tbuckley/cabot-search huggingface dataset:
Phase I study of ACE-041, a novel inhibitor of vascular maturation, in patients with advanced solid tumors or relapsed/refractory multiple myeloma.
Authors: N. G. Borgstein, S. Sharma, J. C. Bendell, M. S. Gordon, H. Hurwitz, N. Solban, D. Mitchell, S. Pearsall, C. H. Condon, M. L. Sherman
Journal: Journal of Clinical Oncology (2010)

TPS179 Background: Activin receptor-like kinase 1 (ALK1) is a type I receptor belonging to the TGFβ superfamily of proteins that is transiently expressed on arterial endothelial cells during development and in response to injury or disease (Seki et al. Circ. Res. 2003). ALK1 signaling plays a pivotal role in the maturation phase of angiogenesis and is therefore critical to vasculature development. ACE-041 is a soluble receptor fusion protein consisting of the ligand-binding extracellular domain of human ALK1 linked to a human IgG1-Fc region. ACE-041 binds with high affinity to BMP9 and BMP10 but does not bind to either TGFβ1, 2 or 3; VEGF or bFGF. By inhibiting their interaction with ALK1, ACE-041 blocks ALK1-mediated signaling, prohibiting vascular endothelial cell maturation and further vascular development. Unlike other angiogenesis inhibitors that act on the initial proliferative phase, ACE-041 blocks a critical and convergent step in the maturation phase of angiogenesis. In vitro and in vivo studies demonstrated that ACE-041 inhibited vascular maturation regardless of which growth factor triggered the proliferative phase (e.g., VEGF, bFGF). ACE-041 has also been shown to inhibit tumor vascular development, resulting in potent antitumor activity in a variety of solid and hematological tumor models (Mitchell et al., MCT 2010, in press). Methods: A phase I study of ACE-041 is ongoing in the United States to evaluate the safety, tolerability, pharmacokinetics, and anti- tumor activity of ACE-041 in patients with advanced solid tumors or relapsed/refractory multiple myeloma. Cohorts of 3 to 6 patients will be enrolled at escalating dose levels and will receive ACE-041 subcutaneously once every 3 weeks for a total of 4 doses or until disease progression. Dose escalation is determined following review of safety data through 21 days from at least 3 patients at each dose level. The safety and efficacy data from this phase I first-in-human study of ACE-041 will be evaluated to plan additional monotherapy and combination studies in patients with solid tumors and hematologic malignancies. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Acceleron Pharma Acceleron Pharma Acceleron Pharma Acceleron Pharma
Integrated transcriptomic and proteomic analyses uncover regulatory roles of Nrf2 in the kidney
Authors: Luke M. Shelton, Adam Lister, Joanne Walsh, Rosalind E. Jenkins, Michael H.L. Wong, Cliff Rowe, Emanuele Ricci, Lorenzo Ressel, Yongxiang Fang, Philippe Demougin, Vanja Vukojevic, Paul M. O'Neill, Christopher E. Goldring, Neil R. Kitteringham, B. Kevin Park, Alex Odermatt, Ian M. Copple
Journal: Kidney International (2015)
한국인 만성 B 형 간염 바이러스 감염에서 B 형 간염 바이러스 유전자형의 분포
Authors: 이숭환(Soong Hwan Lee), 한성희(Sung Hee Han), 조승철(Seung Chul Cho), 노병주(Byung Joo Roh), 손주현(Joo Hyun Sohn), 김덕언(Duck An Kim), 이동후(Dong Hoo Lee), 기춘석(Choon Suhk Kee)
Journal: Clinical and Molecular Hepatology (2001)

