (SAN) and pulmonary vein myocardium where Shox2 and Nkx2-5 are co-expressed. In such regulatory mechanism, the stronger transcription output by Shox2 promotes pacemaker cell fate, while stronger Nkx2-5 output favors working myocardial fate. Interestingly, we also found that a majority of Hcn4-positive cells derived from mouse embryonic stem (mES) cells co-express Shox2 and Nkx2-5, suggesting that in vitro differentiated pacemaker-like cells also adopt such an antagonistic mechanism to regulate cell fate. To establish an in vitro modeling system to further dissecting the functional importance of the Shox2-Nkx2-5 antagonism and for future in vitro differentiation of pacemaker cells, we established induced pluripotent stem (iPS) cell lines from mice carrying allelic series of Shox2 and Nkx2-5, as well as lineage specific Cre and RosamTmG reporter alleles. These iPS cell lines are being tested to prove the principle that the Shox2-Nkx2-5 antagonistic mechanism also functions in iPS cell-derived cardiomycytes to regulate cell fate, and are being used for lineage tracing of differentiated cardiomycytes. Furthermore, these cell lines could also be applied to modeling human diseases with Nkx2-5 mutations in vitro.
S1605: Phase II trial of atezolizumab in BCG-unresponsive nonmuscle invasive bladder cancer.
Authors: Peter C. Black, Tangen Catherine, Seth P. Lerner, David James McConkey, M. Scott Lucia, Michael Woods, Trinity Bivalacqua, Wassim Kassouf, Richard Carlton Bangs, Melissa Plets, Ian Murchie Thompson, Parminder Singh
Journal: Journal of Clinical Oncology (2018)

TPS527 Background: Radical cystectomy is the standard of care for patients with BCG-unresponsive high risk non-muscle invasive bladder cancer (NMIBC). Based on the reported efficacy of atezolizumab in metastatic urothelial carcinoma and the known expression of PD-L1 expression in NMIBC after BCG therapy, this trial will evaluate the activity of atezolizumab in BCG-unresponsive high risk NMIBC. Methods: This is a single arm phase II trial testing systemic atezolizumab (1200 mg IV) every 3 weeks for one year in 135 patients with BCG-unresponsive high risk NMIBC. The study will enroll 70 patients with CIS (with or without concomitant Ta/T1) and 65 with Ta/T1 only. Patients with CIS at baseline will undergo mandatory repeat biopsy at 6 months, and all other patients only for suspected recurrence. Patients with persistent CIS, high grade Ta/T1 recurrence or progression to muscle invasive or metastatic disease will be taken off treatment. The co-primary endpoints are: (1) complete response (CR) at 6 months in the CIS subgroup, and (2) event-free survival (EFS) at 18 months in the overall population. A hierarchical approach will be used to test the two co-primary endpoints. Secondary endpoints include duration of CR as well as progression-free, cystectomy-free, bladder cancer-specific, and overall survival in all patients. Response will be correlated to expression of PD-L1 and CD8 by IHC, and to molecular subtypes and immune signatures by RNA-sequencing. If ≥28 (40%) CIS patients respond, the agent will be considered promising. This design has a significance level of 4.6%, and a power of 96%. If the lower bound of the 90% confidence interval of the 18-month EFS excludes 20%, the investigators will conclude the regimen significantly improves EFS relative to historical data (type I error rate 0.05 and statistical power 0.93). Successful completion of this trial could lead to a new treatment paradigm for patients with BCG-unresponsive high risk NMIBC. Funding: NIH/NCI grants: CA180888, CA180819, CA180820, CA180821, and CA180863. Clinical trial registry: NCT02844816 Clinical trial information: NCT02844816.
Randomized phase II placebo-controlled trial of fulvestrant plus vandetanib in postmenopausal women with bone only or bone predominant, hormone receptor-positive metastatic breast cancer (MBC): OCOG Zamboney study—NCT00811369.
Authors: Mark J. Clemons, Brandy Cochrane, Nadia Califaretti, Stephen K. L. Chia, Rebecca Alexandra Dent, Xinni Song, Andre Robidoux, Gregory Russell Pond, Sameer Parpia, Kathleen I. Pritchard, Mark Norman Levine
Journal: Journal of Clinical Oncology (2013)

