tbuckley/cabot-search huggingface dataset:
<i>AXIN2</i> expression predicts prostate cancer recurrence and regulates invasion and tumor growth.
Authors: Brian Robin Hu, Adrian S Fairey, Anisha Madhav, Dongyun Yang, Meng Li, Susan G. Groshen, Craig Stephens, Philip Kim, Navneet Virk, Lina Wang, Sue Ellen Martin, Nicholas Erho, Elai Davicioni, Robert B. Jenkins, Robert Benjamin Den, Tong Xu, Yucheng Xu, Inderbir S. Gill, David I. Quinn, Amir Goldkorn
Journal: Journal of Clinical Oncology (2015)

e16092 Background: Treatment of prostate cancer (PCa) may be improved by identifying biological mechanisms of tumor growth and renewal that directly impact clinical disease progression. We investigated whether genes associated with a highly tumorigenic, drug resistant, progenitor phenotype impact PCa biology and disease recurrence. Methods: Radical prostatectomy (RP) specimens (+/- disease recurrence) were analyzed by qRT-PCR to quantify expression of genes associated with self-renewal, drug resistance, and tumorigenicity in prior studies. Univariable and multivariable associations between gene expression and PCa recurrence were confirmed by bootstrap internal validation and by external validation in independent cohorts and in-silico. siRNA knockdown and lentiviral overexpression were used to determine the effect of gene expression on PCa proliferation, invasion and tumor growth. Results: Four candidate genes were differentially expressed in PCa recurrence, and of these, low AXIN2 expression was internally validated. In external cohorts and in silico, low AXIN2 was independently associated with more aggressive PCa, biochemical recurrence, and metastasis-free survival after RP. In vitro and in vivo, low AXIN2 expression was associated with a cancer stem-like cell-surface signature and significantly greater invasiveness, proliferative, and tumor growth. Conversely, ectopic overexpression of AXIN2 significantly reduced invasiveness, proliferation, and tumor growth. Conclusions: Low AXIN2 expression was associated with PCa recurrence after RP in our test population as well as in external validation cohorts, and its expression levels in PCa cells significantly impacted invasiveness, proliferation and tumor growth. Given these novel roles, further study of AXIN2 in PCa may yield promising new predictive and therapeutic strategies.
Why men get or don’t get treated for locally advanced prostate cancer: Physicians’ perspectives.
Authors: Sarah Abramson, Jenny J Lin, Ann Scheck McAlearney, Kezhen Fei, Rebeca Franco, Nina A. Bickell
Journal: Journal of Clinical Oncology (2015)

e16068 Background: Locally advanced prostate cancer treatment can improve survival. Yet, African American are more likely than white prostate cancer patients to go untreated. We found that 13% of black and 1% of white men (25/641 men) with Gleason Scores ≥ 7 diagnosed at an academic or municipal inner-city hospital between 2006-2013 did not get definitive treatment. We undertook this study to describe physician reasons for treatment recommendation or underuse of definitive surgical, radiation or cryotherapy treatment. Methods: We interviewed 15/17 physicians (urologists, medical oncologists, and radiation oncologists) treating 22/25 underuse patients; 2 were unreachable. Interview summaries were analyzed using a grounded theory approach. Results: Physician and patient factors influencing treatment recommendation and decision-making include: patient biological (age, life expectancy, comorbidities, tumor histology) and social characteristics (treatment logistics, patient lifestyle); physician specialty and financial incentives - 36% of physicians described reimbursement incentivizing radiation. Among underuse patients, treatment was recommended but not received in 95% (21/22) of men and was not recommended due to small tumor size in 5% (1/22). Among men for whom treatment was recommended, 1 went untreated due to inability to afford androgen deprivation therapy (ADT), 4 patients refused treatment, and the majority, 73% (16/22), were system failures – treatment was recommended, not refused but did not ensue. 88% of system failures were lost to Urology follow up, yet a quarter of these men had subsequent visits at the hospital. 12% of system failures occurred when neoadjuvant ADT was begun while medical workup proceeded but planned primary treatment never ensued. Conclusions: For the vast majority of underuse, treatment is recommended but does not ensue due to loss to follow-up and proposed transitions in care. Since men continue to receive care at the treating hospital, ample missed opportunities exist to redress underuse and reduce racial disparities in cancer care. Financial incentives that influence treatment decisions have the potential to increasecosts of care.
Skeletal muscle toxicity associated with tyrosine kinase inhibitor therapy in patients with chronic myeloid leukemia
Authors: L. Janssen, S. J. C. M. Frambach, N. A. E. Allard, M. T. E. Hopman, T. J. J. Schirris, N. C. Voermans, R. J. Rodenburg, N. M. A. Blijlevens, S. Timmers
Journal: Leukemia (2019)
The RACE to Treat Atrial Fibrillation in the Emergency Department
Authors: Jeff S. Healey, William F. McIntyre
Journal: New England Journal of Medicine (2019)