Background / Aims : Choronic HBV infection is associated with a wide spectrum of clinical manifestations, including asymptomatic carrier state, choronic hepatitis, liver cirrhosis, and hepatocellular carcinoma. Genotypically, HBV genomes have been calssified into seven groups, designated A to G. Several studies have suggested recently that HBV genotypic difference influence the severity of liver disease and clinical outcomes. The distribution of HBV genotypes in Korea and its clinical relevance are poorly understood. We investigated the prevalence of HBV genotypes in Korea and the association between the distinct genotypes and the severity of liver disease. Methods : A total of 214 HBV-DNA positive serum samples, were used for the genotyping. All patients were HBV-bDNA positive chronic HBsAg carries. 199 patients were histologically verified with liver cirrhosis(6), chronic hepatitis(192) and fatty liver(1). The other patients were clinically diagnosed with liver cirrhosis(13) or hepatocelluar carcinoma(2). HBV genotype was determined by PCR using type-specific primers. Results : Genotyping was possible in all patients. Out of 214 patients, 213(99.5%) were HBV genotype C. Only one(0.5%) was genotype A, The patient with genotype A had minimal hepatitis as diagnosed by liver biopsy. Conclusions : These results indicate that almost all chronic HBV infections are genotype C in Korea. HBV grnoytpic difference therefore dose not influence the clinical outcome of HBV infection in Korea. Because genotype C may be associated with more severe liver disease, the predominance of genotype C in Korea may result in more severe outcomes than in other countries where other genotypes are predominant
Abstract MP010: Body Mass Index and Stroke Incidence in Japanese Elderly Men
Authors: Kozo Tanno, Toru Kuribayashi, Masaki Ohsawa, Toshiyuki Onoda, Kazuyoshi Itai, Kiyomi Sakata, Motoyuki Nakamura, Shinichi Omama, Kuniaki Ogasawara, Yasuhiro Ishibashi, Akira Okayama
Journal: Circulation (2012)

Objective: To examine the association between body mass index (BMI) and incident stroke in Japanese elderly men. Methods: A total of 4743 men and aged 65 years and over (mean age, 72 years) who had no history of stroke or myocardial infarction were followed up prospectively for 5.4 years. Stroke events were identified by accessing the Iwate Stroke Registry. Participants were classified into 6 groups according to BMI (kg/m 2 ): less than 18.5, 18.5–20.9, 21.0–22.9, 23.0–24.9 (reference), 25.0–27.4, and 27.5 and over. Multivariate-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for ischemic stroke and hemorrhagic stroke according to BMI were estimated with adjustments for age, systolic blood pressure levels, total cholesterol levels, HDL cholesterol levels, HbA1c levels, current smoking, regular drinking and regular exercise using Cox’s regression. Results: During the follow-up, 171 ischemic and 58 hemorrhagic strokes occurred. Compared to men with BMI of 23.0–24.9, men with BMI of 25.0–27.4 and BMI of 27.5 and over had 1.6- and 1.9-fold higher risks for ischemic stroke, respectively, and men with BMI of less than 18.5 and 18.5–21.9 had 4.1- and 2.5-fold higher risks for hemorrhagic stroke, respectively. (See Table ) Conclusion: The findings suggest that low BMI (less than 21) is an independent risk factor for hemorrhagic stroke and that high BMI (25 and over) is an independent risk factor for ischemic stroke in Japanese elderly men. Table Multivariate HRs (95% CIs) for stroke according to BMI in Japanese eldery men BMI (kg/m 2 ) Less than 18.5 18.5–20.9 21.0–22.9 23.0–24.9 25.0–27.4 27.5 and over No. of subjects 138 725 1126 1283 1018 453 Ischemic stroke No. of cases 3 29 41 33 42 23 Incidence rate 4.32 7.49 6.75 4.81 7.72 9.66 HR (95% CI) 0.82 (0.25–2.72) 1.45 (0.86–2.43) 1.38 (0.87–2.19) 1 (reference) 1.58 (1.00–2.51) 1.92 (1.12–3.30) Hemorrhagic stroke No. of cases 4 15 12 10 11 6 Incidence rate 5.66 3.81 1.94 1.44 1.99 2.45 HR (95% CI) 4.10 (1.24–13.6) 2.53 (1.10–5.82) 1.32 (0.57–3.08) 1 (reference) 1.40 (0.59–3.31) 1.62 (0.58–4.52) Incidence rate was defined as number of cases per 1000 person-years.
Neoadjuvant chemotherapy with DD-MVAC and bevacizumab in high-risk urothelial cancer: Results from a phase II trial at the M. D. Anderson Cancer Center.
