tbuckley/cabot-search huggingface dataset:
Identification of novel antagonistic anti-PD-1 antibodies that are non-blocking of the PD-1 / PD-L1 interaction.
Authors: Craig Fenwick, Celine Pellaton, Alex Farina, Navina Radja, Giuseppe Pantaleo
Journal: Journal of Clinical Oncology (2016)

3072 Background: Monoclonal antibodies (mAbs) that act through PD-1 blockade have had significant clinical success as cancer immunotherapeutic agents particularly in melanoma and non-small cell lung cancers with considerably lower toxicities compared to similar therapies. Current anti-PD-1 Abs have relied on the blockade of the PD-1/PD-L1 interaction. Methods: A screening strategy was established to identify a panel of mAbs that bind with high affinity to diverse epitopes on PD-1. In vitro functional activity of the mAbs was evaluated by the capacity to restore proliferation to exhausted CD8 T cells from viremic HIV infected donors and using a mixed lymphocyte reaction assay (MLR). Results: Our studies show that antagonistic mAbs targeting PD-1 can be blocking or non-blocking of the PD-1/PD-L1 interaction. Compared to benchmark blocking mAbs (pembrolizumab and nivolumab), an epitope specific set of non-blocking anti-PD-1 mAbs have equivalent antagonistic activity in: 1) restoring proliferation to exhausted HIV specific CD8 T cells and 2) promoting proliferation and up-regulating IFNγ production of CD4 T cells in a MLR assay. Importantly, combinations of blocking and non-blocking anti-PD-1 mAbs synergize in significantly improving functional activity as to that achieved with either therapeutic agent alone. Conclusions: A panel of non-blocking mAbs targeting PD-1 with strong antagonistic activity have been generated and extensively characterized in their ability to recover exhausted antigen-specific CD4 and CD8 T cells and to improve a variety of functions. Importantly, combination of non-blocking with blocking anti-PD-1 mAbs resulted in significantly improved functional activity. These results provide the scientific rationale to investigate whether combination therapy may enhance therapeutic benefit in cancer immunotherapy or whether non-blocking anti-PD-1 Abs may be effective in low PD-L1 positive tumors. Humanized non-blocker anti-PD-1 mAbs have been generated and are being advanced into clinical development.
Abstract 3649: Targeted sequencing of 409 cancer-related genes for somatic mutations and copy number variations in human cancer using the semiconductor sequencers
Authors: Yasushi Sasaki, Ryota Koyama, Takafumi Nakagaki, Miyuki Tamura, Masashi Idogawa, Takashi Tokino
Journal: Cancer Research (2016)

Abstract Next-generation sequencing technologies have revolutionized cancer genomics research by providing a comprehensive method of detecting somatic cancer genome alterations. In this study, we describe a next-generation semiconductor sequencing protocol for rapid (2 days), standardized, and cost-effective gene analysis for human cancer specimens including FFPE samples. DNA was extracted from 19 human cancer cell lines and 61 human cancer specimens and their corresponding non-cancerous tissues, including oral squamous cell carcinomas and multiple myelomas. Using the Ion Ampliseq Comprehensive Cancer Panel, we sequenced 15992 loci from 409 tumor suppressor genes and oncogenes frequently cited and frequently mutated in human cancers (covered regions = 95.4% of total). Each sample underwent on average 8.3 million sequencing reads after quality filtering. The mean read depths were 461x, and &amp;gt;95% of targeted bases were represented by at least 20 reads. We also detected copy number variations in which segments of the genome can be duplicated or deleted from sequencing data. We found several genetic alterations that may have been associated with the poor prognosis and poor response to chemotherapy of cancer patients. Pathway assessment has shown that somatic aberrations within myeloma genomes are mainly involved in several important pathways, including cell cycle regulation, RTK-MAPK-PI3K and NF-kB. This study demonstrates the utility of using a semiconductor-based sequencing to efficiently identify human cancer mutations. The targeted next generation sequencing using low amounts of FFPE DNA is a valuable tool for high-throughput genetic testing in research and clinical settings. Citation Format: Yasushi Sasaki, Ryota Koyama, Takafumi Nakagaki, Miyuki Tamura, Masashi Idogawa, Takashi Tokino. Targeted sequencing of 409 cancer-related genes for somatic mutations and copy number variations in human cancer using the semiconductor sequencers. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3649.
huGTPCH Expressing S+S-Antilles Mice Have Reduced Gardos Channel Activity, Endothelin-1 Expression, and Endothelin Receptor A and B Expression, While Total Biopterin and Percent Tetrahydrobiopterin Are Increased
Authors: José R. Romero, Adriana Muniz, Ashley Hale, Nicholas J. Alp, Alicia Rivera, Sandra M. Suzuka, Keith M. Channon, Mary E. Fabry
Journal: Blood (2008)
All-cause mortality after ERCP
Authors: Evangelos Kalaitzakis
Journal: Endoscopy (2016)

