tbuckley/cabot-search huggingface dataset:
Relationship of global DNA hypomethylation-mediated chromosomal instability to the initiation and progression of esophageal squamous cell carcinoma.
Authors: Hiroyuki Kawano, Hiroshi Saeki, Hiroyuki Kitao, Koji Ando, Shuhei Ito, Eiji Oki, Masaru Morita, Yoshihiko Maehara
Journal: Journal of Clinical Oncology (2014)

e15011 Background: Esophageal squamous cell carcinoma (ESCC) is one of the most aggressive malignancies. Both global DNA hypomethylation and p53 mutation occur in the early stage of development of ESCC. The methylation status of the LINE-1 element is a useful surrogate marker for global DNA methylation. Global DNA hypomethylation is associated with increased chromosomal instability and plays an important role in tumorigenesis. Elucidating the correlation of LINE-1 methylation level with tumor suppressor gene mutation, chromosomal instability and clinical significance in ESCC is important to facilitate the treatment of ESCC. Methods: Using resected tumor tissues and the corresponding normal esophageal mucosa from 105 patients with ESCC, bisulfite pyrosequencing analysis was performed to quantify the LINE-1 methylation levels. p53 mutations in exons 2 to 10 were detected by PCR direct sequencing. Chromosomal instability was assessed by single nucleotide polymorphism array comparative genomic hybridization analysis. Results: TheLINE-1 methylation level of ESCC was significantly lower than matched normal mucosa. LINE-1 methylation levels of patients’ normal esophageal mucosa had a significant inverse correlation with both cigarette smoking and alcohol consumption. LINE-1 hypomethylation in ESCC was significantly associated with lymph node metastasis, lymphovascular invasion, the frequency of p53 mutation and poor survivability. LINE-1 hypomethylation in ESCC had a strong correlation with chromosomal instability, including copy number alterations of some cancer-related genes. Conclusions: Global DNA hypomethylation caused by chronic inflammation could initiate esophageal squamous cell carcinogenesis through chromosomal instability. It also might correlate with the progression of ESCC through modulating the expression of some cancer-related genes.LINE-1 methylation levels might be useful for predicting the risk and prognosis of ESCC.
CTL to T-reg ratio as a biomarker in chemotherapy of metastatic colorectal cancer.
Authors: Teruo Sasatomi, Yutaka Ogata, Yoshito Akagi
Journal: Journal of Clinical Oncology (2014)

e14588 Background: Many multiple anti-cancer drugs regimens have been established for metastatic colorectal cancer recently. We investigated cellular immunoreaction of these patients to their cancer and useful predict biomarker of chemotherapy in colorectal cancer. Methods: 32 metastatic colorectal cancer patients have been started chemotherapies. Their PBMC were harvested and investigated their character by Fac scan with fluorescent labeled antibodies (CD3, CD8, CD4, CD25, Foxp3) at before and after chemotherapy. Results: (1.) After chemotherapy, both CTLs (CD3, CD8 positive) and regulatory T cells (CD4, CD25, Foxp3 positive) weredecreased in number among all patients. On the other hand, CTL/T reg ratio were significantly increased among tumor marker decreased patients and significantly decreased among tumor marker increased or stable patients. (2.) CEA levels among 85.7% of increased CTL/T reg ratio patients became to decrease less than half. CEA levels among 66.7% of decreased CTL/T reg ratio patients became to increase or to be stable, if their regimens have not been changed.(3.) The Reactive Rate of chemotherapy of CTL/T reg ratio increased patients was significantly higher than that of ratio decreased patients. (P=0.021). (4.) The Disease Control Rate of chemotherapy of CTL/T reg ratio increased patients was higher than that of ratio decreased patients. (5.) MST of the Ratio increased patients was 23 months, and that of the other patients was 13 months. Conclusions: We found that the CTL/T reg ratio of PBMC in metastatic colorectal cancer patients were useful for prediction of the effect of chemotherapy.
Maintenance with 5-Azacytidine for Acute Myeloid Leukemia and Myelodysplastic Syndrome Patients
Authors: Betul Oran, Marcos de Lima, Guillermo Garcia-Manero, Peter F Thall, Ruitao Lin, Amin M. Alousi, Chitra Hosing, Partow Kebriaei, Uday Popat, Sergio Giralt, Sairah Ahmed, Elizabeth J. Shpall, Borje S Andersson, Qaiser Bashir, Stefan O. Ciurea, Katy Rezvani, Glenda Woodworth, Richard E Champlin
Journal: Blood (2018)
Abstract 12577: The Efficacy and Safety of Third Generation P2Y12 Inhibitors in Women versus Men: A Sex-Specific Meta-Analysis
Authors: Emily S Lau, Eugene Braunwald, Sabina A Murphy, Stephen D Wiviott, Deepak L Bhatt, Robert A Harrington, Marc P Bonaca, Marc S Sabatine, Michelle L O’Donoghue
Journal: Circulation (2015)

