tbuckley/cabot-search huggingface dataset:
Tubulin beta-3: A novel tissue diagnostic marker for intrahepatic peripheral cholangiocarcionoma.
Authors: David J. Britton, Yoh Zen, Vikram Mitra, Stephan Jung, Christopher Loessner, Malcolm Ward, Ian Pike, Debashis Sarker, Nigel Heaton, Alberto Quaglia
Journal: Journal of Clinical Oncology (2014)

e15098 Background: Correct and timely diagnosis ofintrahepatic peripheral cholangiocarcinoma (CC) is a significant challenge, and new tissue markers are required. Methods: We conducted an LC-MS/MS proteomic analysis to examine protein expression profiles of 7 types of liver tissue from 55 patients: normal liver parenchyma, hepatocellular carcinoma (HCC), normal bile duct, peripheral CC, hilar CC, mixed HCC/CC and metastatic colorectal cancer. Proteins extracted from laser micro-dissected, formalin-fixed paraffin-embedded tissue were reduced, alkylated and in-gel trypsin digested. Peptides were analyzed by LC-MS/MS and relative amount of proteins determined using label free quantification (spectral counts & area under curve). Candidate protein markers for CC were further validated by an immunohistochemical study, where 197 separate cases covering various liver tumors and premalignant conditions were examined. Results: The proteomic study identified 58 proteins that were significantly more abundant in peripheral CC than in HCC, and 6 proteins that are significantly overexpressed in peripheral CC than in normal bile ducts. Five proteins identified in both comparisons (Tubulin beta-3 [TUBB3], Tenascin, Periostin, Collagen alpha-1(XII) chain, 6-phosphofructokinase type C) were potential diagnostic markers for peripheral CC. We selected TUBB3 for further analysis, as this had not been examined in liver tumors and its expression was highly specific for peripheral CC based on LC-MS/MS data. On immunostaining, TUBB3 was expressed in 13/28 peripheral CC (46%) and 6/40 hilar CC (15%), but was entirely negative in other primary liver tumors (i.e. HCC, bile duct adenoma), premalignant conditions (i.e. biliary dysplasia), and non-neoplastic liver tissue (i.e. cirrhosis). We also examined TUBB3 expression in three common types of metastatic liver cancers. It was positive in 4/10 colorectal liver metastasis (40%) and 4/10 breast cancer liver metastasis (40%), and negative in well differentiated neuroendocrine tumors. Conclusions: This study revealed that TUBB3 is moderately sensitive and highly specific tissue marker for peripheral CC to discriminate from other primary liver tumors.
Abstract 16188: Sex Differences and Outcomes of Heart Failure Admissions Stratified by Left Ventricle Ejection Fraction
Authors: Ahmad Masri, Andrew D Althouse, Gavin Hickey, Jeffrey McKibben, Ravi Ramani, Michael Mathier, Joon Lee, Oscar Marroquin, Suresh Mulukutla
Journal: Circulation (2017)

Introduction: In 2016, the European Society of Cardiology (ESC) heart failure (HF) guidelines adopted three types of HF: HF with preserved ejection fraction of ≥ 50% (HFpEF), HF with mid-range EF b...
Author Correction: Single CD271 marker isolates mesenchymal stem cells from human dental pulp
Authors: Ruth Alvarez, Hye-Lim Lee, Christine Hong, Cun-Yu Wang
Journal: International Journal of Oral Science (2019)

In the original version of this Article, Figure 1c was inadvertently assembled with a duplicate of Figure 1b. The correct image for Figure 1c, shown below, has been added in the HTML and PDF versions of the Article. This does not affect the conclusions of the study. We sincerely apologize for any inconvenience this may have caused our readers.
Treatment patterns and outcomes in BRAF V600E mutant melanoma patients with brain metastases receiving vemurafenib in the real-world setting.
Authors: Geoffrey Thomas Gibney, Maryna Marynchenko, Philip J Galebach, Charles Ayas, Nathan S. Liu, Eric Qiong Wu, Yeun Mi Yim, Sarang S. Abhyankar, Carolina M. Reyes, Annie Guérin
Journal: Journal of Clinical Oncology (2014)

