tbuckley/cabot-search huggingface dataset:
p95HER2 Methionine 611 Carboxy-Terminal Fragment Is Predictive of Trastuzumab Adjuvant Treatment Benefit in the FinHer Trial
Authors: Jeff Sperinde, Weidong Huang, Aki Vehtari, Ahmed Chenna, Pirkko-Liisa Kellokumpu-Lehtinen, John Winslow, Petri Bono, Yolanda S. Lie, Christos J. Petropoulos, Jodi Weidler, Heikki Joensuu
Journal: Clinical Cancer Research (2018)

Abstract Purpose: Expression of p95HER2 (p95), a truncated form of the HER2 receptor, which lacks the trastuzumab binding site but retains kinase activity, has been reported as a prognostic biomarker for poor outcomes in patients with trastuzumab-treated HER2-positive metastatic breast cancer. The impact of p95 expression on trastuzumab treatment efficacy in early HER2-positive breast cancer is less clear. In the current study, p95 was tested as a predictive marker of trastuzumab treatment benefit in the HER2-positive subset of the FinHer adjuvant phase III trial. Experimental Design: In the FinHer trial, 232 patients with HER2-positive early breast cancer were randomized to receive chemotherapy plus 9 weeks of trastuzumab or no trastuzumab treatment. Quantitative p95 protein expression was measured in formalin-fixed paraffin-embedded samples using the p95 VeraTag assay (Monogram Biosciences), specific for the M611 form of p95. Quantitative HER2 protein expression was measured using the HERmark assay (Monogram Biosciences). Distant disease-free survival (DDFS) was used as the primary outcome measure. Results: In the arm receiving chemotherapy only, increasing log10(p95) correlated with shorter DDFS (HR, 2.0; P = 0.02). In the arm receiving chemotherapy plus trastuzumab (N = 95), increasing log10(p95) was not correlated with a shorter DDFS. In a combined analysis of both treatment arms, high breast tumor p95 content was significantly correlated with trastuzumab treatment benefit in multivariate models (interaction P = 0.01). Conclusions: A high p95HER2/HER2 ratio identified patients with metastatic breast cancer with poor outcomes on trastuzumab-based therapies. Further investigation of the p95HER2/HER2 ratio as a potential prognostic or predictive biomarker for HER2-targeted therapy is warranted. Clin Cancer Res; 24(13); 3046–52. ©2018 AACR.
SINGLE NUCLEOTIDE POLYMORPHISMS AT THE HMGCR GENE LOCUS SIGNIFICANTLY PREDICT TOTAL MORTALITY IN ANGIOGRAPHIED CORONARY PATIENTS WITH THE METABOLIC SYNDROME
Authors: Andreas Leiherer, Axel Muendlein, Christoph Saely, Philipp Rein, Alexander Vonbank, Peter Fraunberger, Heinz Drexel
Journal: Journal of the American College of Cardiology (2018)
Comparative Toxicities and Cost of Intensity-Modulated Radiotherapy, Proton Radiation, and Stereotactic Body Radiotherapy Among Younger Men With Prostate Cancer
Authors: Hubert Y. Pan, Jing Jiang, Karen E. Hoffman, Chad Tang, Seungtaek L. Choi, Quynh-Nhu Nguyen, Steven J. Frank, Mitchell S. Anscher, Ya-Chen Tina Shih, Benjamin D. Smith
Journal: Journal of Clinical Oncology (2018)