Atrial fibrillation is an increasingly common reason for presentation to the emergency department, representing nearly 0.5% of all such visits.1 Appropriate patient care must consider the relief of symptoms, the safety of discharge from the emergency department, the plan for follow-up care, and the use of resources. However, there is great variation in the management of this condition, including the use of cardioversion.2-5 Pluymaekers and colleagues4 now report in the Journal the results of the RACE 7 ACWAS randomized noninferiority trial involving 437 patients with recent-onset (<36 hours) atrial fibrillation who presented to 17 emergency departments in the Netherlands. The . . .
Prevalence of Hypertension, Treatment, and Blood Pressure Targets in Canada Associated With the 2017 American College of Cardiology and American Heart Association Blood Pressure Guidelines
Authors: Stephanie Garies, Sylvia Hao, Kerry McBrien, Tyler Williamson, Mingkai Peng, Nadia A. Khan, Raj S. Padwal, Hude Quan, Alexander A. Leung
Journal: JAMA Network Open (2019)

<h3>Importance</h3> The 2017 American College of Cardiology and American Heart Association (ACC/AHA) blood pressure (BP) guidelines redefined hypertension using a BP threshold of 130/80 mm Hg or greater and applied a treatment target of less than 130/80 mm Hg. <h3>Objective</h3> To evaluate the potential change in the diagnosis, treatment, and control of hypertension in a Canadian cohort of patients with hypertension attending primary care practices using the ACC/AHA guidelines. <h3>Design, Setting, and Participants</h3> This cross-sectional study used primary care practices across Canada electronic medical record data from the Canadian Primary Care Sentinel Surveillance Network, extracted as of June 30, 2015. Adults with at least 1 primary care encounter in the previous 2 years (July 1, 2013, to June 30, 2015) were included in the study. Those with current hypertension were identified using a validated definition consisting of diagnoses, billing codes, and/or antihypertensive medication from within the primary care electronic medical record. Data analysis was conducted from December 2017 to July 2018. <h3>Main Outcomes and Measures</h3> Proportion of individuals with a diagnosis of hypertension, prescribed antihypertensive medication, and meeting treatment BP targets. <h3>Results</h3> Of the 594 492 Canadian participants included in the study, 144 348 (24.2%) had hypertension (45.6% male; mean [SD] age, 65.5 [14.5] years). On applying the ACC/AHA guidelines, 252 279 individuals (42.4%) were considered hypertensive and half (51.0%; 95% CI, 50.8%-51.2%) were prescribed an antihypertensive medication. Individuals who were not previously considered to have hypertension but were reclassified as having elevated BP using the lower cutoff of 130/80 mm Hg or greater tended to be younger and were at lower cardiovascular risk. There was a shift toward more individuals requiring antihypertensive treatment, particularly in the lower-risk categories. The crude prevalence of hypertension increased from 13.3% to 32.0% in those aged 18 to 64 years, and of those aged 65 years and older, 16.6% more individuals were reclassified as having hypertension (from 55.2% to 71.8%). Only 12.3% of those who were considered at high risk were reclassified as hypertensive. <h3>Conclusions and Relevance</h3> Adoption of the ACC/AHA BP guidelines would result in a near doubling in the prevalence of hypertension in Canada. The changes would largely affect individuals who are younger and at low to moderate cardiovascular risk.
Bevacizumab treatment for radiation brain necrosis: mechanism, efficacy and issues
Authors: Hongqing Zhuang, Siyu Shi, Zhiyong Yuan, Joe Y. Chang
Journal: Molecular Cancer (2019)