<b>Background and study aims: </b>This study aimed to externally validate a recently developed English model for the prediction of 30-day mortality after endoscopic retrograde cholangiopancreatography (ERCP). Real-world mortality data beyond 30 days post-ERCP are scarce; thus, the study also aimed to develop a prediction model for mortality up to 12 months post-ERCP. <b>Patients and methods:</b> All patients who underwent their first ERCP during a 3-year period (n = 16 478), as identified from the Swedish Hospital Discharge Registry, were linked to the Swedish Death Registry. Factors associated with all-cause mortality up to 12 months post-ERCP were identified by Cox proportional hazards analysis. A prediction model was developed. <b>Results:</b> Post-ERCP mortality was 5 % at 30 days and increased to 11.9 % at 3 months. The English model slightly overpredicted 30-day mortality, which was corrected with recalibration. Discriminant validity of the recalibrated model was very good (c-statistic = 0.82). Independent predictors of medium-term mortality were: emergency admission (hazard ratio [HR] 1.48), cancer (HR 3.79), noncancer co-morbidity (1.33), gallstone-related diagnosis (HR 0.21), and age (HR 4.86 for ≥ 85 years vs. < 55 years). The c-statistic for 3 – 12-month mortality was 0.86 – 0.88. Specific ERCP complication codes were identified in 1.8 % of deaths within 30 days post-ERCP (0.09 % of ERCPs), and 75 % of deaths (18 % of ERCPs) within 1 year post-ERCP were due to cancer. <b>Conclusions:</b> Mortality doubled from 30 days to 3 months post-ERCP, but it was attributed mainly to underlying disease, notably cancer, and infrequently to ERCP-related causes. A previously developed model predicting 30-day mortality was externally validated. A model accurately predicting mortality up to 12 months post-ERCP was developed.
Simpler psychological treatment is as effective as CBT for depression and is cheaper, study shows
Authors: Susan Mayor
Journal: BMJ (2016)

Behavioural activation, a simpler type of psychological treatment than cognitive behavioural therapy (CBT) that helps people focus on changing how they act rather than how they think, is as effective as and cheaper than CBT in treating adults with depression, a large randomised study has shown.

“Our findings challenge the dominance of CBT as the leading evidence based psychological therapy for depression,” said the lead author, David Richards, professor of mental health services research at the University of Exeter, UK.

CBT is as effective as antidepressants in treating clinical depression, but it is delivered by specialist clinicians and therapists, so access is limited. One in 10 patients in England …
Role and prognostic value of placenta growth factor (PlGF) in colorectal carcinomas.
Authors: M. Baek, S. Bae, S. Cho, D. Jeong, C. Kim
Journal: Journal of Clinical Oncology (2010)