Introduction: Sex-specific differences in the response to antiplatelet therapies have been described. Whether women and men derive comparable efficacy and safety from intensification of antiplatelet therapy with 3rd generation P2Y12 inhibitors is uncertain. Methods: A sex-specific meta-analysis was conducted of phase III or IV randomized trials that examined the efficacy and safety of 3 rd generation P2Y12 inhibitors in patients with CAD, including prasugrel, ticagrelor, and cangrelor. Five trials were included that enrolled a total of 19,536 women and 52,043 men based on published data. MACE was defined as the primary endpoint for each trial (components included CV death and MI for all trials). The safety endpoint was defined as non-CABG major bleeding for each trial. Data used for analyses were obtained from published reports. Results: Administration of a 3 rd generation P2Y12 inhibitor significantly reduced the risk of MACE by 14% in women (HR 0.86, 95% CI 0.77-0.95) and by 17% in men (HR 0.83, 95% CI 0.79-0.88) with no heterogeneity in the magnitude of effect (P interaction =0.66; Figure). The 3 rd generation P2Y12 inhibitors increased the risk of non-CABG major bleeding by 38% in women (HR 1.38, 95% CI 1.05-1.81) and by 50% in men (HR 1.50, 95% CI 1.09-2.07), again without heterogeneity (P interaction = 0.88). Conclusions: In randomized trials, the efficacy and safety of the 3 rd generation P2Y12 inhibitors were comparable between men and women. Since women remain undertreated with guideline-recommended therapies, these data support the administration of 3 rd generation P2Y12 inhibitors in women with appropriate indications for use.
Revealing the Secrets of Idiopathic Pulmonary Fibrosis
Authors: Richard K. Albert, David A. Schwartz
Journal: New England Journal of Medicine (2019)

Pathogenic findings in a mouse model of idiopathic pulmonary fibrosis confirm the pivotal role played by dysfunction of the type 2 alveolar (AT2) epithelial cells in causing the disease. The findings support the use of this model in future investigations.
Nasopharyngeal carcinoma patients with new primaries.
Authors: Musa Altun, Makbule Tambas, Emre Merdan Fayda
Journal: Journal of Clinical Oncology (2014)