Vascular damage is followed by vascular endothelial growth factor (VEGF) expression at high levels, which is an important mechanism forradiation brain necrosis development. Bevacizumab alleviates brain edema symptoms caused by radiation brain necrosis through inhibiting VEGF and acting on vascular tissue around the brain necrosis area. Many studies have confirmed that bevacizumab effectively relieves symptoms caused by brain necrosis, improves patients’ Karnofsky performance status (KPS) scores and brain necrosis imaging. However, necrosis is irreversible, and hypoxia and ischemia localized in the brain necrosis area may easily lead to radiation brain necrosis recurrence after bevacizumab is discontinued. Further studies are necessary to investigate brain necrosis diagnoses, bevacizumab indications, and the optimal mode of administration, bevacizumab resistance and necrosis with a residual or recurrent tumor.
Neurite Development and Repair in Worms and Flies
Authors: Claire E. Richardson, Kang Shen
Journal: Annual Review of Neuroscience (2019)

How the nervous system is wired has been a central question of neuroscience since the inception of the field, and many of the foundational discoveries and conceptual advances have been made through the study of invertebrate experimental organisms, including Caenorhabditis elegans and Drosophila melanogaster. Although many guidance molecules and receptors have been identified, recent experiments have shed light on the many modes of action for these pathways. Here, we summarize the recent progress in determining how the physical and temporal constraints of the surrounding environment provide instructive regulations in nervous system wiring. We use Netrin and its receptors as an example to analyze the complexity of how they guide neurite outgrowth. In neurite repair, conserved injury detection and response-signaling pathways regulate gene expression and cytoskeletal dynamics. We also describe recent developments in the research on molecular mechanisms of neurite regeneration in worms and flies.
α-PD-1 therapy elevates Treg/Th balance and increases tumor cell pSmad3 that are both targeted by α-TGFβ antibody to promote durable rejection and immunity in squamous cell carcinomas
Authors: E. Dodagatta-Marri, D. S. Meyer, M. Q. Reeves, R. Paniagua, M. D. To, M. Binnewies, M. L. Broz, H. Mori, D. Wu, M. Adoumie, R. Del Rosario, O. Li, T. Buchmann, B. Liang, J. Malato, F. Arce Vargus, D. Sheppard, B. C. Hann, A. Mirza, S. A. Quezada, M. D. Rosenblum, M. F. Krummel, A. Balmain, R. J. Akhurst
Journal: Journal for ImmunoTherapy of Cancer (2019)