Authors: Arlene O. Siefker-Radtke, Ashish M. Kamat, Paul G. Corn, Surena F. Matin, H. Barton Grossman, Randall E. Millikan, Colin P.N. Dinney
Journal: Journal of Clinical Oncology (2012)

261 Background: DD-MVAC has shown an improved 5-year survival in metastatic urothelial cancer; however, there is no prospective data on its use in the neoadjuvant setting. Previous work suggested that over-expression of VEGF was associated with a high risk of relapse in our neoadjuvant patients, leading to the hypothesis that combining a VEGFR inhibitor with chemotherapy may improve patient outcomes. Methods: Between 8/07 and 12/10, 60 patients with urothelial carcinoma of the bladder or upper tract tumor were enrolled on a prospective phase II clinical trial. Eligibility requirements included at least one of the following: 3-D mass on EUA (cT3b disease), LVI, hydronephrosis, micropapillary features, tumor in a diverticula, and for upper tract tumors a high grade tumor or radiographically measurable sessile mass. The primary endpoint was pathologic down-staging to &lt;=pT1N0M0. Results: Forty-four patients with bladder/urethral tumors and 16 patients with upper tract tumors were enrolled. Pathologic down-staging to &lt;= pT1N0M0 occurred in 53% of patients overall (bladder/urethra 45%, upper tract 75%), and to &lt;= pT0N0M0 in 38% overall (bladder/urethra 39%, upper tract 38%). At a median follow-up of 21 months, the 2-year OS and DSS was 78% and 85%, respectively (bladder 2-yr OS and DSS 75%, 82%; upper tract 93%, 93%). The median OS and DSS have not yet been reached. The most common grade 3 or greater toxicity was neutropenia in 27% of patients, followed by fatigue in 10%. The following grade 3 toxicities were observed in &lt; 10% of patients: mucositis, DVT/PE, hypertension, nausea/vomiting, thrombocytopenia. One patient experienced cardiac ischemia. Conclusions: Neoadjuvant chemotherapy leads to pathologic down-staging in 45% of patients with bladder cancer. DD-MVAC appears an acceptable alternative to traditional M-VAC in the neoadjuvant setting. Although bevacizumab did not impact down-staging based upon historical expectations, determining the effect on recurrence requires longer follow-up.
Evaluation of baseline serum C-reactive protein (CRP) and benefit from tremelimumab compared to chemotherapy in first-line melanoma.
Authors: M. A. Marshall, A. Ribas, B. Huang
Journal: Journal of Clinical Oncology (2010)

2609 Background: A3671009, a randomized phase III study comparing tremelimumab (anti-CTLA4 monoclonal antibody) to dacarbazine or temozolomide in pts with unresectable melanoma, crossed the futility boundary at the second interim analysis, but survival follow-up continued. An exploratory analysis was done to evaluate baseline serum CRP as a potential predictive factor for benefit from immunotherapy with tremelimumab compared to chemotherapy. Methods: The ratio of the CRP value to the ULN for the local lab was determined at each time point. Baseline CRP was defined as the CRP/ULN ratio on the day or previous day of first dose, prior to dosing, whichever later. Log-rank test and Cox proportional hazard regression model were applied to determine the optimal baseline CRP cutoff value to maximize treatment effect. A permutation test was performed to adjust for multiplicity. Results: BaselineCRP was available for 525 pts. "Low baseline CRP" was identified as ≤1.5 × ULN for optimal hazard ratio (HR) and p value for comparison of survival. Among pts with low baseline CRP (n=326 [62%]), the HR was 1.48 (95% CI: [1.14,1.94]) favoring the tremelimumab arm, with median OS 19.1 mo for tremelimumab arm versus 12.7 mo for chemotherapy arm (p = 0.0037). For pts with baseline CRP>1.5 × ULN, the HR for survival was 0.86 (95% CI: [0.64, 1.15]), favoring the chemotherapy arm, indicating that this group of pts did not apparently benefit from tremelimumab compared to chemotherapy. Tumor response rate to tremelimumab but not to chemotherapy was higher for pts with low CRP. Rates of diarrhea, of SAEs and of AEs grade ≥3 in the first 90 days postrandomization, were similar for pts with low or high baseline CRP. The results were robust for alternative definitions of baseline CRP. Conclusions: Low baseline CRP identifies a subset of pts with significant survival benefit from tremelimumab compared to chemotherapy. A prospective clinical trial of tremelimumab compared to chemotherapy in pts with low serum CRP is warranted. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Pfizer Pfizer Pfizer Pfizer Pfizer
PTH-266 Two week wait referrals: a symptomatic screening programme for colorectal cancer?