574 Background: Biomarkers of bone turnover, including urine N-telopeptide (uNTx) and serum C-telopeptide (sCTx) reflect tumor-related bone breakdown and have been used as surrogate measures of response to therapy in trials. Vascular endothelial growth factor (VEGF) levels correlate with extent of bone metastases (BM). We assessed whether vandetanib, an inhibitor of VEGF, epidermal growth factor receptor and RET signalling, improved uNTx response when added to fulvestrant (F) in patients with BM. Methods: Postmenopausal patients with bone only, or bone predominant, hormone receptor positive MBC were randomised to F (500mg IM day 1, 14, 28, then monthly) with either vandetanib (100mg PO OD) (FV) or placebo (FP) until progression. The primary objective was uNTx response (&gt;30% reduction from baseline). uNTx was collected at baseline, weekly to wk 4, at wk 12 and then every 12 wks. Secondary objectives included PFS, OS, RECIST response, pain and toxicity. Results: 61 patients were allocated to FV and 68 to FP. Median age was 59. 18% had received 1 prior chemotherapy regime and 73% prior endocrine therapy for MBC. uNTx response (n=124 pts) was 64% for FV vs. 52% for FP (p=0.20). No difference was detected between groups for median PFS; 6 months for FV vs. 4.8 months for FP, HR=0.93 (95% CI: 0.64 to 1.36). 16 patients died in FV arm vs. 21 in the FP arm, HR=0.71 (95% CI: 0.37 to 1.36). For those patients with measurable disease, clinical benefit rates were 41% and 43%, respectively, p=1.00. Serious adverse events were similar, 3.3% for FV vs. 5.9% for FP. Elevated baseline uNTx (&gt;65 nM BCE/mmol Cr) was prognostic for PFS, HR=1.62 (95% CI: 1.08 to 2.43 and for mortality, HR= 2.4 (95% CI: 1.2 to 4.6). In an exploratory analysis uNTx was predictive of responsiveness to FV for PFS, HR=0.60 when uNTx &gt;65 vs. HR=1.37 when uNTx &lt;65, P = 0.025 for interaction. Conclusions: The addition of vandetanib to F did not improve biomarker response, PFS or OS compared to F alone in patients with bone predominant disease. Exploratory analyses confirmed that baseline bone turnover markers are prognostic for PFS and OS. Clinical trial information: NCT00811369.
Next Generation Sequencing of CD138+ Myeloma Cells Could Predict Response Rate and Appropriate Therapy at Diagnosis
Authors: Hiroshi Ikeda, Yasushi Sasaki, Soushi Ibata, Masahiro Yoshida, Ayumi Tatekoshi, Satoshi Iyama, Kazuyuki Murase, Kohichi Takada, Shohei Kikuchi, Tsutomu Sato, Masayoshi Kobune, Junji Kato
Journal: Blood (2016)
Abstract P350: Interstitial Volume Regulation in the Heart: Mechanistic Insights from ex Vivo Fluid Dynamics in Pig Myocardia
Authors: Maria P McGee, Michael Morykwas, Jim Jordan, Louis Argenta
Journal: Circulation Research (2011)

Developing and testing specific therapies for myocardial edema require understanding their mode and site of action. However, parsing determinants of interstitial volume/pressure relationships in vivo is difficult, particularly in the myocardium, where rhythmic contractions add to the confounding components of fluid-transfer driving pressures. Here, we describe a novel ex-vivo model system based on osmotic stress techniques and illustrate its application to analyses of local myocardial fluid dynamics that exclude systemic influences and systole/diastole compressive cycles. Freshly harvested ventricular explants were equilibrated in physiologic media at colloidosmotic pressures ranging from 3 to 219 mmHg, and fluid transfer in/out was measured gravimetrically as a function of time and pressure. The relationship between the change in explant volume and the imposed colloidosmotic pressure of the media was linear. The hydration potential , defined empirically as the pressure at which explant volume did not change, was calculated from the abscissa intercept at volume change = 0 , and the compliance from the slope of volume/pressure regression lines. Fluid-transfer rates and energies were derived from volume versus time trajectories measured at 4 and 37 °C. Hydration potential was 71.3 ± 10.6 and 23.0 ± 15.2 mmHg at 4 and 37°C (significant, P = 0.002), while compliance was 1.09 ± 0.3 and 1.22 ± 0.2 µl/g/ mmHg (not significant, P = 0.2, n = 5). Temperature-dependent differences between in/out flow rates were also significant, giving experimental activation energies of −5.9 ± 2.2 and 1.4 ± 0.7 kcal/mol for inflow and outflow, respectively. Results show that at physiologic temperatures, even without vascular hydrostatic pressure gradients and lymphatic drainage, the myocardial bias toward interstitial fluid efflux persists. These findings are consistent with local fluid-control mechanisms actuated by colloidosmotic and tensional forces rather than passive changes in flow resistance. This new approach allows quantitative evaluation of interstitial components of Starling’s forces and should help in mechanistic preclinical characterization of treatments to correct interstitial myocardial edema.
Temporal profile of intracranial pressure and cerebrovascular reactivity in severe traumatic brain injury and association with fatal outcome: An observational study
Authors: Hadie Adams, Joseph Donnelly, Marek Czosnyka, Angelos G. Kolias, Adel Helmy, David K. Menon, Peter Smielewski, Peter J. Hutchinson
Journal: PLoS Medicine (2017)