<h3>Background</h3> Checkpoint blockade immunotherapy has improved metastatic cancer patient survival, but response rates remain low. There is an unmet need to identify mechanisms and tools to circumvent resistance. In human patients, responses to checkpoint blockade therapy correlate with tumor mutation load, and intrinsic resistance associates with pre-treatment signatures of epithelial mesenchymal transition (EMT), immunosuppression, macrophage chemotaxis and TGFβ signaling. <h3>Methods</h3> To facilitate studies on mechanisms of squamous cell carcinoma (SCC) evasion of checkpoint blockade immunotherapy, we sought to develop a novel panel of murine syngeneic SCC lines reflecting the heterogeneity of human cancer and its responses to immunotherapy. We characterized six Kras-driven cutaneous SCC lines with a range of mutation loads. Following implantation into syngeneic FVB mice, we examined multiple tumor responses to α-PD-1, α-TGFβ or combinatorial therapy, including tumor growth rate and regression, tumor immune cell composition, acquired tumor immunity, and the role of cytotoxic T cells and Tregs in immunotherapy responses. <h3>Results</h3> We show that α-PD-1 therapy is ineffective in establishing complete regression (CR) of tumors in all six SCC lines, but causes partial tumor growth inhibition of two lines with the highest mutations loads, CCK168 and CCK169. α-TGFβ monotherapy results in 20% CR and 10% CR of established CCK168 and CCK169 tumors respectively, together with acquisition of long-term anti-tumor immunity. α-PD-1 synergizes with α-TGFβ, increasing CR rates to 60% (CCK168) and 20% (CCK169). α-PD-1 therapy enhances CD4 + Treg/CD4 + Th ratios and increases tumor cell pSmad3 expression in CCK168 SCCs, whereas α-TGFβ antibody administration attenuates these effects. We show that α-TGFβ acts in part through suppressing immunosuppressive Tregs induced by α-PD-1, that limit the anti-tumor activity of α-PD-1 monotherapy. Additionally, in vitro and in vivo, α-TGFβ acts directly on the tumor cell to attenuate EMT, to activate a program of gene expression that stimulates immuno-surveillance, including up regulation of genes encoding the tumor cell antigen presentation machinery. <h3>Conclusions</h3> We show that α-PD-1 not only initiates a tumor rejection program, but can induce a competing TGFβ-driven immuno-suppressive program. We identify new opportunities for α-PD-1/α-TGFβ combinatorial treatment of SCCs especially those with a high mutation load, high CD4+ T cell content and pSmad3 signaling. Our data form the basis for clinical trial of α-TGFβ/α-PD-1 combination therapy (NCT02947165).
Abstract 032: Rural Versus Urban Living and Incident Cognitive Impairment in the Reasons for Geographic and Racial Differences in Stroke Study (REGARDS)
Authors: Matthew L Harris, Erica Bennion, Kristine MaWhinney, Virginia J Howard, Virginia G Wadley, Leslie A McClure, Deborah A Levine, Jennifer J Manly, Maria M Glymour, Jonathan J Wisco, Robert A Chaney, Evan L Thacker
Journal: Circulation (2019)

Objective: To estimate the association of rural vs urban living in the United States (US) with incident cognitive impairment (ICI), and to assess confounding, mediation, and effect heterogeneity by demographic, social, behavioral, and clinical risk factors. Methods: REGARDS is a cohort of 30,239 adults aged 45+ in the 48 contiguous states. We analyzed 20,592 participants who at baseline (2003-2007) were cognitively intact with no history of stroke and had cognition assessed an average of 7.1 years later. We used Rural-Urban Commuting Area (RUCA) codes to classify participants as urban (n = 16,436), large city/town (n = 2,420), or small/isolated rural (n = 1,736) at baseline. We defined ICI as falling ≥1.5 SD below the mean on at least two of three cognitive tests administered during follow-up: word list learning, word list delayed recall, and animal naming. Using urban as the referent, we estimated odds ratios of ICI for rural and for large city/town. Results: ICI occurred in 1,291 participants (6.3%). Rural residents had 49% higher odds of ICI adjusted for confounding by demographics (Model 2 in Table, OR = 1.49 [95% CI: 1.19, 1.85]). After further adjusting for potential mediators (Models 3-6), odds of ICI remained 25% higher for rural vs urban (Model 6, OR = 1.25 [0.99, 1.56]). In assessing effect heterogeneity, we found synergism of rural dwelling with black race, physical inactivity, and low self-rated health (all P &lt; 0.1; see ORs in Table), but not for other ICI risk factors. We found no difference in ICI for large city/town vs urban (demographics-adjusted OR = 1.08 [0.88, 1.33]; fully adjusted OR = 0.95 [0.77, 1.18]), and no effect heterogeneity of ICI risk factors by large city/town (all P &gt; 0.2). Conclusion: Rural living is an important social determinant of cognitive health in the US. ICI was significantly more frequent among rural dwellers than urban dwellers, partly due to confounding or mediation by ICI risk factors. Odds of ICI were highest for rural dwelling combined with black race, physical inactivity, or low self-rated health.
Genomic alterations to predict response to irinotecan-based chemotherapy in metastatic colorectal cancer.
Authors: Christelle De La Fouchardiere, Xiaojun Jiang, Daniel Pissaloux, Christelle Seigne, Qing Wang, Françoise Desseigne, Marie-Eve Fondrevelle, Philippe Alexandre Cassier, Valéry Attignon, Valérie Combaret, David Pérol, Olivier Tredan, Jean-Yves Blay
Journal: Journal of Clinical Oncology (2015)

