tbuckley/cabot-search huggingface dataset:
Genetic Predisposition to Therapy-Related Myeloid Neoplasm By Rare, Deleterious Germline Variants in DNA Repair Pathway and Myeloid Driver Genes
Authors: Deepak Singhal, Christopher N. Hahn, Cassandra M. Hirsch, Amilia Wee, Monika M Kutyna, Milena Babic, Rakchha Chhetri, Smita Hiwase, Wendy Parker, Jinghua Feng, Andreas Schreiber, Joel Goeghegan, Peer Arts, Nimit Singhal, Karin Kassahn, Susan Branford, Anna L. Brown, Ian D Lewis, Richard D'Andrea, Hamish S. Scott, Jaroslaw P. Maciejewski, Devendra K Hiwase
Journal: Blood (2018)
Thiol–Gelatin–Norbornene Bioink for Laser‐Based High‐Definition Bioprinting
Authors: Agnes Dobos, Jasper Van Hoorick, Wolfgang Steiger, Peter Gruber, Marica Markovic, Orestis G. Andriotis, Andreas Rohatschek, Peter Dubruel, Philipp J. Thurner, Sandra Van Vlierberghe, Stefan Baudis, Aleksandr Ovsianikov
Journal: Advanced Healthcare Materials (2019)

Two-photon polymerization (2PP) is a lithography-based 3D printing method allowing the fabrication of 3D structures with sub-micrometer resolution. This work focuses on the characterization of gelatin-norbornene (Gel-NB) bioinks which enables the embedding of cells via 2PP. The high reactivity of the thiol-ene system allows 2PP processing of cell-containing materials at remarkably high scanning speeds (1000 mm s-1 ) placing this technology in the domain of bioprinting. Atomic force microscopy results demonstrate that the indentation moduli of the produced hydrogel constructs can be adjusted in the 0.2-0.7 kPa range by controlling the 2PP processing parameters. Using this approach gradient 3D constructs are produced and the morphology of the embedded cells is observed in the course of 3 weeks. Furthermore, it is possible to tune the enzymatic degradation of the crosslinked bioink by varying the applied laser power. The 3D printed Gel-NB hydrogel constructs show exceptional biocompatibility, supported cell adhesion, and migration. Furthermore, cells maintain their proliferation capacity demonstrated by Ki-67 immunostaining. Moreover, the results demonstrate that direct embedding of cells provides uniform distribution and high cell loading independently of the pore size of the scaffold. The investigated photosensitive bioink enables high-definition bioprinting of well-defined constructs for long-term cell culture studies.
A phase II trial of BAY 43–9006 in metastatic melanoma with molecularly characterized B-Raf status
Authors: E. Hardin, A. C. Pavlick, L. Liebes, I. Osman, A. Hamilton, J. Soon, D. Polsky, K. Friedman, J. Wright, F. Muggia
Journal: Journal of Clinical Oncology (2006)