Background Both intracranial pressure (ICP) and the cerebrovascular pressure reactivity represent the dysregulation of pathways directly involved in traumatic brain injury (TBI) pathogenesis and have been used to inform clinical management. However, how these parameters evolve over time following injury and whether this evolution has any prognostic importance have not been studied. Methods and findings We analysed the temporal profile of ICP and pressure reactivity index (PRx), examined their relation to TBI-specific mortality, and determined if the prognostic relevance of these parameters was affected by their temporal profile using mixed models for repeated measures of ICP and PRx for the first 240 hours from the time of injury. A total of 601 adults with TBI, admitted between September 2002 to January 2016, and with high-resolution continuous monitoring from a single centre, were studied. At 6 months postinjury, 133 (19%) patients had a fatal outcome; of those, 88 (78%) died from nonsurvivable TBI or brain death. The difference in mean ICP between those with a fatal outcome and functional survivors was only significant for the first 168 hours after injury (all p < 0.05). For PRx, those patients with a fatal outcome also had a higher (more impaired) PRx throughout the first 120 hours after injury (all p < 0.05). The separation of ICP and PRx was greatest in the first 72 hours after injury. Mixed models demonstrated that the explanatory power of the PRx decreases over time; therefore, the prognostic weight assigned to PRx should similarly decrease. However, the ability of ICP to predict a fatal outcome remained relatively stable over time. As control of ICP is the central purpose of TBI management, it is likely that some of the information that is reflected in the natural history of ICP changes is no longer apparent because of therapeutic intervention. Conclusions We demonstrated the temporal evolution of ICP and PRx and their relationship with fatal outcome, indicating a potential early prognostic and therapeutic window. The combination of dynamic monitoring variables and their time profile improved prediction of outcome. Therefore, time-driven dynamic modelling of outcome in patients with severe TBI may allow for more accurate and clinically useful prediction models. Further research is needed to confirm and expand on these findings.
Child poverty: what should doctors do?
Authors: Guddi Singh
Journal: BMJ (2017)

Child poverty is finally getting some attention thanks to the recent report from the Royal College of Paediatrics and Child Health and the Child Poverty Action Group, as reported in The BMJ .1

Is “policy lacking to prevent adverse health in poor UK children,” as the Lancet asserts?2 After all, it was policy abrogation that removed poverty reduction targets in 2015.3 Indeed, the Welfare Reform …
Cabazitaxel vs docetaxel in chemotherapy-naive (CN) patients with metastatic castration-resistant prostate cancer (mCRPC): A three-arm phase III study (FIRSTANA).
Authors: A. Oliver Sartor, Stephane Oudard, Lisa Sengelov, Gedske Daugaard, Fred Saad, Steinbjoern Hansen, Marie Hjelm-Eriksson, Jacek Jassem, Antoine Thiery-Vuillemin, Orazio Caffo, Daniel E. Castellano, Paul N. Mainwaring, John P Bernard, Liji Shen, Mustapha Chadjaa, Karim Fizazi
Journal: Journal of Clinical Oncology (2016)