586 Background: No evidence exists concerning the superiority of oxaliplatin versus irinotecan-based chemotherapy for metastatic colorectal cancer. The choice is currently made by the clinicians according to awaited toxicity and association with targeted therapy. The correlation between response to chemotherapy (oxaliplatin and irinotecan containing regimens) and genomic alterations was investigated in metastatic colorectal cancer patients included in the ProfiLER protocol (NCT 02029001). Methods: From 03/2013 to 03/2014, 62 patients with metastatic colorectal cancer were included in the ProfiLER trial. Tumor samples were analyzed for mutations/insertions/deletions and copy number variations using target high-throughput sequencing (NGS) and comparative genomic hybridization array (CGH). Clinical data were collected retrospectively. We defined irinotecan and/or oxaliplatin responders as patients having CR, PR, SD as best response and non-responders as those having PD as best response. Results: 50/62 tumor samples fulfilled DNA quality requirements. CGH was feasible in 40 patients (64.5%). Among these 40 patients, 36 received oxaliplatin and irinotecan. None of the genomic alterations correlated to response to oxaliplatin. Conversely, analysis of the CGH and NGS data revealed different genomic alterations of tumors in patients receiving Irinotecan, allowing the separation between Irinotecan responders (IriR, n=27) and non-responders (IriNR, n=9) (Table). Conclusions: Specific genomic alterations of CRC cells seem to be associated with responses to systemic combination Irinotecan based-chemotherapy, including high GI, specific chromosomal gains, and tyrosine kinases mutations. A prospective validation of the CGH profile is planned and definitive results will be presented at the meeting. Clinical trial information: NCT 02029001. [Table: see text]
Dose-escalation of the first-in human phase I/Ib study of ABTL0812, a novel antitumor drug inhibiting the Akt/mTOR pathway in patients with advanced solid tumors.
Authors: Laura Vidal Boixader, Lydia Gaba, Iván Victoria, Merce Brunet, Pilar Paredes, Elvira Buxo, Teresa Vilella, Gisela Riu, Marc Cortal, Mariana Gomez-Ferreria, Jose Alfon, Carles Domenech, Pedro Gascon
Journal: Journal of Clinical Oncology (2015)