8046 Background: BAY 43–9006 is a multikinase inhibitor. The RAS/BRAF/MEK/MAPK pathway (pw) is a major pw for transmitting extracellular growth factor signals to the nucleus. Activating mutations in any of the pw kinases would be expected to result in uncontrolled cell proliferation. Approximately 60% of melanomas carry B-Raf mutations. The primary trial goals are: 1) determine if treatment (tx) with BAY 43–9006 can disrupt the RAS/BRAF/MEK/MAPK pw by depleting intra-tumor stores of B-Raf and/or CDK4; and 2) determine if tx with BAY 43–9006 results in differential anti-tumor responses in pts whose tumors have been molecularly characterized. Methods: Eligibility criteria: Biopsy (bx)-accessible, untreated metastatic melanoma. Measurable disease (RECIST). Adequate hematologic and serologic parameters. Signed ICF. All pts had tumor bx for B-Raf status determined by PCR sequencing prior to tx. Exon 3 of N-Ras and exon 15 of B-Raf were sequenced. Pts stratified by B-Raf. Tx: BAY 43–9006 was administered at 400 mg po BID. D1–28 q4w. Repeat bx was done on Day 28. Re-imaging was done every 2 cycles and pts treated until POD. Stats: Stratification by B-Raf mutation status. 2 stage study design with accrual of 13 pts/arm in first stage and total of 29 pts/arm if ≥ 1 objective response (OR) in initial cohort. Results: 8 pts (2-M1a, 1-M1b, 5-M1c) enrolled. 7 wild type (WT) and 1 mutant (M) B-Raf. Median age: 54 (range 22–91). No pts with LDH ≥ 1.5 × nl. 2 withdrew prior to tx. Responses: M B-Raf (1 evaluable)-PR (lymph nodes and large SQ arm masses); WT B-Raf-1 POD during cycle 1 (NE), 1PD, 3 too early. Toxicity: Grade I diarrhea, Grade II hypertension, fatigue and oral mucositis. Correlative immunoassays of tumor B-Raf, CDK4, phospho-MAPK and cyclin-D1 and correlation of DNA extracted from peripheral blood cells assayed by fluorescent, mutant-specific PCR and tumor B-RAF are being evaluated. Conclusions: This Phase II trial will molecularly characterize tumors for B-Raf status prior to tx with BAY 43–9006 and assess the effects on Ras-Raf signaling and correlate clinical responses. This trial will address potential differences in sensitivity to BAY 43–9006 based on B-Raf. While premature, 1 pt with M B-Raf has had an OR with a significant decrease in tumor volume. Supported by NCI N01-CM17103 and TRI. No significant financial relationships to disclose.
Assessment of efficacy, safety, and tolerability of aprepitant in adult patients with chemotherapy-induced vomiting
Authors: A. D. Sharma, P. K. Julka, A. Rastogi, T. Suri, G. K. Rath, B. N. Sharma, V. P. Baliga
Journal: Journal of Clinical Oncology (2009)

e20729 Background: Approximately 70 to 80% of all cancer patients receiving chemotherapy experience emesis and 10 to 44% experience anticipatory emesis. Aprepitant a neurokinin 1 (NK 1) receptor antagonist is used in chemotherapy induced nausea and vomiting. The present study was undertaken to assess efficacy, safety, and tolerability of Aprepitant in adult patients with chemotherapy induced nausea and vomiting. Methods: The study was conducted as a prospective, multicenter, randomized, open label, single group, phase III study in adult patients with chemotherapy induced nausea and vomiting and patients admitted to hospital for any type of cancer. The final protocol was approved by the Institutional ethics committee before the initiation of the study. Informed consent was obtained from all the patients before enrollment in the study. Aprepitant capsules were given in the dose of 125mg orally one hour prior to chemotherapy on day 1 followed by 80 mg orally in the morning on days 2 &amp; 3.Aprepitant was combined with oral Dexamethasone 12mg oral 30 minutes prior to chemotherapy on day one and 8mg on the following two days. Efficacy of aprepitant was evaluated through number of emetic episodes within 24 hours or requirement for the rescue medication. Self assessment of nausea was done by patients using a 100 mm visual analog scale. Safety and tolerability was assessed through monitoring of adverse events and physical examination. Results: A total 30 patients (13 males) (mean age 40.45 years) were enrolled in the study. Significant (p&lt;0.05)changes in emetic episodes were seen after treatment with aprepitant. Overall global assessment of vomiting indicated that 19 patients (82.6 %) had very good improvement, 3 patients (13%) had good improvement and one patient (4.4%) showed fair improvement after treatment with aprepitant. The most common adverse events included fever, headache, diarrhoea skin rash, constipation, and blisters. Severity of adverse events was mild to moderate and the adverse events disappeared with continued therapy. Conclusions: Treatment with aprepitant is a useful therapeutic option for the management of chemotherapy induced nausea and vomiting. [Table: see text]
Quality and accessibility of oncology-related clinical trials information: A content analysis of Internet media.
Authors: Gregory Alan Abel, Angel Cronin, Angela Stroupe, Kristofer Earles, Stacy W. Gray
Journal: Journal of Clinical Oncology (2013)