Purpose To compare the toxicities and cost of proton radiation and stereotactic body radiotherapy (SBRT) with intensity-modulated radiotherapy (IMRT) for prostate cancer among men younger than 65 years of age with private insurance. Methods Using the MarketScan Commercial Claims and Encounters database, we identified men who received radiation for prostate cancer between 2008 and 2015. Patients undergoing proton therapy and SBRT were propensity score–matched to IMRT patients on the basis of clinical and sociodemographic factors. Proportional hazards models compared the cumulative incidence of urinary, bowel, and erectile dysfunction toxicities by treatment. Cost from a payer’s perspective was calculated from claims and adjusted to 2015 dollars. Results A total of 693 proton therapy patients were matched to 3,465 IMRT patients. Proton therapy patients had a lower risk of composite urinary toxicity (33% v 42% at 2 years; P &lt; .001) and erectile dysfunction (21% v 28% at 2 years; P &lt; .001), but a higher risk of bowel toxicity (20% v 15% at 2 years; P = .02). Mean radiation cost was $115,501 for proton therapy patients and $59,012 for IMRT patients ( P &lt; .001). A total of 310 SBRT patients were matched to 3,100 IMRT patients. There were no significant differences in composite urinary, bowel, or erectile dysfunction toxicities between SBRT and IMRT patients ( P &gt; .05), although a higher risk of urinary fistula was noted with SBRT (1% v 0.1% at 2 years; P = .009). Mean radiation cost for SBRT was $49,504 and $57,244 for IMRT ( P &lt; .001). Conclusion Among younger men with prostate cancer, proton radiation was associated with significant reductions in urinary toxicity but increased bowel toxicity at nearly twice the cost of IMRT. SBRT and IMRT were associated with similar toxicity profiles; SBRT was modestly less expensive than IMRT.
Reply to Pirus Ghadjar and Thomas Wiegel's Letter to the Editor re: Daniel E. Spratt, Robert T. Dess, Zachary S. Zumsteg, et al. A Systematic Review and Framework for the Use of Hormone Therapy with Salvage Radiation Therapy for Recurrent Prostate Cancer. Eur Urol 2018;73:156–65
Authors: Daniel E. Spratt, Robert T. Dess, Felix Y. Feng
Journal: European Urology (2017)
PREFERENCES AND ATTITUDES OF YOUNG CHINESE CLINICIANS ABOUT USING A SHARED DECISION MAKING TOOL FOR CARDIOVASCULAR RISK COMMUNICATION
Authors: Rongchong Huang, Xiantao Song, Dongfeng Zhang, Jiaying Xu, Kasey R. Boehmer, Aaron A. Leppin, Michael Gionfriddo, Henry H. Ting, Victor Montori
Journal: Journal of the American College of Cardiology (2018)
Doctors should state clearly that vaping is much lower risk than smoking, says report
Authors: Jacqui Wise
Journal: BMJ (2018)

E-cigarettes pose only a small fraction of the risk of smoking, and encouraging smokers to switch completely to vaping would produce substantial health benefits, says a review of the evidence commissioned for Public Health England.1

The review, written by an independent panel of experts, says that under half of adults in Britain think that e-cigarettes are less harmful than smoking. This falls to a third among smokers who have never tried e-cigarettes.

Health professionals should tell smokers clearly that “vaping is at least 95% less harmful than smoking” to communicate the large difference in relative risk unambiguously and to encourage more smokers to make the switch, the report says.

Public Health England says that compelling evidence shows …
Human Tissue Models: Engineering 3D Hydrogels for Personalized In Vitro Human Tissue Models (Adv. Healthcare Mater. 4/2018)
Authors: Chya‐Yan Liaw, Shen Ji, Murat Guvendiren
Journal: Advanced Healthcare Materials (2018)

The use of hydrogel scaffolds for developing in vitro patient-specific tissue and organ models using human-derived cells is a powerful platform for studying the mechanism of disease initiation and progression, screening of potential drug candidates, and ultimately, the regeneration of fully functional tissues and organs. In article number 1701165, Murat Guvendiren and co-workers review the current developments in hydrogel-based in vitro tissue models and fabrication techniques, with particular focus on liver and cancer tissues.
Oral Anticoagulation in Very Elderly Patients With Atrial Fibrillation
Authors: Tze-Fan Chao, Chia-Jen Liu, Yenn-Jiang Lin, Shih-Lin Chang, Li-Wei Lo, Yu-Feng Hu, Ta-Chuan Tuan, Jo-Nan Liao, Fa-Po Chung, Tzeng-Ji Chen, Gregory Y.H. Lip, Shih-Ann Chen
Journal: Circulation (2018)