10606 Background: Placenta growth factor (PlGF) is a member of the vascular endothelial growth factor (VEGF) family. PlGF is implicated in several pathologic processes, including the growth, spread of cancer and tumor angiogenesis. The aim of this study was to evaluate expression and clinical implications of PlGF in colorectal cancer. Methods: In order to ascertain the clinical significance of PlGF expression in colorectal cancer, we analysed the expression pattern of PlGF using both immunohistochemical method and real time quantitative PCR and attempted to establish if a relationship existed between PlGF and microvessel density (MVD), and subsequently between PlGF and the predicted prognosis. We investigated 72 tumor/non-tumor pairs of fresh colorectal tissues for real time PCR and a total of 83 patients with colorectal cancer were included for immunohistochemical staining. Clinico-pathological characteristics were defined according to the TNM criteria of the UICC. Clinico-pathologic factors, such as age, sex, histological types of tumors, tumor cell grade, TNM stage, lymphovascular invasion, lymph node metastasis, were reviewed. Results: The mRNA expression levels for PlGF was significantly higher in tumor than in non- tumor tissues (p = 0.001). The ratio of PlGF expression in tumor to non-tumor in the advanced staged group was significantly higher than for the early staged group. PlGF mRNA was significantly higher in III-IV stage patients than in stage I-II patients (p = 0.011). The relationship between PlGF mRNA expression and sex, histological type, lymph node status was otherwise not statistically significant. Immunohistochemically, PlGF protein expression level was significantly correlated with MVD, patient survival, and clinicopathological factors such as lymph node metastasis, TNM staging, lymphatic invasion and vascular invasion in this study. Conclusions: PlGF may be an important angiogenic factor in human colorectal cancer, and PlGF expression level was significantly correlated with positive lymph node metastases, tumor stages, and patient survival. These findings suggest that PlGF expression correlates with disease progression and may be used as a tumor marker for colorectal cancer. No significant financial relationships to disclose.
The immunophenotypic spectrum of primary mediastinal large B‐cell lymphoma reveals prognostic biomarkers associated with outcome
Authors: Jacob R. Bledsoe, Robert A. Redd, Robert P. Hasserjian, Jacob D. Soumerai, Ha T. Nishino, Daniel F. Boyer, Judith A. Ferry, Lawrence R. Zukerberg, Nancy Lee Harris, Jeremy S. Abramson, Aliyah R. Sohani
Journal: American Journal of Hematology (2016)

Primary mediastinal large B-cell lymphoma (PMBL) is a distinct subtype of diffuse large B-cell lymphoma (DLBCL) that shows overlap with classical Hodgkin lymphoma (CHL) and a favorable prognosis compared to mediastinal gray-zone lymphoma (MGZL). We performed immunohistochemistry on initial diagnostic specimens of 49 cases of uniformly treated PMBL to determine the frequency and clinical significance of expression of antigens commonly seen in CHL and MGZL, along with markers previously shown to be prognostic in DLBCL, not otherwise specified. The median age was 37 years with a female:male ratio of 2.3. After a median follow-up of 78 months, 24% of patients had relapsed or refractory disease and 22% had died; the 5-year PFS was 70%. Variable CD15 expression was seen in 31% of cases, but was not associated with adverse outcome. Hans cell-of-origin, proliferation index, and MYC/BCL2 coexpression were not associated with outcome, while low PDL1 (P = 0.011) and high MUM1 (P = 0.065) staining were each associated with shorter PFS. A biologic risk score (one point each for low PDL1 and high MUM1) stratified patients into three prognostic risk groups for PFS (P = 0.001) and OS (P = 0.032). On separate multivariate models, low PDL1 was independent of R-IPI risk group for PFS (HR 6.0, P = 0.023), as was a biologic risk score of 2 (HR 5.6, P = 0.011). Incorporation of the biologic risk score sub-stratified patients within R-IPI groups for both PFS (P < 0.001) and OS (P < 0.001). In summary, we characterize the immunophenotypic spectrum of PMBL and identify PDL1 and MUM1 as prognostic biomarkers for high-risk disease. Am. J. Hematol. 91:E436-E441, 2016. © 2016 Wiley Periodicals, Inc.
Eating more plant protein is associated with lower risk of death
Authors: Jacqui Wise
Journal: BMJ (2016)

Eating more protein from plant sources was associated with a lower risk of death, and animal protein was associated with a higher risk of death, in people with at least one lifestyle risk factor such as smoking or being overweight, research published in JAMA Internal Medicine has shown.1

The prospective cohort study included 131 342 participants from the Nurses’ Health Study and the Health Professionals Follow-Up Study. Diet and other lifestyle data were collected every two years, and participants were followed up for as long as 32 years.