6547 Background: The Internet is a communication tool that may be used to improve awareness of and access to cancer-related clinical trials; however, few data characterize how the Internet may encourage clinical trial education and accrual. Methods: In January of 2013, we simulated the experience of a user without knowledge of clinical trials by simply searching “breast cancer treatment”; “lung cancer treatment”; “MDS treatment”; and “prostate cancer treatment” in three popular search engines (Google, Bing, and Yahoo). The top ten unsponsored websites for each were recorded, after eliminating news articles and duplications. Sites were independently evaluated for quality and accessibility by two coders, and discordant data were resolved by consensus. Differences in content by disease type were evaluated using Fisher’s exact tests. Results: The searches yielded 40 unique websites. Before consensus, inter-observer agreement ranged from 75% to 100% (average kappa .67). Overall, 85% of the sites (95% CI: 70% to 94%) mentioned clinical trials on the landing page. Selected measures of quality and accessibility are detailed in the table. Lung cancer and MDS sites were less likely to have interactive features as compared to breast and prostate cancer sites (20% vs. 82%, p=0.004). Conclusions: These data suggest that basic clinical trial information is widely available for naive users searching for cancer treatment information. The quality of that information is highly variable, with only about three-quarters of sites defining clinical trials, one-half providing information about the benefits and risks of enrollment, and only one third of sites Health on Net certified. Moreover, for certain cancers, few sites offer interactive features to facilitate access to information about relevant clinical trials. [Table: see text]
Impact of skeletal related events (SREs) on health-related quality of life (HRQoL) and healthcare resource utilization (HRU) in prostate cancer patients with bone metastases (BM).
Authors: Jorge Arellano, Kristina S Chen, Carolyn Atchison, Alex Rider, Andrew Worsfold, Helen Collins
Journal: Journal of Clinical Oncology (2013)

e16046 Background: Advanced prostate cancer often leads to the development of BM and as a result SREs. Treatment and management of SREs, as well as the underlying disease, influences the patient’s HRQoL and HRU. We evaluated the impact of SREs on HRQoL (FACT-P) and HRU in patients with BM. Methods: Data were extracted from the Adelphi Prostate Cancer Disease-Specific Programme (DSP), a cross-sectional survey of 150 urologists and oncologists and their prostate cancer patients conducted from March to June 2012 in the US. Each specialist completed comprehensive record forms on 12 of their patients being treated for prostate cancer. Patients were invited to complete a questionnaire, which included the FACT-P HRQoL instrument. Patients were stratified by SRE experience to assess the impact of SRE on patients with BM. SRE was defined as an event of bone radiation, bone surgery, fracture, or spinal cord compression. Results: Data were collected from 1,749 prostate cancer patients, of which 941 were identified with BM; SRE status was recorded in 499 BM patients (Table). HRQoL was significantly lower in patients experiencing SREs, while the rate of consultations and likelihood of being hospitalized was significantly higher. Conclusions: SREs result in a significant economic burden on the healthcare system and negative impact on HRQoL in prostate cancer patients with BM. [Table: see text]
PREPARATION FOR MARRIAGE
Authors: Th. H. van de Velde
Journal: BMJ (1932)

This is the first report describing up-regulation of telomerase activity in human normal cells. Telomerase, a ribonucleoprotein enzyme, has been thought to be involved in maintaining telomere length stability in germline and most cancer cells, but not in normal cells. However, in the present study, we demonstrate that telomerase activity is detectable at low levels in normal human T and B cells, increases by in vitro mitogenic stimulation, increases in hematopoietic progenitor cells upon their proliferation and differentiation, and decreases with aging. Understanding the regulation of telomerase activity in normal cells may provide important insights not only into the mechanisms of normal cellular senescence but also into the mechanisms of telomerase activity deregulation as part of cancer development.
Chronic lymphocytic leukemia: 2020 update on diagnosis, risk stratification and treatment
Authors: Michael Hallek
Journal: American Journal of Hematology (2019)