Stroke prevention with oral anticoagulants (OACs) is the cornerstone for the management of atrial fibrillation (AF). However, data about the use of OACs among patients ≥90 years of age are limited. We aimed to investigate the risk of ischemic stroke and intracranial hemorrhage (ICH) and the net clinical benefit of OAC treatment for very elderly patients with AF (≥90 years of age).This study used the National Health Insurance Research Database in Taiwan. Risks of ischemic stroke and ICH were compared between 11 064 and 14 658 patients with and without AF ≥90 years of age without antithrombotic therapy from 1996 to 2011. Patients with AF (n=15 756) were divided into 3 groups (no treatment, antiplatelet agents, and warfarin), and the risks of stroke and ICH were analyzed. The risks of ischemic stroke and ICH were further compared between patients treated with warfarin and nonvitamin K antagonist OACs (NOACs) from 2012 to 2015 when NOACs were available in Taiwan.Compared with patients without AF, patients with AF had an increased risk of ischemic stroke (event number/patient number, incidence = 742/11 064, 5.75%/y versus 1399/14 658, 3.00%/y; hazard ratio, 1.93; 95% confidence interval, 1.74-2.14) and similar risk of ICH (131/11 064, 0.97%/y versus 206/14 658, 0.54%/y; hazard ratio, 0.85; 95% confidence interval, 0.66-1.09) in competing risk analysis for mortality. Among patients with AF, warfarin use was associated with a lower stroke risk (39/617, 3.83%/y versus 742/11 064, 5.75%/y; hazard ratio, 0.69; 95% confidence interval, 0.49-0.96 in a competing risk model), with no difference in ICH risk compared with nontreatment. When compared with no antithrombotic therapy or antiplatelet drugs, warfarin was associated with a positive net clinical benefit. These findings persisted in propensity-matched analyses. Compared with warfarin, NOACs were associated with a lower risk of ICH (4/978, 0.42%/y versus 19/768, 1.63%/y; hazard ratio, 0.32; 95% confidence interval, 0.10-0.97 in a competing risk model), with no difference in risk of ischemic stroke.Among patients with AF ≥90 years of age, warfarin was associated with a lower risk of ischemic stroke and positive net clinical benefit. Compared with warfarin, NOACs were associated with a lower risk of ICH. Thus, OACs may still be considered as thromboprophylaxis for elderly patients, with NOACs being the more favorable choice.
Cancer-testis specific gene OIP5: a downstream gene of E2F1 that promotes tumorigenesis and metastasis in glioblastoma by stabilizing E2F1 signaling
Authors: Jiang He, Yuzu Zhao, Erhu Zhao, Xianxing Wang, Zhen Dong, Yibiao Chen, Liqun Yang, Hongjuan Cui
Journal: Neuro-Oncology (2018)

The cancer-testis specific gene Opa interacting protein 5 (OIP5) is reactivated in many human cancers, but its functions in glioblastoma remain unclear. Here, we assessed the significance of OIP5 in the tumorigenesis and metastasis of glioblastoma for the first time.An immunohistochemistry assay was performed to detect OIP5 expression changes in glioblastoma patients. Overall survival analysis was performed to evaluate the prognostic significance of OIP5. Growth curve, colony formation, and transwell assays were used to analyze cell proliferation and metastasis. Tumorigenicity potential was investigated in orthotopic tumor models, and immunoprecipitation, chromatin immunoprecipitation, and luciferase assays were employed to explore the mechanisms underlying the activation of OIP5 expression by E2F transcription factor 1 (E2F1) to stabilize and maintain E2F1 signaling.OIP5 was found to be upregulated in glioblastoma patients and to impair patient survival, and the increased expression of OIP5 was positively correlated with tumor stage. Compared with short hairpin green fluorescent protein cells, cells in which OIP5 was knocked down exhibited significantly reduced proliferation, metastasis, colony formation, and tumorigenicity abilities, whereas OIP5 recovery enhanced these abilities. OIP5 was highly correlated with cell cycle progression but had no obvious effects on apoptosis. Notably, we demonstrated a feedback loop in which E2F1 activates the expression of OIP5 to stabilize and maintain E2F1 signaling and promote the E2F1-regulated gene expression that is required for aggressive tumor biology.Collectively, our findings demonstrate that OIP5 promotes glioblastoma progression and metastasis, suggesting that OIP5 is a potential target for anticancer therapy.
Disseminated Asymptomatic Papules Over the Body
Authors: Ruojun Wang, Zhimiao Lin
Journal: JAMA Dermatology (2018)