9035 Background: Metastatic Melanoma (mM) patients (pts) with brain metastases (BM) have a poor prognosis and median survival of <6 months. Selective BRAF inhibitors may play a role in the treatment of BM, but data from the “real-world” setting is limited. This study aimed to investigate treatment and survival patterns among BRAFV600E mM pts with active BM receiving vemurafenib (vem). Methods: Clinical data for BRAFV600E mM pts with active BM treated with vem after 8/2011 were reviewed from a panel of US oncologists. Demographic and clinical characteristics, mM treatment history pre- and post- vem, treatment response, and death were recorded. 6-month survival rate was estimated using Kaplan-Meier (K-M) method. Prognostic factors for death were measured prior to vem initiation and assessed using a Cox proportional-hazards regression model. Results: 283 BRAFV600E mM pts who received vem after diagnosis (dx) of BM were analyzed. Mean age was 57 years; 60.8% were male; 67.5% were ECOG 0-1. Median follow-up time from vem initiation was 5.7 months. Prior to vem, 109 (38.5%) pts received local treatment and 23 (8.1%) pts received systemic treatment for BM. Median vem treatment duration among pts who discontinued vem was 5.0 months. 21 (7.4%) pts required a dose reduction of vem. Reasons for vem discontinuation included systemic disease progression (42.9%), intracranial progression (18.1%), death (16.4%), and pt decision (5.6%). 136/283 (48.1%) were reported to achieve overall intracranial response (CR/PR). No new safety issues were identified. K-M survival at 6-month was 85.7% (95% CI: 80.1, 89.8). Pts with ≥5 BM (HR 3.8; 95% CI: 1.7, 8.5), progressive extracranial metastases (HR 2.6; 95% CI: 1.4, 4.6), and ≥2 sites of extracranial metastases (HR 5.3; 95% CI: 1.4, 20.4) were found to be significant prognostic factors for death. Conclusions: In the real world setting, the use of vem treatment is associated with clinical benefit in BRAFV600E mM patients with active BM.
Incorporation of FGFR1 and FGFR2 amplification status determination in routine molecular prescreening for targeted therapies.
Authors: Ludmila Prudkin, Claudia Aura, Jose Jimenez, Nerea Peiro, Debora Moreno, Paola Martinez, Gertrudis Sanchez, maria Del Carmen Diaz, Alejandra Iglesias, Maria Angeles Diaz, Ana Vivancos, Jordi Rodon, Javier Cortes, Ana Oaknin, Jose Maria Del Campo, Enriqueta Felip, Josep Tabernero, Paolo Nuciforo
Journal: Journal of Clinical Oncology (2014)