6087 Background: Due to improvements in treatment, the importance of new primaries in nasopharyngeal carcinoma (NPC) patients is increasing. The aim of this study is to evaluate new primaries in NPC. Methods: NPC patients treated between 1980 and 2008 are divided according to age at diagnosis; pediatric (≤17), and adult (> 17). In each group, new primaries (NP) are classified depending on the organ, latent period, histopathology and location (in or out of the radiation field). Results: 97 pediatric, 709 adult were treated between 1980 and 2008. Male: female ratio of the whole group and the patients with NP are 2:1 and 3:1, respectively. Median follow-up time was 7 years. 7 (7%) pediatric, 44 (6%) adult patients had NP. All NP were confirmed histopathologically. 6 of the 7 NP detected in pediatric patients were in-field and 4 of them were sarcomas. In the adult group, 37 metachron, 3 synchronic, 5 previous tumors were observed. 35% of metachron primaries were in the irradiated area. Larynx and lung cancers were the commonest NP in the in-field and outfield primaries. Median latent period of metachron tumors was 125 months (range 11-462) (Table). 46% of NP were located in HNC region. The incidence of radiation induced sarcoma (RIS) was significantly higher in pediatrics compared with adults (4,12% vs.0,14%, p<0,005). Conclusions: The significantly increased incidence of RIS in pediatric NPC patients is striking. Viral or field-cancerization relationship in NP seems not as obvious as in other HNC. Physicians should be aware of NP during follow-up for early diagnosis in this group of patients. The characteristics of the new primaries. Age Timing Out-field In-field Total Organ Time interval (month) Organ Time interval ≤17 Previously to NPC Prostate 1 30 Larynx 1 310 5 Stomach 1 78 Tonsilla 1 690 HL 1 209 Synchronic Lung 1 0 Larynx 2 0 3 Metachron Lung 10 11,17,23,28,36,40,70,71,224 Larynx 5 11,14,88,141,162 36 Breast 3 23,26,56,145 Tonsilla 2 63,72 Colon 2 13 Oropharynx 1 108 Stomach 2 56 Palate 1 152 Prostate 1 244 Esophagus 1 169 Pancreas 1 41 Parotid 1 163 Kidney 1 171 Sarcoma 1 42 Bladder 1 22 NHL 1 42 Tymoma 1 46 ALL 1 95 Total 27 17 44 >17 Metachron Bladder RMS 1 61 Sarcoma 4 45,462,182,213 7 Tongue 1 240 HL 1 68 Total 1 6 Total 28 23 51
Body mass index (BMI) as prognostic in metastatic colorectal cancer (mCRC): A pooled analysis of 21 first-line trials in the ARCAD database.
Authors: Lindsay A. Renfro, Fotios Loupakis, Richard A. Adams, Matthew T. Seymour, Hans-Joachim Schmoll, Jean-Yves Douillard, Herbert Hurwitz, Charles S. Fuchs, Eduardo Diaz-Rubio, Rainer Porschen, Christophe Tournigand, Alfredo Falcone, Niall C. Tebbutt, J. Randolph Hecht, Cornelis J. A. Punt, Richard M. Goldberg, Leonard Saltz, Aimery De Gramont, Daniel J. Sargent, Heinz-Josef Lenz
Journal: Journal of Clinical Oncology (2014)

3537 Background: Recent retrospective analyses in early CRC showed low and high BMI associated with worse outcomes; limited data exist on BMI as a prognostic or predictive factor in mCRC. Methods: Data from 18,564 pts enrolled to 21 first line mCRC trials from 1997-2009 were pooled. BMI was studied as possibly non-linear in Cox models for overall survival (OS) and progression-free survival (PFS); both prognostic and predictive effects were tested. Adjustments for and interactions with age, sex, and performance status (PS) were considered. Subgroup analyses within anti-EGFR vs. anti-angiogenesis were performed. Clinically relevant effects with p < 0.05 were deemed significant. Results: BMI was prognostic for OS (p < 0.0001) and PFS (p < 0.0001) with “L” shape risk; i.e., risk of progression and/or death was greatest near BMI = 15, risk decreased as BMI increased to approximately BMI = 28, then plateaued. Relative to obese pts, low BMI pts had 46% increased risk of a PFS event and 85% increased risk of death. Low BMI was associated with poorer survival for males than females (interaction p = 0.0003); high BMI was associated with worse survival for patients with PS 2+ but not lower PS (interaction p = 0.003); other interactions and predictive tests were not significant. The BMI effect was similar in anti-EGFR and anti-angiogenesis therapy. Conclusions: Low BMI was associated with higher risk of progression or death among the mCRC trial pts studied, with decreased risk for higher BMI, opposite of reports in the adjuvant setting. Possible explanations include cancer cachexia in low BMI pts and increased dose or selection bias in high BMI pts, who may have comorbidities making them ineligible for clinical trials. Further study to understand the mechanisms of this association are warranted.
A Randomized, Controlled Trial of Cyclosporine A Cationic Emulsion in Pediatric Vernal Keratoconjunctivitis
Authors: Andrea Leonardi, Serge Doan, Mourad Amrane, Dahlia Ismail, Jesús Montero, János Németh, Pasquale Aragona, Dominique Bremond-Gignac
Journal: Ophthalmology (2018)

