tbuckley/cabot-search huggingface dataset:
Abstract 3941: Novel biomarkers and multiplexed NGS to stratify FFPE NSCLC by tumor infiltrating lymphocytes and histopathology phenotypes
Authors: Ann Mongan, Sophie Rozenzhak, Geoffrey Bien, David Chi, Hiroyoshi Nishikawa, Fiona Hyland, Jim Godsey
Journal: Cancer Research (2016)

Abstract There is increasing evidence supporting the association of tumor infiltrating lymphocytes (TIL) and drug sensitivity of solid tumors. In particular, primary and meta-analyses have reported a positive correlation between TIL level and outcome in advanced non-small cell lung cancer (NSCLC) treated with checkpoint inhibitors such as PD-1 and PD-L1. Recent trials with immunotherapies have started including TIL assessment in the study protocol in recognition of this metric as a predictive and prognostic biomarker. TIL levels are typically quantified by visual assessment of H&amp;E-stained tumor sections. While this approach is generally accepted as the standard, there is an increased recognition that visual assessment of H&amp;E-stained slides lacks precision and is relatively subjective (Salgado R, 2015; Schalper KA, 2015). Furthermore, as investigators are often also interested in measurements of additional biomarkers such as IFNg as well as the drug targets, a gene panel approach offers a convenient solution to objectively quantify expression levels of these informative markers. Here we report the discovery and verification of a unique gene expression signature that is capable of stratifying FFPE samples of NSCLC tumors by TIL levels and histopathology phenotypes (adenocarcinoma vs. squamous cell carcinoma). Gene expression was measured by an RNA Ion AmpliSeq Gene Expression research panel* containing 200 assays. Each research sample was measured with replicates at library generation step and sequencing step. Technical replicates were found to have &amp;gt;0.99 correlation among each other. Assays on the panels were also found to be robust with respect to low input amount (1-10 ng RNA). *For Research Use Only. Not for use in diagnostic procedures. Citation Format: Ann Mongan, Sophie Rozenzhak, Geoffrey Bien, David Chi, Hiroyoshi Nishikawa, Fiona Hyland, Jim Godsey. Novel biomarkers and multiplexed NGS to stratify FFPE NSCLC by tumor infiltrating lymphocytes and histopathology phenotypes. [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 3941.
MLN9708 Elicits Pharmacodynamic Response in the Bone Marrow Compartment and Has Strong Antitumor Activity in a Preclinical Intraosseous Model of Plasma Cell Malignancy.
Authors: Edmund Lee, Bret Bannerman, Michael Fitzgerald, Jennifer Terkelsen, Daniel Bradley, Zhi Li, Ping Li, Siegfried Janz, Brian G Van Ness, Mark Manfredi, Erik Kupperman
Journal: Blood (2009)
Proton pump inhibitor-responsive oesophageal eosinophilia: too early to change clinical practice
Authors: Amanda B Muir, Mei-Lun Wang, David Metz, Gary Falk, Jonathan Markowitz, Jonathan M Spergel, Chris A Liacouras
Journal: Gut (2016)

We read the article by Molina-Infante et al 1 with great concern as it proposes a major change in the current practice guidelines for managing patients presenting for care by gastroenterologists worldwide. Proton pump inhibitor-responsive oesophageal eosinophilia (PPI-REE)1 is characterised by an eosinophilic infiltrate of the oesophageal epithelium that is responsive to PPI therapy alone. The authors suggest that endoscopies should be performed prior to a therapeutic trial of PPI, so as not to miss this subtype of eosinophilic oesophagitis (EoE). We maintain that these two entities not only have yet to be proven to be the same pathophysiological process, but also that performing an initial endoscopy with biopsy would not change the current practice of first using a PPI before or after the …
Abstract 2095: Toxicity of selective allosteric FGFR2 inhibition in preclinical studies
Authors: Nataliya V. Lapina, Marina V. Melikhova, Olga A. Vakunenkova, Vadim A. Kashuro
Journal: Cancer Research (2016)