A woman in her 30s had a 15-year history of generalized asymptomatic papules on her arms, trunk, legs, neck, and face; examination revealed skin-colored to red-brown papules distributed over her trunk, extremities, neck, forehead, and periocular regions. What is your diagnosis?
Gut microbiota modify risk for dietary glycemia-induced age-related macular degeneration
Authors: Sheldon Rowan, Allen Taylor
Journal: Gut Microbes (2018)

Age-related macular degeneration (AMD) is a leading cause of blindness world-wide. Although the etiology of AMD is multifactorial, diet and nutrition have strong epidemiologic associations with disease onset and progression. Recent studies indicate a role for gut microbiota in development of AMD in mouse models and in some forms of human AMD. We previously found that consuming lower glycemia diets is associated with protection against AMD in humans and switching from higher to lower glycemia diets arrests AMD phenotypes in mice. Gut microbiota populations and circulating microbial cometabolites were altered in response to dietary carbohydrates, indicating a gut-retina axis. Here we explore additional gut microbiota-AMD interactions that point toward pathogenic roles for some gut microbiota families, including Ruminococcaceae and Lachnospiraceae, and individual members of Turicibacteraceae, Clostridiaceae, and Mogibacteriaceae. We also speculate on potential mechanisms by which gut microbiota influence AMD, with the objective of devising new AMD diagnoses and treatments.
Improved identification of thrombolysis candidates amongst intermediate-risk pulmonary embolism patients: implications for future trials
Authors: Stefano Barco, Eric Vicaut, Frederikus A. Klok, Mareike Lankeit, Guy Meyer, Stavros V. Konstantinides
Journal: European Respiratory Journal (2018)

Contemporary classification of acute pulmonary embolism (PE) severity is based on the risk of early death, which is influenced by demographic factors, comorbidity, and the functional status of the right ventricle (RV) under acute pressure overload [1]. Shock or persistent arterial hypotension, indicating overt RV failure at presentation, has long been identified as a key determinant of poor prognosis [2] and represents the only widely accepted indication for (systemic) thrombolytic therapy to date [3]. In contrast, for normotensive patients who present with imaging findings that indicate RV dysfunction and biochemical evidence of myocardial injury, anticoagulation remains the primary treatment option [3, 4]. This recommendation is supported by the Pulmonary Embolism Thrombolysis (PEITHO) trial, which showed that patients fulfilling these latter criteria were unlikely to derive a net clinical benefit from routine use of systemic thrombolysis in view of the high risk for major bleeding [5]. Defining a "higher-risk" population among intermediate-risk patients with pulmonary embolism included in PEITHO <http://ow.ly/JM7u30hcSgN>
Starting as second on-call in obstetrics and gynaecology without UK work experience
Authors: R Rajagopal
Journal: BMJ (2006)

Starting a career in obstetrics and gynaecology in the United Kingdom as second on-call is a challenging task, however much experience you have had in your own country. You might think that surgical techniques are the same anywhere, so why should there be any problems? Surgical techniques may be the same, but things are organised differently especially in emergency obstetrics. Here are a few tips.
Correlation of patient characteristics and biomarkers with clinical outcomes of JCAR017 in R/R aggressive B-NHL (TRANSCEND NHL 001 study).
Authors: Tanya Siddiqi, Jeremy S. Abramson, Maria Lia Palomba, Leo I. Gordon, Matthew Alexander Lunning, Jon E. Arnason, Michael Wang, Andres Forero-Torres, David G. Maloney, Mark Heipel, Jeffrey Smith, William Brown, Mandana Karimi, Benhuai Xie, Daniel Li, Tina Albertson, Jacob Garcia, Kedar Dave, Todd DeVries, Claire Sutherland
Journal: Journal of Clinical Oncology (2018)