Authors: J Voll, N Waraich, S Thomson, S Asgari Mowahad, H Edis, T Hossain, A Ahmed, R Briggs, D Humes, A Banerjea
Journal: Gut (2015)

<h3>Introduction</h3> Public expectation, media scrutiny and political posturing around early cancer diagnosis continue to escalate. Primary and secondary care face increasing demands to diagnose and treat cancer earlier and more quickly. Nottingham Colorectal Service receives 2WW referrals at 2 sites: Nottingham University Hospitals and a private Diagnostic Treatment Centre. To address increasing referrals and failure to treat within 62 days we introduced a “Direct to test (DTT)” initiative as part of our 2WW pathway. <h3>Method</h3> We amended our 2WW referral form to include ECOG performance status and Charlson co-morbidity. GPs were asked to provide eGFR and FBC/Ferritin. 2WW referrals received between 1/8/14 and 30/11/14 were vetted by a Colorectal Consultant and selected for DTT according to a pre-defined protocol. DTT patients were telephoned by a Nurse Specialist (NS) to confirm suitability and explain the process. Those not deemed suitable for DTT were offered outpatient assessment (OPA). All referrals were logged in a database and outcomes of investigation and treatment were analysed. (Statistical comparisons: GraphPad Prism). <h3>Results</h3> 553,2WW referrals were received - mean age at time of referral 67.6 y (Range 18.9–93.7y). 355 patients (64.1%) were deemed suitable for DTT but 64 (11.6%) failed telephone assessment. 11 (2.0%) failed to complete the pathway. 291 patients were sent DTT: 222 patients for colonoscopy, 45 OGD/colonoscopy, 4 colonoscopy/CT scan, 13 flexible sigmoidoscopy and 3 flexible sigmoidoscopy/CT scan, and 4 CT scan only. 280 patients successfully completed a DTT pathway (50.6%). 233 (42.1%) completed OPA/investigation. 40 patients (7.2%) excluded due to inappropriate referral, patient choice/DNA, or OPA that investigation was not appropriate. The DTT group (mean age 64.9y) was significantly younger (p &lt; 0.0001) than the OPA group (71.0y). In the OPA group, 105 (19%) were seen by a consultant and 128 (23.1%) by a NS. 37 colorectal cancers (CRC), including anal SCC, were detected from all 2WW referrals (6.7%). 15 CRC were detected in the DTT group (5.4%) and 22 CRC in the OPA group (9.4%). The lower CRC detection rate in DTT did not reach statistical significance (Fisher’s Exact Test p = 0.087). Notably our local BCSP hub had a CRC detection rate of 8.5% in patients with positive FOBT. <h3>Conclusion</h3> DTT was safe and effective at selecting out a group of symptomatic patients who could proceed straight to test – usually involving endoscopy (98.6%). Unsurprisingly, this group was younger and fitter and yielded a lower CRC detection rate. In fact, CRC detection rate in all of our symptomatic 2WW referrals was lower than BCSP patients with a positive FOBT. Is it time to re-evaluate our symptomatic 2WW screening programme? <h3>Disclosure of interest</h3> None Declared.