11105 Background: Enriching PhI trials with patients harboring alteration in the FGFR pathway is key to the successful development of FGFR pathway inhibitors. FGFR1 and 2 amplification (amp) are considered a driver event in many carcinomas. Methods: ISO-accredited FGFR1 and 2 FISH assays were run in samples from candidates to enter a PhI clinical study. FGFR amp status was defined as a ratio gene/centromere ≥2.2. FGFRs status was correlated with available PTEN expression (IHC) and mutations data (AKT, KRAS, BRAF, PIK3CA, among others). Results: From January 2012 we screened 272 samples for FGFR1 and 190 for FGFR2. Samples came from primary tumors in 196 cases (PT=71.8%), and 141 (PT=74.2%); and metastatic disease in 61 cases (MET=22.3%), and 41 (21.6%) for FGFR1 and FGFR2, respectively. Rest of cases was of unknown (UKN) origin. Overall, FGFR1 gene amp was observed in 11% and FGFR2 in 3% of cases with amplification rates similar between PT and MET. After subgrouping by tumor origin, FGFR1 ampl was most frequently observed in breast cancer (19%) followed by lung cancer (8%). FGFR2 was amplified in 5% of gastric and gynecological cancers, followed by breast cancer (2.5%). No associations were observed with FGFR1 and 2 amplifications and PTEN loss. Mutation results were available in 141 and 122 samples with FGFR1 and 2 amp data, respectively. Only one point mutation in AKT and one in PIK3CA genes were observed in FGFR1 amplified samples, while none in FGFR2 amplified cases. Conclusions: Incorporation of FGFRs gene amp status in a routine molecular prescreening is feasible and may provide clinicians with a tool to select patients to targeted therapies. FGFR1 Organ PT (n.) MET (n.) PT FGFR1 ampl MET FGFR1 ampl Breast 86 30 15 (17,5%) 7 (23.3%) Lung and pleura 30 6 2 (6,7%) 1 (16,6%) Gyn 23 1 1 (4.3%) 0 Stomach 28 3 1 (3,6%) 0 Others / unknown* 29 21 1 (3.5%) 0 FGFR1 196 61 20 (10,2%) 8 (13,1%) FGFR2 Organ PT (n.) MET (n.) PT FGFR2 ampl MET FGFR2 ampl Breast 60 21 1 (1.7%) 1 (4,7%) Lung and pleura 2 3 0 0 Gyn 20 1 1 (5%) 0 Stomach 38 4 1 (2,6%) 1 (25%) Others / unknown* 21 12 0 0 FGFR2 141 41 3 (2,1%) 2 (4,9%) * Others = bone, CRC, esoph, liver, skin, soft tissues, thyroid.
Characteristics, prognosis and treatments of 294 patients with poorly differentiated neuroendocrine carcinoma: The FFCD-GTE national cohort.
Authors: Thomas Walter, David Tougeron, Eric Baudin, Karine Le Malicot, Thierry Lecomte, Joel Guigay, Olivia Hentic, Sylvain Manfredi, Isabelle Bonnet, Rosine Guimbaud, Romain Coriat, Philippe Rougier, Christophe Desauw, Anne Thirot-Bidault, Laetitia Dahan, Guillaume Roquin, Thomas Aparicio, Catherine Lombard-Bohas, Come Lepage, Guillaume Cadiot
Journal: Journal of Clinical Oncology (2015)

4095 Background: Data on poorly differentiated neuroendocrine carcinoma (NEC) are limited or retrospective. We designed a French cohort to describe characteristics, prognosis and treatments of NEC Methods: All patients with a diagnosis of NEC (WHO 2010) performed between 01/01/2010 and 31/12/2013 could be included in this national prospective cohort. Patients with small-cell NEC from lung, mixed tumors, and well-differentiated neuroendocrine tumors (NET) were not included Results: 294 patients from 49 centers were included: median age was 66 (range: 23-92) years, 6 (2%) had functional tumors, performance status (PS) was 0-1 in 79% of patients, fortuitous diagnosis was done in 10 (3%) patients. Main primary locations were pancreas (18%), colorectal (24%), oeso-gastric (15%), large-cell lung NEC (15%), and unknown (17%). Most of the patients were metastatic (75%). At that time, 85 (29%) pathological specimens have been reviewed by the French national referent pathological network (TENpath). Pathological data showed: small/large cell NEC in 38%/62%, with necrosis in 79%, and a median Ki67 index of 70% (range: 10%-100%). Median overall survival (OS) was 15.7 months (95% CI: 13.9-17.8). GEP-NEC had similar characteristics and survival than other NEC. Factors associated with worse OS in multivariate analysis were PS > 1 (HR = 2.9, p < 0.001), metastatic disease (HR = 2.2, p < 0.001), NSE > 2 ULN (upper limit of normal) (HR = 4.1, p < 0.001), and LDH > 2ULN (HR = 2.7, p < 0.001). Ki67 index > 55% and primary location were not significantly associated with different OS. OS were 11.8 months from first-line (L1) systemic palliative chemotherapy (n = 202 pts), 7.6 months from L2 (n = 117), and 5.9 months from L3 (n = 58). The type of L1 was mainly platinum-etoposide (n = 176), whereas folfiri (79 patients) and folfox (37 patients) were mainly given in L2 or further lines. Efficacy of these treatments will be presented at the meeting Conclusions: This is the largest prospective series of NEC showing that worse prognosis factors are performance status, tumor burden, and elevated biologic markers (NSE and LDH). Further prospective studies are needed to improve treatment in L2
Concizumab (Anti-TFPI) Exposure-Response Modeling in Patients with Hemophilia A
Authors: Hermann Eichler, Pantep Angchaisuksiri, Kaan Kavakli, Paul Knöbl, Jerzy Windyga, Victor Jimenez-Yuste, Ute Friedrich, Philip Delff Andersen, Pratima Chowdary
Journal: Blood (2017)
Abstract 18432: The Incidence of Contrast Induced Nephropathy in Radial Access Compared to Femoral Access in Patients Undergoing Coronary Angiography: A Meta-Analysis
Authors: Toufik Mahfood Haddad, Amjad Kabach, Muhammad Azzouz, Aravdeep S Jhand, Michael D White, Michael Delcore
Journal: Circulation (2017)