<h3>Purpose</h3> Vernal keratoconjunctivitis (VKC) is a chronic, allergic, and potentially severe ocular disease affecting children and adolescents that can lead to impaired quality of life (QoL) and loss of vision. This study evaluated the efficacy and safety of an investigational therapy for severe VKC, cyclosporine A (CsA) cationic emulsion (CE), an oil-in-water emulsion with increased bioavailability versus conventional CsA formulations. <h3>Design</h3> The VErnal KeratoconjunctiviTIs Study (VEKTIS) is a phase 3, multicenter, double-masked, vehicle-controlled trial. <h3>Participants</h3> Pediatric patients (4 to younger than 18 years) with active severe VKC (grade of 3 or 4 on the Bonini severity scale) and severe keratitis (corneal fluorescein staining [CFS] score of 4 or 5 on the modified Oxford scale). <h3>Methods</h3> One hundred sixty-nine patients were randomized to CsA CE 0.1% (1 mg/ml) eye drops 4 times daily (high dose), CsA CE twice daily (low dose) plus vehicle twice daily, or vehicle 4 times daily for 4 months. <h3>Main Outcome Measures</h3> The primary end point was a mean composite score that reflected CFS, rescue medication use (dexamethasone 0.1% 4 times daily), and corneal ulceration over the 4 months. <h3>Results</h3> Differences in least-squares means versus vehicle for the primary end point were statistically significant for both the high-dose (0.76; <i>P</i> = 0.007) and the low-dose (0.67; <i>P</i> = 0.010) groups, with treatment effect mainly driven by CFS score. Significant differences were found between both active treatment groups and vehicle for use of rescue medication. Vernal keratoconjunctivitis symptoms and patient QoL (assessed by visual analog scale and the Quality of Life in Children with Vernal Keratoconjunctivitis questionnaire) improved in all 3 groups, with significant improvements for high-dose CsA CE versus vehicle. <h3>Conclusions</h3> The efficacy of high-dose CsA CE in improving keratitis, symptoms, and QoL for those with severe VKC was demonstrated in these study patients. In addition, in this study cohort, CsA CE was well tolerated.
Identifying purine nucleoside phosphorylase as the target of quinine using cellular thermal shift assay
Authors: Jerzy M. Dziekan, Han Yu, Dan Chen, Lingyun Dai, Grennady Wirjanata, Andreas Larsson, Nayana Prabhu, Radoslaw M. Sobota, Zbynek Bozdech, Pär Nordlund
Journal: Science Translational Medicine (2019)

A cellular thermal shift assay (CETSA) protocol identifies and resolves antimalarial drug targets in P. falciparum .
Y-90 microsphere selective internal radiation treatment (SIRT) in treatment of primary and metastatic liver cancer.
Authors: Nakia Lashawn Brooks, Gaurav Patel, David J Weitz, Melinda Kelly, Madappa N. Kundranda
Journal: Journal of Clinical Oncology (2014)