5006 Background: The Phase III TROPIC study (NCT00417079) reported significant improvement in overall survival (OS) for cabazitaxel 25 mg/m2IV Q3W plus prednisone 10 mg PO QD (P) vs. mitoxantrone plus P in mCRPC pts previously treated with a docetaxel (D)-containing regimen. The FIRSTANA study examined if cabazitaxel 20 mg/m² (C20) or 25 mg/m² (C25) IV Q3W plus P is superior to docetaxel 75 mg/m² (D75) IV Q3W plus P in terms of OS in CN mCRPC pts. Methods: In this multinational, open label phase III study, mCRPC pts, ECOG PS 0-2, who had progressed after castration were randomized 1:1:1 to C20, C25 or D75 IV Q3W plus P. The primary endpoint was OS. Key secondary endpoints were safety, progression free survival (PFS), tumor PFS, tumor response (RECIST 1.1), PSA response, PSA PFS, pain response, pain PFS, time to skeletal-related events (SRE) and health-related quality of life (HRQOL). Results: Between May 2011 and April 2013, 1168 pts were randomized (C20=391, C25=389, D75=388). Baseline demographics and disease characteristics were similar across cohorts. The median number of treatment cycles was 9 for all dose groups. In the ITT analysis, median OS was 24.5 months for C20, 25.2 months for C25 and 24.3 months for D75. HR for C20 vs. D75 was 1.009 (0.85 to 1.197, p=0.9967) and for C25 vs. D75 was 0.97 (0.819 to 1.16, p=0.7574), indicating that C20 and C25 were not superior to D75 in terms of OS. PFS was 4.4 months for C20, 5.1 months for C25 and 5.3 months for D75 (NS). Tumor responses were superior in C25 (41.6%) compared to D75 (30.9%), p=0.0370. Other secondary endpoints did not significantly differ across dose groups. Adverse events (AEs) grade 3-4 were 41.2% in C20, 60.1% in C25 and 46.0% in D75; pts discontinuing treatment due to an AE were 25.2% in C20, 31.7% in C25 and 33.9% in D75. Febrile neutropenia, diarrhea and hematuria were more frequent in C25; peripheral neuropathy, peripheral edema, alopecia and nail disorders were more frequent in D75. Conclusions: C20 and C25 did not demonstrate superiority for OS compared to D75 in CN mCRPC pts. Among secondary endpoints only tumor responses were significantly superior for C25. AEs were less frequent in C20 for most categories. Clinical trial information: NCT01308567.
Concerns About Methodology of a Trial Investigating Vaginal Health During Aromatase Inhibitor Therapy for Breast Cancer
Authors: V. Craig Jordan
Journal: JAMA Oncology (2017)

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EphrinB2 Regulates Cardiac Fibrosis Through Modulating the Interaction of Stat3 and TGF-β/Smad3 Signaling
Authors: Sheng-an Su, Du Yang, Yue Wu, Yao Xie, Wei Zhu, Zhejun Cai, Jian Shen, Zurong Fu, Yaping Wang, Liangliang Jia, Yidong Wang, Jian-an Wang, Meixiang Xiang
Journal: Circulation Research (2017)

Cardiac fibrosis is a common feature in left ventricular remodeling that leads to heart failure, regardless of the cause. EphrinB2 (erythropoietin-producing hepatoma interactor B2), a pivotal bidirectional signaling molecule ubiquitously expressed in mammals, is crucial in angiogenesis during development and disease progression. Recently, EphrinB2 was reported to protect kidneys from injury-induced fibrogenesis. However, its role in cardiac fibrosis remains to be clarified.We sought to determine the role of EphrinB2 in cardiac fibrosis and the underlying mechanisms during the pathological remodeling process.EphrinB2 was highly expressed in the myocardium of patients with advanced heart failure, as well as in mouse models of myocardial infarction and cardiac hypertrophy induced by angiotensin II infusion, which was accompanied by myofibroblast activation and collagen fiber deposition. In contrast, intramyocardial injection of lentiviruses carrying EphrinB2-shRNA ameliorated cardiac fibrosis and improved cardiac function in mouse model of myocardial infarction. Furthermore, in vitro studies in cultured cardiac fibroblasts demonstrated that EphrinB2 promoted the differentiation of cardiac fibroblasts into myofibroblasts in normoxic and hypoxic conditions. Mechanistically, the profibrotic effect of EphrinB2 on cardiac fibroblast was determined via activating the Stat3 (signal transducer and activator of transcription 3) and TGF-β (transforming growth factor-β)/Smad3 (mothers against decapentaplegic homolog 3) signaling. We further determined that EphrinB2 modulated the interaction between Stat3 and Smad3 and identified that the MAD homology 2 domain of Smad3 and the coil-coil domain and DNA-binding domain of Stat3 mediated the interaction.This study uncovered a previously unrecognized profibrotic role of EphrinB2 in cardiac fibrosis, which is achieved through the interaction of Stat3 with TGF-β/Smad3 signaling, implying a promising therapeutic target in fibrotic diseases and heart failure.