After the researchers adjusted for major lifestyle and dietary risk factors they found that every 10% increment of animal protein intake …
Abstract 4957: Keratin 13 drives the dissemination of bone and brain metastases of human prostate and breast cancer cells
Authors: Lijuan Yin, Qinlong Li, Jen-Ming Huang, Michael Lewis, Isla P. Garraway, Quanlin Li, Hong Bu, Leland W. K Chung, Haiyen E. Zhau
Journal: Cancer Research (2016)

Abstract Introduction and Objective: Bone and brain metastases are prevalent in human prostate and breast cancer patients. Keratin 13 (KRT13), a member of the intermediate filament proteins and an epithelial stem cell differentiation marker, induces cancer cell migration and progression toward increased malignant state. The objectives of this study are: 1) to determine KRT13 expression in human prostate and breast cancer and its clinical correlation; 2) to determine the functional cell signaling role of KRT13 in prostate and breast cancer cells using gene transfer technology. Methods and Results: We evaluated KRT13 protein expression in primary prostate cancer tissues from 44 cases with well-documented overall survival by quantitative quantum dot immuno-labelling. We found that KRT13 expression in primary prostate cancer correlated with patient overall survival and bone metastasis (p&amp;lt;0.05). We next evaluated KRT13 protein expression in 36 prostate and 58 breast cancer tissue specimens by immunohistochesmistry (IHC) and found that KRT13 is overexpressed in breast cancer bone (5/8) and brain (7/10) metastases and prostate cancer bone (6/12) metastasis specimens (p&amp;lt;0.05). KRT13 expression in primary prostate and breast cancer specimens is associated with decreased patient overall survival based on our data as well as publicly available Oncomine gene expression datasets. To elucidate the mechanisms by which KRT13 promotes cancer invasion, migration and metastasis, we genetically overexpressed KRT13 in human prostate CWR22 Rv1 and LNCaP, and human breast MCF7 and MCF10A cells, with respectively high or low malignant potential. KRT13-overexpressing prostate and breast cancer cells increase differential expression of genes associated with epithelial to mesenchymal transition (EMT; E-Cadherin and Vimentin), stemness (Nanog), neuromimicry (Chromagranin A and Synaptophysin), osteomimicry (RANKL) related genes as analyzed by qRT-PCR, western blot, and IHC. KRT13 also promotes increased cancer cell proliferation, migration and invasion in vitro, and bone and brain metastases in vivo. Conclusion: These results suggest that KRT13 drives prostate and breast cancer bone and brain metastases via osteomimicry and neuromimicry associated genes resulting in downstream cell signaling network convergence between EMT, stemness, cell growth, and survival pathways. Funded in part by NCI-P01-CA098912 Citation Format: Lijuan Yin, Qinlong Li, Jen-Ming Huang, Michael Lewis, Isla P. Garraway, Quanlin Li, Hong Bu, Leland W. K Chung, Haiyen E. Zhau. Keratin 13 drives the dissemination of bone and brain metastases of human prostate and breast cancer cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4957.
COLET (NCT02322814): A multistage, phase 2 study evaluating the safety and efficacy of cobimetinib (C) in combination with paclitaxel (P) as first-line treatment for patients (pts) with metastatic triple-negative breast cancer (TNBC).
Authors: David Miles, Sung-Bae Kim, V. A. McNally, Brian P. Simmons, Matthew Wongchenko, Jessie J. Hsu, Adam M. Brufsky
Journal: Journal of Clinical Oncology (2016)