Abstract Alofanib (RPT835, Ruspharmtech LLC) is a novel selective allosteric inhibitor binding to the extracellular domain of FGFR2. Alofanib had no direct effect on activation of FGFR1 and FGFR3 in vitro. Selective effect of the compound may reduce toxicity compared to multi-targeted VEGFR/FGFR or pan-FGFR inhibitors. This study characterizes the organ toxicity of alofanib in Sprague-Dawley rats and Chinchilla rabbits, and the reversibility of any treatment-induced effects. 240 rats and 30 rabbits received alofanib (0-40.5 and 0-21.6 mg/kg/day, respectively) intravenously on a consecutive daily dosing schedule for thirteen weeks. Clinical observations and laboratory parameters were recorded. Necropsy was conducted following treatment/recovery periods, and histologic examinations were performed. There was no treatment-related mortality, severe toxicity and significant changes in organs in the thirteen-week study. Alofanib was well-tolerated in vivo. Clinical signs of first injection (8.1 mg/kg) included moderate local irritative reaction and decreased activity during hour in rats. Clinical symptoms of toxicity were not observed over study. Animals were active. Body weight remained stable and it was comparable to vehicle groups. Abnormal electrocardiogram findings and blood pressure changes were not detected. It was notable that in the study, none of the hematologic changes was present at the end of the recovery period. Minimal significant decrease in ALT/AST, slight increase in alkaline phosphatase in male rats and mild increase in urea, decrease in chlorine in female rats were found throughout treatment period. Minimal significant decrease in albumin and chlorine was identified in rabbits. Rate of hyperphosphatemia, an on-target side-effect of pan-FGFR inhibitors, will be presented at the AACR Meeting. We conclude that toxicity of alofanib was mild in the thirteen-week study. Slight decrease of chlorine in blood was most common side effect. The final conclusion will be made after six-month study. This study was supported by a grant from the Skolkovo Foundation. Citation Format: Nataliya V. Lapina, Marina V. Melikhova, Olga A. Vakunenkova, Vadim A. Kashuro. Toxicity of selective allosteric FGFR2 inhibition in preclinical studies. [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 2095.
Prevalence of Firmicutes in Lesions of Hidradenitis Suppurativa in Obese Patients
Authors: Alessandra Haskin, Alexander H. Fischer, Ginette A. Okoye
Journal: JAMA Dermatology (2016)

and how many patients are investigated, given their usually subtle presentation of yellow-orange macules involving the palm creases.These are considered pathognomonic of FD, but may be confused with planar xanthoma seen in cholestasis diseases, which are usually white plaques that extend beyond the palmar creases. 4Since FD has important cardiac 5 and dermatologic manifestations that respond well to treatment, 3 identification of FD is critical.Recognition by all physicians, especially dermatologists, of the rare diagnostic and pathognomonic physical sign of PCXs of apoE2/2 dysbetalipoproteinemia, opens the door to early diagnosis, documentation, and therapy; all focused on resolution of both cutaneous xanthomas and atherosclerotic lesions.The dermatologist is the gatekeeper for early diagnosis and treatment.
Abstract 339: Identification of novel covalent inhibitors of K-Ras G12C that are efficacious in a xenograft model of NSCLC
Authors: Leena Khare Satyam, Dinesh Chikkanna, Aswani K. G, Vinayak V. Khairnar, Sreekanth Reddy, Vakkapatla Durgaprasad, Kowju Radhakrishna, Sunil K. Panigrahi, Anuradha Ramanathan, Kumari Mahasweta, Anirudha Lakshminarasimhan, Narasimha R. K, Vinutha R, Sreevalsam Gopinath, Suryakant Kumar, Mubarak H. Shah, Raghuveer Ramachandra, Kiran A. B, Chetan Pandit, Murali Ramachandra
Journal: Cancer Research (2016)