e15174 Background: Y-90 SIRT is rapidly emerging as an effective treatment modality in patients with liver predominant disease. Aims: #1 Assess comparative efficacy and toxicity between Y-90 resin (R) (SIR-Spheres, Sirex Medical Ltd., Australia) and glass (G) microspheres (TheraSphere, MDS Nordion, Canada). #2 Determine prognostic prediction of baseline tumor enhancement by cross-sectional tumor imaging (CSTI)on survival. Methods: Retrospective chart review of patients treated with Y-90 between January 2010-Nov 2013. Review of a 26-point data collection sheet including demographics, tumor details, treatment history, toxicity and responses. Responses were evaluated by CT (RESIST) or PET/CT (PERCIST) by board-certified radiologists. Descriptive analysis (using Chi-Square or Fisher’s exact test) of the groups (G vs. R) and survival analysis were performed. CSTI was characterized as hypo, hyper or rim-enhancing. Results: Cohort N = 55 (G=21 vs. R=34); mean age = 51yrs; 49% females. ECOG (PS 0 = 20% ; PS 1-2=79%); Cancer Type: CRC 22%, HCC 20%, NET 15%, Cholangiocarcinoma 4%, others 40%; Extrahepatic involvement 60% and > 80% had ≥2 prior systemic treatments. No statistical differences were observed in the baseline characters between the 2 groups. No procedure related complications were noted and the overall toxicity profile (all grades) was similar in both groups; increased fatigue observed in the R group (50 vs. 19%, P=0.054). Grade 3 toxicities included thrombocytopenia (G=1 vs. R=2); abdominal pain (G=4 vs. R=3); hyperbilirubinemia (G= 0 vs. R=2) and nausea (G=0 vs. R=1).The tumors were hypervascular in 43% of the G group (vs. 15% R, P=0.038). Radiological responses: CR=5%, PR 63%, SD 9% and PD 18%. The median PFS after Y-90 was 4.6 months (CI 95%; 3.4-9) and median OS was 26.6 months (CI 95%; 11.3 - >36). There was no statistical survival difference between the G and R groups [trend favoring G (P=0.317)]. CSTI hyper enhancement at baseline was not significant, but favored better OS (P=0.094). Conclusions: We found no significant difference in efficacy and toxicity between G vs. R Y-90 microspheres. Future studies need to be conducted to determine the definitive role of CSTI in liver-directed therapy.
Cardiac outcomes in aging survivors of childhood cancer exposed to cardiotoxic therapy: A report from the St. Jude Lifetime (SJLIFE) Cohort Study.
Authors: Daniel A. Mulrooney, Gregory T. Armstrong, Sujuan Huang, Kirsten K. Ness, Vijaya Joshi, Daniel M. Green, Deo Kumar Srivastava, Aimee Santucci, Matthew J. Krasin, Leslie L. Robison, Melissa M. Hudson
Journal: Journal of Clinical Oncology (2014)

10025 Background: Cardiac studies among adult survivors of childhood cancer have generally relied on self-report or registry data; few have systematically performed comprehensive clinical assessments. Methods: We assessed 1,831 childhood cancer survivors, ≥ 18 yrs. of age and ≥10 yrs. from cardiotoxic therapy (radiation and/or anthracyclines). Cardiomyopathy (CMP), coronary artery disease (CAD), valve and conduction abnormalities, poor fitness (6-minute walk test < 490 minutes) and health status (SF-36 Physical Component score ≤ 40) were assessed. Cumulative prevalence was calculated by the Kaplan-Meir method. Cox proportional hazard models were used to calculate rate ratios (RR) and 95% confidence intervals (CI). Results: Survivors (52% male) were on average 8.3 yrs. (range: 0-21) at diagnosis and 32 yrs. (18-60) at evaluation. CMP was diagnosed in 6.7% (yield from screening 3.4%), CAD in 7.1% (yield 4.5%), valve disorders in 52% (yield 44%), and conduction abnormalities in 11% (yield 8%). By age 50 yrs. the estimated cumulative prevalence of CMP, CAD, valve and conduction disorders was 24% (CI 18-30%), 25% (CI 18-32%), 86% (CI 81-90%), and 42% (CI 34-49%), respectively. Diastolic dysfunction was present in 12%, and 18% of survivors had > 1 cardiac condition. Anthracycline exposure ≥ 250 mg/m2 increased the risk of CMP (RR 4.1, CI 2.3-7.2), valve disorders (RR 1.4, CI 1.1-1.9), and conduction abnormalities (RR 2.0, CI 1.3-3.2) compared to unexposed survivors. Radiation to the heart increased the risk of CAD (RR 3.5, CI 1.8-6.7), valve disorders (RR 1.3, CI 1.1-1.6), and conduction abnormalities (RR 1.5, CI 1.1-2.1) compared to those unexposed. Survivors with CMP and CAD had poorer physical fitness compared to those without (31% vs. 19%, p=0.006 and 37% vs. 20%, p=0.003), and lower health status among those with CMP (46% vs. 16%, p<0.001), CAD (49% vs. 16%, p<0.001), valve (27% vs. 18%, p<0.002) and conduction abnormalities (36% vs. 15%, p<0.001). Conclusions: A substantial proportion of survivors exposed to cardiotoxic therapy have cardiac disease by 50 years of age. Systematic screening of adult survivors of childhood cancer identified considerable subclinical disease.
Recent Advances in Function-Based Metagenomic Screening
Authors: Tanyaradzwa Rodgers Ngara, Houjin Zhang
Journal: Genomics Proteomics & Bioinformatics (2018)