TPS1100 Background: Preclinical data suggest that up-regulation of the MAPK pathway is a potential resistance mechanism against taxane chemotherapy. Often, resistance to taxane chemotherapy occurs in TNBC pts, and genetic alterations (including mutations and gene amplifications) in the MAPK pathway are present in many TNBC tumors; therefore, the combination of taxane chemotherapy and MEK inhibition could be an effective treatment option. Methods: COLET is evaluating the safety and efficacy of C+P in pts with metastatic or locally advanced TNBC who have not previously received systemic therapy for metastatic disease. There are 2 stages: an initial safety run-in stage (n≈12), followed by a 1:1 randomized stage (n≈100) of C+P or placebo (PBO) + P. Pts are stratified by prior neoadjuvant/adjuvant taxane therapy and disease-free interval from last chemotherapy dose. Pts will receive P 80 mg/m2 on Days 1, 8, and 15 of each 28-day cycle and C/PBO 60 mg/day on Days 3-23 of each 28-day cycle until disease progression or toxicity occurs. Key eligibility criteria include metastatic or locally advanced TNBC, no prior systemic therapy (neoadjuvant or adjuvant therapy is allowed if completed >6 mo prior), measureable disease per RECIST v1.1, and left ventricular ejection fraction > institutional lower limit of normal or > 50%. A key exclusion criterion is progressive/unstable brain metastases. The specific aims of the safety run-in stage were to determine the safety and tolerability of C+P. The specific aims of the randomized stage include investigator-assessed PFS (primary end point), safety, pharmacokinetics, the effect of subtypes and genetic alterations on PFS, mechanisms of resistance, and health-related quality of life. In the randomized stage, pts will be followed up until 60 PFS events occur across the 2 arms. This provides 77% power to detect a hazard ratio of 0.5 at a two-sided significance level of 0.05. Recruitment into safety run-in is complete; randomization stage accrual has begun. Pts from sites across Europe, North America, and the Asia-Pacific region will be enrolled. Clinical trial information: NCT02322814.
Functional and Clinical Relevance of Splicing Factor SRSF1 in Multiple Myeloma (MM)
Authors: Mariateresa Fulciniti, Manoj Bhasin, Mehmet Kemal Samur, Rajya Lakshmi Bandi, Naim Rashid, Reyes Jaime, Charles Lin, Kenneth C. Anderson, Giovanni Parmigiani, James E. Bradner, Nikhil C. Munshi
Journal: Blood (2014)
Effect of bortezomib on complete remission (CR) rate when added to bendamustine-rituximab (BR) in previously untreated high-risk (HR) follicular lymphoma (FL): A randomized phase II trial of the ECOG-ACRIN Cancer Research Group (E2408).
Authors: Andrew M. Evens, Fangxin Hong, Thomas Matthew Habermann, Ranjana H. Advani, Randy D. Gascoyne, Thomas E. Witzig, Andrew Quon, Lynne I. Wagner, Stephen Maxted Ansell, Adam Matthew Petrich, Julie E. Chang, Timothy E. O'Brien, Puneet S. Cheema, Terrence Cescon, Keren Sturtz, Brad S. Kahl
Journal: Journal of Clinical Oncology (2016)