Abstract KRAS is the frequently mutated isoform in RAS driven cancers. The G12C mutation is more predominantly associated with various tumor types over other changes in K-Ras. Although direct targeting of RAS is very challenging, it is possible to selectively target G12C mutant K-Ras using a covalent approach. Mutant specific covalent inhibitors with high selectivity against wild type K-Ras and other GTPases are expected to lead to efficacy with a very high degree of tolerability. Here, we report identification of lead compounds from two distinct chemical series that selectively target K-Ras G12C. Molecular modeling based on the reported crystal structures aided in the identification of these compounds. Covalent binding of the lead compounds to K-Ras G12C was demonstrated by MALDI-TOF. Lead compounds were potent in selectively inhibiting proliferation of cell lines with K-Ras G12C mutation but not with wild type K-Ras. The anti-proliferative activity of the lead compounds correlated well with their potency in a cellular mechanistic assay. Lead compounds from both series exhibited excellent drug-like properties including solubility, metabolic stability, permeability lack of CYP inhibition and desired exposure in pharmacokinetic studies. In a xenograft model of NSCLC, the lead compound demonstrated dose-dependent tumor growth inhibition with excellent tolerability upon oral dosing. In summary, we have identified a novel, potent and selective K-Ras G12C inhibitor with optimized drug-like properties including oral bioavailability and efficacy in a NSCLC derived xenograft model. Toxicity evaluation is ongoing towards progressing the lead compound to the clinic. Citation Format: Leena Khare Satyam, Dinesh Chikkanna, Aswani K. G, Vinayak V. Khairnar, Sreekanth Reddy, Vakkapatla Durgaprasad, Kowju Radhakrishna, Sunil K. Panigrahi, Anuradha Ramanathan, Kumari Mahasweta, Anirudha Lakshminarasimhan, Narasimha R. K, Vinutha R, Sreevalsam Gopinath, Suryakant Kumar, Mubarak H. Shah, Raghuveer Ramachandra, Kiran A. B, Chetan Pandit, Murali Ramachandra. Identification of novel covalent inhibitors of K-Ras G12C that are efficacious in a xenograft model of NSCLC. [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 339.
HER2 amplification as a negative predictive biomarker for anti-epidermal growth factor receptor antibody therapy in metastatic colorectal cancer.
Authors: Kanwal Pratap Singh Raghav, Michael J. Overman, Ruoxi Yu, Funda Meric-Bernstam, David Menter, Bryan K. Kee, Andrea Muranyi, Shalini Singh, Mark Routbort, Ken Chen, Kenna Rael Shaw, Kandavel Shanmugam, Dipen M. Maru, Marwan Fakih, Scott Kopetz
Journal: Journal of Clinical Oncology (2016)