2585 Background: ABTL0812 is a novel drug with reported preclinical activity in several tumor types. In vitro and in vivo assays have shown that ABTL0812 is an inhibitor of the Akt/mTOR pathway by a novel mechanism of action. Methods: A Phase I/Ib First in Human (FiH) clinical trial started on February 2014 (NCT02201823) in which patients with solid tumors and no standard treatment were enrolled. ABTL0812 was administered daily, by the oral route in 28-day cycles. The primary objective of the trial was to obtain a maximum tolerated dose and a recommended phase II dose (RP2D). The secondary objectives of the trial were assessment of dose-limiting toxicity (DLT), response rate, progression-free survival and overall survival. Pharmacokinetic (days 1 and 29) and pharmacodynamic (inhibition of the phosphorylation of Akt in platelets at day 29 vs. predose, as biomarker) end-points were also introduced. The study design consisted in a 3+3 dose escalation with up to five cohorts. An expansion phase with 12 patients is planned. Results: The dose-escalation, in which 15 patients were recruited, started at 500 mg/day and was completed in December 2014 at 4,000 mg/day. ABTL0812 showed overall a good safety profile. Grade 1-2 adverse events included swallowing disturbance, asthenia, increase of hepatic enzymes, hyperglycemia and nausea; grade > 2 adverse events were rare and included anemia and asthenia. No DLTs were observed and therefore, RP2D has been determined as 1,300 mg tid by pharmacokinetic-pharmacodynamic modeling of drug plasma concentrations at steady state vs. platelet pAkt inhibition. One patient with endometrial cancer and one patient with sigmoid colon cancer currently show stable disease (SD) after 10 and 5 months of treatment, respectively. Conclusions: RP2D of ABTL0812 has been determined. ABTL0812 has demonstrated a good safety profile, with only mild adverse events. Additionally, ABTL0812 has shown activity on biomarkers, and hints of activity in two patients presenting prolonged SD. Clinical trial information: NCT02201823.
First-in-human phase I trial of the PI3Kb-selective inhibitor SAR260301 in patients with advanced solid tumors (NCT01673737).
Authors: Philippe L. Bedard, Michael A. Davies, Scott Kopetz, Keith T. Flaherty, Geoffrey Shapiro, Jason John Luke, Anna Spreafico, Bin Wu, Corinne Gomez, Sylvaine Cartot-Cotton, Florent Mazuir, Sandrine Micallef, Brigitte Demers, Dejan Juric
Journal: Journal of Clinical Oncology (2015)

2564 Background: SAR260301 (SAR) is a potent (IC50 52 nM) PI3Kb inhibitor selectively inhibiting the PI3K pathway in PTEN-null models. This phase I Sanofi sponsored study was initiated to evaluate SAR maximum tolerated dose (MTD), overall safety, pharmacokinetics (PK), pharmacodynamics (PD) and preliminary antitumor activity in patients with advanced solid tumors. Methods: Patients (pts) with locally advanced/metastatic solid tumors, ECOG PS ≤ 1, and adequate organ function were eligible. PTEN was evaluated in archival tissue by IHC. SAR was orally administered fasted in 28-day cycles. Dose escalation used an overdose control Bayesian strategy. Serial PK sampling was performed on Days 1 and 28 of Cycle (C) 1, and at C2 for food effect evaluation (n = 6). Platelet phospho-AKT (pAKT) was assessed at pre- and post-SAR for PD by MesoScale Discovery. Physiologically based PK modelling (PBPK) was used for exposure predictions. Results: 21 pts were treated at 6 dose levels from 100 mg QD to 800 mg BID. The MTD was not reached. Two DLTs were observed: Gr 3 pneumonitis (400 mg BID) and Gr 3 increase in GGT (600 mg BID). No other Gr ≥ 3 related AE was reported. The most frequent related AEs ( ≥ 3 pts): nausea (3), vomiting (3), and diarrhea (3). SAR absorption was rapid (tmax 0.5-1.5h) and showed a biphasic elimination profile with a rapid decrease in concentration after Cmax. No significant accumulation or deviation from dose proportionality was observed. Cmax and AUCtau decreased respectively by 56% and 22% with food. Maximal inhibition of pAKT/tAKT in platelets correlated with exposure at steady state; Cmax thresholds for 60% & 80% inhibition were respectively ~ 7 & ~11 µM. Concentrations > 7 µM were reached in 3 pts but for no longer than 2h out of 24h. The PBPK model predicted that doses > 1.2g BID would be needed to reach concentrations sufficient to maintain PD effect between doses. No objective response were documented in this study (3 of 21 pts had PTEN-null disease). Conclusions: SAR has an acceptable safety profile at pharmacologically active doses. However, the rapid clearance of SAR does not allow for sustained pathway inhibition that is required for anti-tumor activity in preclinical models. Clinical trial information: NCT01673737.