7507 Background: Treatment strategies to improve outcomes in HR FL are needed. E2408 tested whether bortezomib (V) improves the CR rate when added to standard BR induction in untreated HR FL and whether lenalidomide (len) improves remission duration when added to maintenance rituximab (MR). Methods: Eligible pts had untreated HR grade I/II or IIIa FL. HR was defined as high tumor burden by GELF and/or FLIPI 3-5. Pts were randomized to 1 of 3 arms in a 1:2:2 ratio: A) BR x 6 followed by MR x 2 years (yrs) vs B) BVR x 6 (V 1.3 mg/m2 IV/SQ days 1, 4, 8, 11) then MR x 2 yrs vs C) BR x 6 then MR x 2 yrs + len 20 mg/day x 1 yr. Pts enrolled 1/11-5/15. Response was assessed by 2007 IWG criteria using PET/CT. This analysis reports on the first primary objective of CR rate with induction therapy (Tx) with arms A) + C) combined for induction comparison (90% power at 1-sided α of 0.15). Results: Among 250 randomized HR FL pts, 28 were excluded for not starting Tx (n = 5), ineligibility (n = 8) or central pathology review (n = 15). Analyses are based on 222 pts (BVR n = 85 vs BR n = 137); the arms were well balanced. Among all pts, GELF was high 92%; FLIPI 3-5 55%; ECOG PS 0 = 55%, 1 = 42% and 2 = 3%; marrow involvement 55%; and stages II 7%, III 27% and IV 66%. 86% of all pts received 6 induction cycles without differences between arms. The overall response for BVR was 91% vs 90% for BR, while CR rates were 74% vs 58%, respectively (2-sided P= 0.016). Respective ‘off treatment’ reasons for BVR vs BR were progressive disease in 4% and 7% and toxicity in 6% and 4%. The most common grade 3-4 toxicities (n = 241) for BVR vs BR were neutropenia (35%/30%), sensory neuropathy (SN) (12%/1%), thrombocytopenia (10%/5%), fatigue (6%/7%), febrile neutropenia (3%/5%) and diarrhea (5%/1%); 91% of grade 3 SN occurred with IV bortezomib (grade 3 SN incidence: 14% IV vs 4% SQ, OR = 3.7, P= 0.2). During induction Tx, there were 3 deaths (2 due to disease), all on arm C. Conclusions: This initial reportof E2408 for untreated HR FL shows that the CR rate for BVR induction Tx was significantly superior compared with BR. Continued follow up is needed to assess survival and if len added to MR improves outcomes. Clinical trial information: NCT01685008.
PTU-019 Antithrombotic Vs. Ulcer Effects In Non-variceal Bleeding In Users Of Antithrombotic Drugs: Abstract PTU-019 Table 1
Authors: AS Taha, C McCloskey, T Craigen, WJ Angerson
Journal: Gut (2014)

<h3>Introduction</h3> The use of antithrombotic drugs (ATDs) remains a considerable challenge in the aetiology and management of non-variceal upper gastrointestinal bleeding (NVUGIB). In the upper gastrointestinal tract, ATD use may result in bleeding by mucosal damage (ulcer effect) or through its basic antithrombotic effect. The clinical significance of these effects is unclear. In this controlled analysis, we AIMED to clarify the significance of the antithrombotic effect as compared with the ulcer effect in patients with NVUGIB using ATDs. <h3>Methods</h3> We previously found that ATD users tended to be older and to have higher comorbidity and different endoscopy findings. To overcome these confounding factors, we compared 202 patients with NVUGIB using ATDs (ATD Group) with 202 patients with NVUGIB but not using ATDs (Controls), having matched both groups in a pairwise manner for age, Charlson comorbidity score and a composite endoscopic score covering the oesophagus, stomach, and duodenum. Antithrombotic drugs included low-dose aspirin, clopidogrel, dipyridamole, warfarin, and heparin. Patients using NSAIDs were excluded. Characteristics of the groups were compared using the Wilcoxon signed rank test and McNemar's test. Continuous variables are reported as median (IQR). <h3>Results</h3> The characteristics of the two matched study groups are shown in Table 1. <h3>Conclusion</h3> After matching for age, comorbidity, and composite endoscopy score, patients with NVUGIB and using ATDs had significantly lower haemoglobin level, higher Blatchford risk score, and were 1.5 times more likely to be transfused. These effects are most likely to be due to the antithrombotic activity of ATDs rather than ulcers alone, and they need to be considered in the management of NVUGIB. <h3>Disclosure of Interest</h3> A. Taha Consultant for: Almiral Pharma UK, Vifor Pharma UK, Horizon Pharma USA, C. McCloskey: None Declared, T. Craigen: None Declared, W. Angerson: None Declared.