3517 Background: HER2 amplification (HERamp), seen in 5% of KRAS wildtype (WT) metastatic colorectal cancers (mCRC), is associated with resistance to anti-epidermal growth factor receptor antibodies (antiEGFRabs). The purpose of this study was to validate the predictive impact of HERamp in mCRC. Methods: We performed systematic analyses of RAS and BRAF WT mCRC patients (pts) across 2 distinct cohorts. We tested HERamp in cohort 1 (N = 97) using immunohistochemistry and dual in-situ hybridization (HERamp: HER2/CEP17 ≥ 2.2). We validated these findings in cohort 2 (N = 99), which comprised of 37 cases of HERamp mCRC pts identified by next-generation sequencing (HERamp: ≥ 4 copies) and 62 HER2 non-amplified (HER2NA) pts treated previously with antiEGFRabs who served as controls. The primary objective was to compare progression-free survival (PFS) in pts treated with antiEGFRabs. PFS and overall survival (OS) were estimated using Kaplan Meier method and compared using log rank test. Results: HERamp was seen in 14 (14 %) of RAS/BRAF WT pts in cohort 1. In this cohort, median OS (29.1 v 45.1 months (m), P = 0.78) and PFS on first line therapy without an antiEGFRab (PFS1) (9.7 v 8.4 m, P = 0.70) was similar between HERamp and HER2NA pts. A total of 66 pts in cohort 1 received antiEGFRab after first line therapy. Median PFS on antiEGFRab therapy (PFS2) was significantly shorter in pts with HERamp compared to HER2NA tumors (2.9 v 8.1 m, hazard ratio (HR) 5.0, P < 0.0001). These findings were confirmed in cohort 2, in which 69 pts received antiEGFRab after first line therapy and median PFS2 was significantly shorter for HERamp pts compared to HER2NA pts (2.8 v 9.3 m, HR 6.6, P < 0.0001) with a similar OS (P = 0.86) and PFS1 (P = 0.62). Conclusions: HER2 amplification in mCRC is a predictive biomarker for lack of efficacy of antiEGFRab therapy. This magnitude of effect is comparable to RAS mutations; the only other validated predictive biomarker for antiEGFRabs, and affects 1 in 8 patients currently receiving these agents. Patients with RAS/RAF WT mCRC should be screened for HER2 amplification prior to treatment with antiEGFRabs and should be considered for early referral to clinical trials.
JARID1B Enables Transit between Distinct States of the Stem-like Cell Population in Oral Cancers
Authors: Nicole D. Facompre, Kayla M. Harmeyer, Xavier Sole, Sheheryar Kabraji, Zachary Belden, Varun Sahu, Kelly Whelan, Koji Tanaka, Gregory S. Weinstein, Kathleen T. Montone, Alexander Roesch, Phyllis A. Gimotty, Meenhard Herlyn, Anil K. Rustgi, Hiroshi Nakagawa, Sridhar Ramaswamy, Devraj Basu
Journal: Cancer Research (2016)

The degree of heterogeneity among cancer stem cells (CSC) remains ill-defined and may hinder effective anti-CSC therapy. Evaluation of oral cancers for such heterogeneity identified two compartments within the CSC pool. One compartment was detected using a reporter for expression of the H3K4me3 demethylase JARID1B to isolate a JARID1B(high) fraction of cells with stem cell-like function. JARID1B(high) cells expressed oral CSC markers including CD44 and ALDH1 and showed increased PI3K pathway activation. They were distinguished from a fraction in a G0-like cell-cycle state characterized by low reactive oxygen species and suppressed PI3K/AKT signaling. G0-like cells lacked conventional CSC markers but were primed to acquire stem cell-like function by upregulating JARID1B, which directly mediated transition to a state expressing known oral CSC markers. The transition was regulated by PI3K signals acting upstream of JARID1B expression, resulting in PI3K inhibition depleting JARID1B(high) cells but expanding the G0-like subset. These findings define a novel developmental relationship between two cell phenotypes that may jointly contribute to CSC maintenance. Expansion of the G0-like subset during targeted depletion of JARID1B(high) cells implicates it as a candidate therapeutic target within the oral CSC pool. Cancer Res; 76(18); 5538-49. ©2016 AACR.
Quantifying benefits and risks of vaccinating Australian children aged six months to four years with trivalent inactivated seasonal influenza vaccine in 2010
Authors: H Kelly, D Carcione, G Dowse, P Effler
Journal: Eurosurveillance (2010)

Australian and New Zealand health authorities identified seasonal trivalent inactivated influenza vaccines manufactured by CSL Biotherapies as the probable cause of increased febrile convulsions in children under five within 24 hours of vaccination and recommended against their use in this age group. We quantified the benefit-risk profile of the CSL vaccines using the number needed to vaccinate and suggest they might have caused two to three hospital admissions due to febrile convulsions for every hospital admission due to influenza prevented.
Response to Comments on Fedorko et al. Hyperbaric Oxygen Therapy Does Not Reduce Indications for Amputation in Patients With Diabetes With Nonhealing Ulcers of the Lower Limb: A Prospective, Double-Blind, Randomized Controlled Clinical Trial. Diabetes Care 2016;39:392–399
Authors: Ludwik Fedorko, James M. Bowen, Wilhelmine Jones, George Oreopoulos, Ron Goeree, Robert B. Hopkins, Daria J. O’Reilly
Journal: Diabetes Care (2016)