Background: Contrast induced nephropathy (CIN) is a well-known complication of coronary angiography. The occurrence is rare (<1%) but is associated with high in-hospital mortality and poor long-ter...
Negative Prognostic Relevance of a Specific 3-Gene Cluster in Myelodysplastic Syndromes during Azacitidine and Lenalidomide Therapy
Authors: Matilde Y Follo, Andrea Pellagatti, Richard N Armstrong, Stefano Ratti, Sara Mongiorgi, Annalisa Astolfi, Valentina Indio, Maria Teresa Bochicchio, Cristina Clissa, Domenico Russo, Marco Gobbi, Sarah Parisi, Miriam Fogli, Giovanni Martinelli, Andrea Pession, Michele Cavo, Lucia Manzoli, Lucio Cocco, Jacqueline Boultwood, Carlo Finelli
Journal: Blood (2018)
LDI<sub>FLARE </sub> to assess chemotherapy-induced peripheral neuropathy.
Authors: Ramachandran Venkitaraman, Sanjeev Sharma, Prashanth Vas, Gerry Rayman
Journal: Journal of Clinical Oncology (2014)

e20630 Background: Accurate and objective assessment of chemotherapy-induced peripheral neuropathy (CIPN) is often difficult. Most studies of CIPN utilize questionnaire methods which are subjective. Conventional methods like quantitative sensory testing (QST), nerve biopsy and electrophysiological measurements including nerve conduction tests are limited in their utility to detect subclinical changes, cause discomfort to patients and importantly, do not correlate with symptoms and severity of functional impairment. LDI (laser doppler imager)FLARE technique has been shown to be highly efficacious in diagnosing early diabetic neuropathy and correlate well with nerve biopsy results. Methods: We conducted a study to assess the utility of LDIFLARE to diagnose CIPN, and to correlate the results with symptoms. In this case-control study, 24 patients with established CIPN who had completed chemotherapy with either Platinum analogues or Taxanes (12 patients in each group), more than a year prior to evaluation were compared with 24 age, sex and body mass index (BMI) matched healthy controls. All participants underwent complete neuron-physiological examination including QST, sural nerve amplitude (SNAP) and conduction velocity (SNCV), LDIFLARE, EORTC QLQ-CIPN20 questionnaire and fasting blood biochemistry for exclusion of confounders like diabetes. Results: All the patient groups (controls and chemotherapy groups, as well as individual chemotherapy groups) were equally matched for age (p=0·87), sex (p=0·35), BMI (p=0·63), smoking history (p=0·66) and blood pressure (p=0·09). LDIFLARE was significantly reduced in the chemotherapy group compared to controls (p=<0.0001), while SNAP (p=0.058) and SNCV (p=0.054) failed to show any significant difference between the groups. LDIFLARE correlated significantly with the EORTC QLQ-CIPN20 scores in the combined chemotherapy group (p=<0.0001), as well as individual Platinum (p=0.001) and Taxane (p=0.027) groups, while QST, SNAP and SNCV failed to show any significance. Conclusions: Our findings suggest that the LDIFLARE technique can objectively assess CIPN. The LDIFLARE results correlate well with subjective symptom scores and hence has utility in quantifying the severity of CIPN.
Survival in lung cancer patients with brain metastases compared to patients without CNS involvement: A retrospective registry-based outcomes analysis.
Authors: Usha Sree Chamarthy, Sandra Ann Mazzoni, Harsha Trivedi
Journal: Journal of Clinical Oncology (2014)