Comparing Intelligence Quotient Change After Treatment With Proton Versus Photon Radiation Therapy for Pediatric Brain Tumors
Authors: Lisa S. Kahalley, M. Douglas Ris, David R. Grosshans, M. Fatih Okcu, Arnold C. Paulino, Murali Chintagumpala, Bartlett D. Moore, Danielle Guffey, Charles G. Minard, Heather H. Stancel, Anita Mahajan
Journal: Journal of Clinical Oncology (2016)

Compared with photon radiation (XRT), proton beam radiation therapy (PBRT) reduces dose to normal tissues, which may lead to better neurocognitive outcomes. We compared change in intelligence quotient (IQ) over time in pediatric patients with brain tumors treated with PBRT versus XRT.IQ scores were available for 150 patients (60 had received XRT, 90 had received PBRT). Linear mixed models examined change in IQ over time since radiation therapy (RT) by RT group, controlling for demographic/clinical characteristics. Craniospinal and focal RT subgroups were also examined.In the PBRT group, no change in IQ over time was identified (P = .130), whereas in the XRT group, IQ declined by 1.1 points per year (P = .004). IQ slopes did not differ between groups (P = .509). IQ was lower in the XRT group (by 8.7 points) versus the PBRT group (P = .011). In the craniospinal subgroup, IQ remained stable in both the PBRT (P = .203) and XRT groups (P = .060), and IQ slopes did not differ (P = .890). IQ was lower in the XRT group (by 12.5 points) versus the PBRT group (P = .004). In the focal subgroup, IQ scores remained stable in the PBRT group (P = .401) but declined significantly in the XRT group by 1.57 points per year (P = .026). IQ slopes did not differ between groups (P = .342).PBRT was not associated with IQ decline or impairment, yet IQ slopes did not differ between the PBRT and XRT groups. It remains unclear if PBRT results in clinically meaningful cognitive sparing that significantly exceeds that of modern XRT protocols. Additional long-term data are needed to fully understand the neurocognitive impact of PBRT in survivors of pediatric brain tumors.
Possible role of 25-hydroxycholesterol on the pahogenesis of chronic obstructive pulmonary
Authors: Hisatoshi Sugiura, Akira Koarai, Tomohiro Ichikawa, Masakazu Ichinose
Journal: European Respiratory Journal (2011)

(Background)  25-Hydroxycholesterol (25-HC) is produced from cholesterol by cholesterol 25-hydroxylase and is related to atherosclerosis in vessels. Recently, 25-HC was reported to cause inflammation in various types of cells. The aim of this study is to assess the production of 25-HC in the airways of COPD and to elucidate the effects of 25-HC in neutrophil infiltration in the airways of chronic obstructive pulmonary disease (COPD).   (Methods)  Eleven healthy never-smokers, 6 healthy ex-smokers, and 13 COPD patients took part in the lung tissue study. The expression of cholesterol 25-hydroxylase in the lung was investigated. Twelve healthy subjects and 17 COPD patients also took part in the sputum study. The amount of 25-HC in the sputum was also quantified. To elucidate the effects of 25-HC on neutrophil infiltration in the airways, 25-HC was intratracheally administered in mice.   (Results)  The expression of cholesterol 25-hydroxylase was significantly enhanced in the lung tissue from COPD patients compared to healthy subjects. Cholesterol 25-hydroxylase was localized in alveolar macrophages and pneumocytes in COPD. The amounts of 25-HC in the sputum were significantly increased in COPD patients and the degree of 25-HC production was negatively correlated with the lung function. The amounts of 25-HC in the sputum had significant positive correlations with the interleukin-8 (IL-8) levels and neutrophil counts in the sputum. Treatment with 25-HC augmented neutrophil accumulation in the airways and the production of chemokines in mice.   (Conclusions)  25-HC production was enhanced in the airways of COPD patients and could cause neutrophilic inflammation.
The BEST trial (E2804): A randomized phase II study of VEGF, RAF kinase, and mTOR combination targeted therapy (CTT) with bevacizumab (bev), sorafenib (sor), and temsirolimus (tem) in advanced renal cell carcinoma (RCC).