We welcome this opportunity to respond to the comments (1–3) regarding our study (4). There are a few common themes that we would like to clarify. The first theme is around the criticism of using “meeting criteria for amputation” instead of “amputation event.” It is ideal to use more final patient outcomes in all research; however, the sample size and time needed to recruit and follow patients of sufficient duration to observe final events is often prohibitive. This is the reason why intermediate markers and outcomes are used in many disease areas, including diabetes. In addition, final events like amputations may be an inappropriate outcome in small, randomized controlled trials (RCTs) where other factors may confound the true treatment effect. For example, patient cultural preferences, psychological trauma, and procedure-booking logistics (among other factors) frequently override medical advice about whether and when the limb should be amputated. This (extrinsic to disease) variability precludes using actual amputation event as a consistent outcome measure unless a very large sample and long follow-up times are used. This is impractical and prohibitively costly in placebo-controlled hyperbaric treatment trials. However, Margolis et al. (5) have done it elegantly in a study of different design. This multicenter observational cohort with propensity score matching methodology showed no amputation-sparing effect or improved wound healing in over 700 patients treated with hyperbaric oxygen therapy (HBOT) matched with over …
Elevated Tricuspid Regurgitant Jet Velocity In Lebanese Patients With Sickle Cell Disease Is Associated With Severe Disease and Is Clustered In Families
Authors: Rouba Abdennour, Mariam Arabi, Paul Nietert, Sarah Keyrouz, Ruby Khoury, Raya Saab, Samar A. Muwakkit, Jad El Abiad, Nadim El Majzoub, Ibrahim A. Dabbous, Fadi Bitar, Miguel R. Abboud
Journal: Blood (2013)
Abstract 5252: Skin cancer prevention by traditional Chinese medicinal formula Si-Wu-Tang and its constituents
Authors: Kevin Huang, Mandy Liu, Suhui Zhang, Steven Yeung, Andy Chang, Li Qian, Payal Chatterjee, Rui Li, Su Zhou, Nan Mei, Zhijun Wang, Cyrus Parsa, Robert Orlando, Yun Luo, Ying Huang
Journal: Cancer Research (2016)