e19161 Background: Despite recent advances in prognostication with molecular markers, stage at diagnosis is still the most important determinant of lung cancer survival. In the USA >57% are Stage 4 at diagnosis and primary lung cancers account for >50% of intracranial metastases. In patients with brain metastases, one important factor found to influence survival includes extra-cranial disease burden. In this retrospective analysis, we sought to study the converse – the influence of brain metastases on survival. Methods: Using registry data between 2004-2008, stage 4 lung cancer patients were divided into stage 4 with brain mets (group A) and stage 4 without brain mets (group B). Both de novo stage 4 and delayed metastatic patients were included. Parameters analyzed included age, sex, histologic type (NSCLC sub-types and SCLC), brain metastases. Molecular markers (ALK, EGFR) data was not available. Results: Of the 487 lung cancer cases diagnosed, 47% (229) were considered to be metastatic. In both subgroups, more than 85% were Stage 4 at presentation. 13-15 % progressed from stage 3 at diagnosis. Small cell histology, as expected was less common – 18%, however, relatively more patients had evidence of CNS involvement (39%). This representation of histological subtypes persisted in the two study groups. There was a slight male predominance in both groups. About one third of the patients had brain metastases (Group A) and two-thirds had no CNS involvement. The median age in group A was only 51.5 years (range 41-84 years) compared to a median age of 79 years (range 24 – 90 years) in group B. Conclusions: Medial overall survival seemed to be slightly longer in patients without CNS involvement (6 months versus 7.5months). Very early deaths represented approximately 25% of the patients without brain metastases - this most likely represents the medical co-morbidities and more advanced age of the population in group B. In group A, the younger median age may be reflective of a more aggressive biology.
Development of a Novel Next-Generation Sequencing (NGS)-Based Assay for Measurable Residual Disease (MRD) in FLT3-ITD AML and Its Potential Clinical Application in Patients Treated with Chemotherapy Plus FLT3 Inhibitors
Authors: Mark J. Levis, Wenge Shi, Ken CN Chang, Christian Laing, Flora Berisha, Emily Adams, Christopher D Gocke, Wei Ding, Kenji Nakamaru, Jelveh Lameh, Reinhold Pollner, Ken Kobayashi
Journal: Blood (2018)
Microglial Cells Impact Gut Microbiota and Gut Pathology in Angiotensin II-Induced Hypertension
Authors: Ravindra K. Sharma, Tao Yang, Aline C. Oliveira, Gilberto O. Lobaton, Victor Aquino, Seungbum Kim, Elaine M. Richards, Carl J. Pepine, Colin Sumners, Mohan K. Raizada
Journal: Circulation Research (2019)