122 Background: JCAR017 is a defined composition, CD19-directed 4-1BB CAR T cell product administered at a precise dose of CD8 and CD4 CAR T cells in a seamless design Ph1 pivotal trial of R/R B-cell NHL (TRANSCEND NHL 001; NCT02631044). Methods: Blood samples were collected for biomarker analyses at protocol-defined time points. PK (CAR T cell expansion and persistence) was measured using flow cytometry. Cytokines were measured on a Luminex platform. Additional analytes will be presented. All reported p-values are 2-sided without multiplicity adjustment. Results: Safety (n = 59) and efficacy (n = 54) outcomes were analyzed for correlations with patient (pt) characteristics and biomarkers. Dose level did not correlate with cytokine release syndrome (CRS) or neurotoxicity (NT) despite higher median C max and median AUC 0-28 at DL2. In pts with NT or ≥Gr 2 CRS, CD4 and CD8 CAR T cell levels were 5-10 fold and 3-5 fold higher, respectively, than median DL2 levels. Pt factors that correlated with any grade CRS and NT were ECOG 2 (p = 0.03) and high disease burden (p &lt; 0.05). Higher levels of IL-8, IL-10, and CXCL10 before CART cell infusion were associated with Gr 3-4 NT (each p&lt; 0.05), suggesting that inherent pt factors may result in higher CAR T expansion and associated CRS and NT. Lower pre-CAR T cell ferritin, LDH, CXCL10, G-CSF, and IL-10 were associated with CR/PR, and lower pre-CAR T cell ferritin, CRP, LDH, CXCL10, IL-8, IL-10, IL-15, MCP-1, MIP-1β, TNF-α were associated with 3-month durable response (each p&lt; 0.05). Median C max and AUC 0-28 of CD8 CAR T cells were higher in responding patients and with durable response at Month 3 (CD8 C max median = 20.8 vs 5.5; CD8 AUC median = 235 vs 55 in CR/PR vs PD at Month 3). Of pts evaluable for persistence at 3 months (n = 29), 90% and 93% had detectable CD8+ and CD4+ CAR+ T cells; of those with available PK results at time of relapse (n = 11), 82% had persistence at time of relapse. Conclusions: JCAR017 demonstrated increased CAR T cell expansion and persistence and higher durability of response at higher dose levels, with manageable toxicities. CAR T cells were also detected at time of relapse, suggesting potential opportunities for future combination clinical trials. Clinical trial information: NCT02631044.
Dissection of Bmi1-mediated epigenetic regulation of target genes in glioblastoma
Authors: Barbara Ricci, Loredana Guglielmi, Michael Barnes, Silvia Marino
Journal: Neuro-Oncology (2018)

Glioblastoma multiforme (GBM) is the most malignant adult brain tumour. Recent studies on gliomagenesis have provided new insights into the genomic and epigenomic landscape of this disease. Particular interest has been focused on the Polycomb group proteins (PcG), which are chromatin modifiers regulating heritable gene repression. Our previous data has shown that overexpression of the PcG gene Bmi1 in mouse embryonic neural stem cells (NSCBmi1Over) increases self-renewal and proliferation without inducing neoplastic transformation.However, repression of Bmi1 in patient-derived GBM initiating cells (GBM-IC) and in a mouse model of GBM, impairs both self-renewal and proliferation, demonstrating that Bmi1 plays a crucial role in tumour maintenance. In genome wide transcriptomic and histone modification analysis we identified 180 genes specifically deregulated in mouse GBM-IC overexpressing Bmi1 as compared to mouse NSC. Ingenuity Pathway Analysis (IPA) revealed a significant enrichment in canonical pathways such as axonal guidance and Eph/ephrin signalling with a similar signature found in publicly available human GBM-IC ChIPSeq data. Functional assays in vitro demonstrated that EfnA5 is a direct target of Bmi1 that mediates Bmi1 impact on cell morphology, proliferation and migration in murine GBM-IC. Taken together, these data suggest EfnA5 as a potential druggable target in GBM overexpressing Bmi1.
Farnesoid X receptor signaling activates the hepatic X‐box binding protein 1 pathway in vitro and in mice
Authors: Xiaoying Liu, Grace L. Guo, Bo Kong, David B. Hilburn, Susan C. Hubchak, Seong Park, Brian LeCuyer, Antony Hsieh, Li Wang, Deyu Fang, Richard M. Green
Journal: Hepatology (2018)