Metagenomes from uncultured microorganisms are rich resources for novel enzyme genes. The methods used to screen the metagenomic libraries fall into two categories, which are based on sequence or function of the enzymes. The sequence-based approaches rely on the known sequences of the target gene families. In contrast, the function-based approaches do not involve the incorporation of metagenomic sequencing data and, therefore, may lead to the discovery of novel gene sequences with desired functions. In this review, we discuss the function-based screening strategies that have been used in the identification of enzymes from metagenomes. Because of its simplicity, agar plate screening is most commonly used in the identification of novel enzymes with diverse functions. Other screening methods with higher sensitivity are also employed, such as microtiter plate screening. Furthermore, several ultra-high-throughput methods were developed to deal with large metagenomic libraries. Among these are the FACS-based screening, droplet-based screening, and the in vivo reporter-based screening methods. The application of these novel screening strategies has increased the chance for the discovery of novel enzyme genes.
Needs and preferences of patients with BCC and SCC
Authors: S. Egmond, M. Wakkee, M. Droger, M.T. Bastiaens, A. Rengen, K.P. Roos, T. Nijsten, M. Lugtenberg
Journal: British Journal of Dermatology (2019)

Basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) are the two most common subtypes of skin cancer. About 5.5 million people worldwide had at least one of these cancers in 2013 and this number is still rising. To find out what the needs and preferences of these patients are about their healthcare, the authors (based at the dermatology department of the Erasmus MC in the Netherlands) invited skin cancer patients for group interviews. A total of 42 patients with either BCC or SCC participated and were divided into six groups to share their thoughts and ideas. These focus groups were all audio taped and transcribed literally. Next, these documents were loaded into the software programme ‘Atlas.ti’. Two of the authors assigned codes to the texts to capture the meaning of it. These codes were subsequently clustered in groups of codes dealing with the same topic. In the end the authors could determine which main topics were the most important to patients. The similarity in needs and preferences about healthcare between BCC and SCC patients was surprisingly high. Both patient groups indicated that they needed (1) to receive all relevant, tailored information (2) a physician that takes you seriously and communicates well (3) a short waiting period and the best treatment with direct results (4) to be seen by the same physician (5) a preference for dermatologist during treatment and (6) follow-up and (7) structured follow-up care (8) including a full body skin examination. In addition, BCC patients expressed the need for openness and transparency and to be involved in decisions about their healthcare. By knowing now what patients want, their perspectives could be added to current guidelines, and the patient could be put in the centre of care.
T cell receptor–triggered nuclear actin network formation drives CD4 <sup>+</sup> T cell effector functions
Authors: N. Tsopoulidis, S. Kaw, V. Laketa, S. Kutscheidt, C. Baarlink, B. Stolp, R. Grosse, O. T. Fackler
Journal: Science Immunology (2019)

This study defines calcium-dependent actin polymerization by nuclear Arp2/3 complex as essential for CD4 + T cell help.