Rationale: Increased microglial activation and neuroinflammation within autonomic brain regions have been implicated in sustained hypertension, and their inhibition by minocycline—an anti-inflammatory antibiotic—produces beneficial effects. These observations led us to propose a dysfunctional brain-gut communication hypothesis for hypertension. However, it has been difficult to reconcile whether an anti-inflammatory or antimicrobial action is the primary beneficial effect of minocycline in hypertension. Accordingly, we utilized chemically modified tetracycline-3 (CMT-3)—a derivative of tetracycline that has potent anti-inflammatory activity—to address this question. Objective: Test the hypothesis that central administration of CMT-3 would inhibit microglial activation, attenuate neuroinflammation, alter selective gut microbial communities, protect the gut wall from developing hypertension-associated pathology, and attenuate hypertension. Methods and Results: Rats were implanted with radiotelemetry devices for recording mean arterial pressure. Ang II (angiotensin II) was infused subcutaneously using osmotic mini-pumps to induce hypertension. Another osmotic mini-pump was surgically implanted to infuse CMT-3 intracerebroventricularly. Intracerebroventricular CMT- 3 infusion was also investigated in SHR (spontaneously hypertensive rats). Physiological, pathological, immunohistological parameters, and fecal microbiota were analyzed. Intracerebroventricular CMT-3 significantly inhibited Ang II-induced increases in number of microglia, their activation, and proinflammatory cytokines in the paraventricular nucleus of hypothalamus. Further, intracerebroventricular CMT-3 attenuated increased mean arterial pressure, normalized sympathetic activity, and left ventricular hypertrophy in Ang II rats, as well as in the SHR. Finally, CMT-3 beneficially restored certain gut microbial communities altered by Ang II and attenuated pathological alterations in gut wall. Conclusions: These observations demonstrate that inhibition of microglial activation alone was sufficient to induce significant antihypertensive effects. This was associated with unique changes in gut microbial communities and profound attenuation of gut pathology. They suggest, for the first time, a link between microglia and certain microbial communities that may have implications for treatment of hypertension.
Molecular targeted therapy for osteosarcoma using glycogen synthase kinase-3 beta (GSK-3β) inhibitors.
Authors: Shingo Shimozaki, Norio Yamamoto, Hideji Nishida, Hiroaki Kimura, Akihiko Takeuchi, Takashi Kato, Yu Aoki, Takashi Higuchi, Toshinari Minamoto, Hiroyuki Tsuchiya
Journal: Journal of Clinical Oncology (2014)

10536 Background: Chemotherapy for osteosarcoma has improved the 5-year survival rate in osteosarcoma patients to 70%. However, development of new therapies for osteosarcoma is warranted, as chemotherapy is associated with several disadvantages such as toxicity and drug resistance. Although use of molecular targeted therapies has been reported for many types of cancer, their use in osteosarcoma treatment has not been reported yet. Glycogen synthase kinase-3 beta (GSK-3β) has been reported to sustain tumor cell survival, proliferation, and invasion in some types of cancer. Accordingly, GSK-3β has emerged as a potential therapeutic target for the treatment of cancer. Methods: Four osteosarcoma cell lines and 1 osteoblast cell line were used for this study. Each cell line was treated with the GSK-3β inhibitors, AR-A014418 and SB-216763. GSK-3β activity was analyzed for all cell lines using western blotting analysis. Cell viability and proliferation were analyzed using the WST-8 assay kit and the BrdU ELISA kit, respectively. Apoptosis that occurred after treatment with GSK-3β inhibitors was analyzed using the TUNEL imaging assay kit. Results: The expression of the active form of GSK-3β was high in all osteosarcoma cell lines as determined by western blotting analysis. Cell proliferation was suppressed in the 4 osteosarcoma cell lines 48 hours after the administration of GSK-3β inhibitors, but not in the osteoblast cell line. The IC50 of the GSK-3β inhibitors for each osteosarcoma cell line was below 20 μM. The t-test analysis showed a significant difference in cell proliferation in the osteosarcoma cell lines between the AR-A014418-treated group and the control group. Apoptosis was seen in all osteosarcoma cell lines but not in the osteoblast cell line. Conclusions: It was suspected that the activity of GSK-3β was strongly associated with cell proliferation in osteosarcoma. Our findings indicate that GSK-3β inhibitors could have a therapeutic effect on osteosarcomas in vivo. In the future, we aim to investigate the role of GSK-3β in osteosarcoma and to perform in vivo studies in mice transplanted with osteosarcoma cells to understand the mechanism underlying the therapeutic effect of GSK-3β inhibitors in this tumor.