Bile acids are endogenous ligands of the nuclear receptor, farnesoid X receptor (FXR), and pharmacological FXR modulators are under development for the treatment of several liver disorders. The inositol-requiring enzyme 1α/X-box binding protein 1 (IRE1α/XBP1) pathway of the unfolded protein response (UPR) is a protective cellular signaling pathway activated in response to endoplasmic reticulum (ER) stress. We investigated the role of FXR signaling in activation of the hepatic XBP1 pathway. Mice were treated with deoxycholic acid (DCA), cholestyramine, GW4064, or underwent bile duct ligation (BDL), and hepatic UPR activation was measured. Huh7-Ntcp and HepG2 cells were treated with FXR agonists, inhibitor, small interfering RNA (siRNA), or small heterodimer partner (SHP) siRNA to determine the mechanisms of IRE1α/XBP1 pathway activation. DCA feeding and BDL increased and cholestyramine decreased expression of hepatic XBP1 spliced (XBP1s). XBP1 pathway activation increased in Huh7-Ntcp and HepG2 cells treated with bile acids, 6α-ethyl-chenodeoxycholic acid (6-ECDCA) or GW4064. This effect decreased with FXR knockdown and treatment with the FXR inhibitor guggulsterone. FXR agonists increased XBP1 splicing and phosphorylated IRE1α (p-IRE1α) expression. Overexpression of SHP similarly increased XBP1 splicing, XBP1s, and p-IRE1α protein expression. SHP knockdown attenuated FXR agonist-induced XBP1s and p-IRE1α protein expression. Co-immunoprecipitation (Co-IP) assays demonstrate a physical interaction between overexpressed green fluorescent protein (GFP)-SHP and FLAG-IRE1α in HEK293T cells. Mice treated with GW4064 had increased, and FXR and SHP null mice had decreased, basal Xbp1s gene expression. FXR signaling activates the IRE1α/XBP1 pathway in vivo and in vitro. FXR pathway activation increases XBP1 splicing and enhances p-IRE1α expression. These effects are mediated, at least in part, by SHP. IRE1α/XBP1 pathway activation by bile acids and pharmacological FXR agonists may be protective during liver injury and may have therapeutic implications for liver diseases. (Hepatology 2018;68:304-316).
FDA Approval: Gemtuzumab Ozogamicin for the Treatment of Adults with Newly Diagnosed CD33-Positive Acute Myeloid Leukemia
Authors: Emily Y. Jen, Chia-Wen Ko, Jee Eun Lee, Pedro L. Del Valle, Antonina Aydanian, Charles Jewell, Kelly J. Norsworthy, Donna Przepiorka, Lei Nie, Jiang Liu, Christopher M. Sheth, Marjorie Shapiro, Ann T. Farrell, Richard Pazdur
Journal: Clinical Cancer Research (2018)

On September 1, 2017, the FDA granted approval for gemtuzumab ozogamicin (Mylotarg; Pfizer Inc.) in combination with daunorubicin and cytarabine and as a monotherapy for the treatment of adult patients with newly diagnosed CD33-positive acute myeloid leukemia (AML). Gemtuzumab ozogamicin is a CD33-targeted antibody-drug conjugate joined to calicheamicin. Approval of gemtuzumab ozogamicin combination treatment was based on a randomized trial of 271 patients with newly diagnosed AML treated with daunorubicin and cytarabine with or without 3 mg/m2 fractionated gemtuzumab ozogamicin, which resulted in an event-free survival (EFS) of 13.6 months for gemtuzumab ozogamicin + daunorubicin and cytarabine and 8.8 months for daunorubicin and cytarabine alone [HR = 0.68 (95% confidence interval (CI), 0.51-0.91)]. Hemorrhage, prolonged thrombocytopenia, and veno-occlusive disease were serious toxicities that were more common in patients treated with gemtuzumab ozogamicin + daunorubicin and cytarabine. Approval of gemtuzumab ozogamicin monotherapy was based on a randomized trial of 237 patients with newly diagnosed AML treated without curative intent. Median overall survival (OS) was 4.9 months with gemtuzumab ozogamicin versus 3.6 months on best supportive care [HR = 0.69 (95% CI, 0.53-0.90)]. Adverse events were similar on both arms. Postapproval, several studies are required including evaluation of fractionated gemtuzumab ozogamicin pharmacokinetics, safety of combination gemtuzumab ozogamicin in the pediatric population, immunogenicity, and the effects of gemtuzumab ozogamicin on platelet function. Clin Cancer Res; 24(14); 3242-6. ©2018 AACR.