Abstract Si-Wu-Tang (SWT), comprising the combination of four herbs, Rehmanniae, Angelica, Chuanxiong and Paeoniae, is one of the most popular Chinese medicines for women's diseases. Previously we showed that SWT was able to upregulate genes in the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway, suggesting a potential application for cancer chemoprevention. The present study examined the chemopreventive activity of SWT using models of skin carcinogenesis. In JB6 P+ cells, a non-cancerous murine epidermal cell line for studying skin tumor promotion, SWT inhibited epidermal growth factor (EGF)-induced neoplastic transformation. In a 7,12-dimethylbenz(a)anthracene (DMBA)-induced murine skin tumorigenesis model, both topical and oral treatment of SWT inhibited epidermal hyperplasia, proliferating cell nuclear antigen expression, and H-ras mutations induced by DMBA treatment. In addition, SWT exhibited a significant antimutagenic activity against DMBA-induced mutagenicity, determined by the Ames Test using Salmonella typhimurium TA100 in the presence of metabolic activator S9 system. To identify active components in SWT, among nine compounds previously reported in commercial SWT products, in silico molecular docking analysis predicted some as potential Nrf2 activators due to an ability of interfering the forming of Nrf2-Keap1 complex. Three of these compounds, gallic acid, Z-liguistilide and senkyunolide A, were confirmed with highest potency of increasing the antioxidant response element luciferase reporter activity, inducing Nrf2-regulated genes Hmox1, Slc7A11 and Nqo1, and inhibiting EGF-induced JB6 P+ transformation. Further mechanistic studies showed that SWT and the three compounds suppressed EGF-induced activation of the activator protein 1 (AP-1), an essential transcription factor involved in skin carcinogenesis. The antimutagenic activity for the three compounds was also confirmed with the Ames Test. In conclusion, these results provide evidence that SWT and its constituents are able to prevent skin cancer, at least partly, by activating the Nrf2 pathway and blocking the activation of AP-1. Thus, this widely used Chinese medicinal formula may provide a promising option toward preventing skin cancer or may be other types of cancer. Citation Format: Kevin Huang, Mandy Liu, Suhui Zhang, Steven Yeung, Andy Chang, Li Qian, Payal Chatterjee, Rui Li, Su Zhou, Nan Mei, Zhijun Wang, Cyrus Parsa, Robert Orlando, Yun Luo, Ying Huang. Skin cancer prevention by traditional Chinese medicinal formula Si-Wu-Tang and its constituents. [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 5252.
Phase II study of low-dose methotrexate to reduce the incidence of human anti-mouse antibodies in patients receiving I-131 tositumomab as first-line treatment for follicular lymphoma.
Authors: Daniel Lebovic, Anca M Avram, Yuni Dewaraja, Judith Estes, Kathryn Jacobi, Sara Goeman, Sarah Kyle, Erica Chapman, Kent A. Griffith, Mark Stefan Kaminski
Journal: Journal of Clinical Oncology (2013)

e19519 Background: I-131 tositumomab is a radiolabeled murine anti-CD20 antibody. In a frontline phase II follicular lymphoma (FL) trial, treatment with I-131 tositumomab produced a 95% ORR with 75% CR (NEJM 352:441, 2005). Median PFS was 6.1 yrs. However, 30% of patients (pts) developed high levels of human anti-mouse antibodies (HAMA) and a serum sickness syndrome within 7 weeks of treatment (early onset HAMA). The 5-yr PFS for this group was 35% compared to 70% for the others (p = 0.003). Low-dose oral methotrexate (mtx) reduces the incidence of human anti-chimeric antibody (HACA) formation in rheumatoid arthritis pts receiving infliximab. We hypothesized that low-dose mtx would likewise reduce the incidence of early onset HAMA when given in combination with I-131 tositumomab. Methods: This is a single arm, phase II study in pts with FL, grade 1-2, stage III or IV disease without limits on marrow involvement, and ≥ 1 of the GELF criteria. Prior therapy, other than focal radiotherapy, is not allowed. Pts must have adequate hematologic, hepatic and renal function, and serum HAMA levels ≤ ULN. I-131 tositumomab is given as a dosimetric dose followed within 1-2 weeks by a therapeutic dose of 75cGy of total body radiation. Pts take mtx 7.5 mg orally once weekly for 3 weeks prior to their dosimetric dose, followed by 7 additional weekly doses. The primary endpoint is the rate of HAMA formation within 7 wks of I-131 tositumomab treatment. Secondary endpoints are overall HAMA incidence, ORR, CR, PFS OS, and safety. Results: Between 8/2011 and 10/2012, 15 pts were enrolled. Median age was 56 (39-83); 11 were male. Three pts had serum HAMA levels &gt;ULN at baseline. One pt had a spontaneous remission prior to starting treatment, leaving 11 evaluable pts. One pt developed early onset HAMA (9%). ORR = 82%, CR = 64%. Two pts progressed with DLBCL. Grade 3 or 4 toxicities included thrombocytopenia n = 3, neutropenia n = 2 and pain n = 3. Conclusions: These preliminary results show that concurrent low-dose oral mtx appears to reduce the incidence of early onset HAMA in FL patients receiving first- line I-131 tositumomab (9% vs. 30% in historical controls) while preserving efficacy. Clinical trial information: NCT01389076.