Authors: David F. McDermott, Judith Manola, Michael Pins, Keith T. Flaherty, Michael B. Atkins, Janice P. Dutcher, Daniel J. George, Kim Allyson Margolin, Robert S. DiPaola
Journal: Journal of Clinical Oncology (2013)

345 Background: Single-agent VEGF and MTOR directed targeted therapy have improved outcomes for pts with RCC. Phase I trials suggested that CTT might delay resistance. This randomized phase II trial was designed to find the best CTT regimen in comparison to bev alone for potential comparison to the best available single-agent therapy in a phase III trial. Methods: 361 treatment naïve RCC pts were randomized to receive Bev (10mg/kg Q2wks), Tem (25mg Qwk) + Bev (10mg/kg), Bev (5mg/kg Q2wks) + Sor (200mg po 5d on/2d off), or Sor (200mg QD) + Tem (25mg Qwk) until disease progression or unacceptable toxicity. The study was designed to detect a 67% improvement in median PFS on the combination arms, compared to single-agent bev (median 9 vs. 15 mo). Results: The median PFS was 8.7 mo for Bev versus 7.3 mo for Bev/Tem (HR = 0.91; 95% CI, 0.68-1.23), 11.3 mo for Bev/Sor (HR = 0.84; 95% CI, 0.62-1.13), 7.7 mo for Sor/Tem (HR = 1.11; 95% CI, 0.83-1.49). The response rates (CR+PR) were 12% for Bev versus 28% for Bev/Tem, 30% for Bev/Sor and 27% for Sor/Tem. No difference in OS was observed. Common toxicities included hypertension, fatigue, hand-foot syndrome, and diarrhea. Grade 3/4 adverse events and dose reductions were more common on CTT. Conclusions: CTT was not superior to single-agent Bev for the PFS primary endpoint. Common severe toxicities were expected, but more prevalent with CTT than with Bev alone. The VEGF/VEGFR co-inhibition strategy may warrant further investigation possibly with more selective VEGFR inhibitors. Clinical trial information: NCT00378703.
Activation of zebrafish Src family kinases by the prion protein is an amyloid-β-sensitive signal that prevents the endocytosis and degradation of E-cadherin/β-catenin complexes in vivo
Authors: Emily Sempou, Emiliano Biasini, Alejandro Pinzón-Olejua, David A. Harris, Edward Málaga-Trillo
Journal: Molecular Neurodegeneration (2016)

Prions and amyloid-β (Aβ) oligomers trigger neurodegeneration by hijacking a poorly understood cellular signal mediated by the prion protein (PrP) at the plasma membrane. In early zebrafish embryos, PrP-1-dependent signals control cell-cell adhesion via a tyrosine phosphorylation-dependent mechanism. Here we report that the Src family kinases (SFKs) Fyn and Yes act downstream of PrP-1 to prevent the endocytosis and degradation of E-cadherin/β-catenin adhesion complexes in vivo. Accordingly, knockdown of PrP-1 or Fyn/Yes cause similar zebrafish gastrulation phenotypes, whereas Fyn/Yes expression rescues the PrP-1 knockdown phenotype. We also show that zebrafish and mouse PrPs positively regulate the activity of Src kinases and that these have an unexpected positive effect on E-cadherin-mediated cell adhesion. Interestingly, while PrP knockdown impairs β-catenin adhesive function, PrP overexpression enhances it, thereby antagonizing its nuclear, wnt-related signaling activity and disturbing embryonic dorsoventral specification. The ability of mouse PrP to influence these events in zebrafish embryos requires its neuroprotective, polybasic N-terminus but not its neurotoxicity-associated central region. Remarkably, human Aβ oligomers up-regulate the PrP-1/SFK/E-cadherin/β-catenin pathway in zebrafish embryonic cells, mimicking a PrP gain-of-function scenario. Our gain- and loss-of-function experiments in zebrafish suggest that PrP and SFKs enhance the cell surface stability of embryonic adherens junctions via the same complex mechanism through which they over-activate neuroreceptors that trigger synaptic damage. The profound impact of this pathway on early zebrafish development makes these embryos an ideal model to study the cellular and molecular events affected by neurotoxic PrP mutations and ligands in vivo. In particular, our finding that human Aβ oligomers activate the zebrafish PrP/SFK/E-cadherin pathway opens the possibility of using fish embryos to rapidly screen for novel therapeutic targets and compounds against prion- and Alzheimer's-related neurodegeneration. Altogether, our data illustrate PrP-dependent signals relevant to embryonic development, neuronal physiology and neurological disease.