Abstract Disease overview Chronic lymphocytic leukemia (CLL) is the commonest leukemia in western countries. The disease typically occurs in elderly patients and has a highly variable clinical course. Leukemic transformation is initiated by specific genomic alterations that impair apoptosis of clonal B‐cells. Diagnosis The diagnosis is established by blood counts, blood smears, and immunophenotyping of circulating B‐lymphocytes, which identify a clonal B‐cell population carrying the CD5 antigen, as well as typical B‐cell markers. Prognosis The two similar clinical staging systems, Rai and Binet, create prognostic information by using results of physical examination and blood counts. Various biological and genetic markers also have prognostic value. Deletions of the short arm of chromosome 17 ( del [17p] ) and/or mutations of the TP53 gene, predict resistance to chemoimmunotherapy and a shorter time to progression, with most targeted therapies. A comprehensive, international prognostic score (CLL‐IPI) integrates genetic, biological and clinical variables to identify distinct risk groups of CLL patients. Therapy Only patients with active or symptomatic disease, or with advanced Binet or Rai stages require therapy. When treatment is indicated, several options exist for most CLL patients: a combination of venetoclax with obinutuzumab, ibrutinib monotherapy, or chemoimmunotherapy. For physically fit patients younger than 65 (in particular when presenting with a mutated IGVH gene), chemoimmunotherapy with fludarabine, cyclophosphamide and rituximab remains a standard therapy, since it may have curative potential. At relapse, the initial treatment may be repeated, if the treatment‐free interval exceeds 3 years. If the disease relapses earlier, therapy should be changed using an alternative regimen. Patients with a del (17p) or TP53 mutation are a different, high‐risk category and should be treated with targeted agents. An allogeneic SCT may be considered in relapsing patients with TP53 mutations or del (17p) , or patients that are refractory to inhibitor therapy. Future Challenges Targeted agents (ibrutinib, idelalisib, venetoclax, obinutuzumab) will be increasingly used in combination to allow for short, but potentially definitive therapies of CLL. It remains to be proven that they generate a superior outcome when compared to monotherapies with inhibitors of Bruton tyrosine kinase, which can also yield long‐lasting remissions. Moreover, the optimal sequencing of drug combinations is unknown. Therefore, CLL patients should be treated in clinical trials whenever possible.
Circulating adhesion molecules and subclinical interstitial lung disease: the Multi-Ethnic Study of Atherosclerosis
Authors: Claire F. McGroder, Carrie P. Aaron, Suzette J. Bielinski, Steven M. Kawut, Russell P. Tracy, Ganesh Raghu, R. Graham Barr, David J. Lederer, Anna J. Podolanczuk
Journal: European Respiratory Journal (2019)

Adhesion molecules may contribute to the development of interstitial lung disease (ILD) and have been proposed as prognostic biomarkers in idiopathic pulmonary fibrosis. Our objective was to determine whether the circulating adhesion molecules soluble intracellular adhesion molecule (sICAM)-1, soluble vascular cell adhesion molecule (sVCAM)-1 and P-selectin are associated with subclinical ILD in community-dwelling adults.The Multi-Ethnic Study of Atherosclerosis enrolled males and females aged 45-84 years from six communities in the United States in 2000-2002. High attenuation areas were defined as the percentage of imaged lung volume with attenuation -600--250 HU on cardiac computed tomography (CT). Interstitial lung abnormalities were visually assessed on full-lung CT. Spirometry was performed on a subset of individuals. ILD hospitalisations and deaths were adjudicated.In fully adjusted analyses, higher levels of sICAM-1, sVCAM-1 and P-selectin were associated with greater high attenuation areas (2.94%, 95% CI 1.80-4.07%; 1.24%, 95% CI 0.14-2.35%; and 1.58%, 95% CI 0.92-2.23%, respectively), and greater rate of ILD hospitalisations (HR 1.36, 95% CI 1.03-1.80; 1.40, 95% CI 1.07-1.85; and 2.03, 95% CI 1.16-3.5, respectively). sICAM-1 was associated with greater prevalence of interstitial lung abnormalities (OR 1.39, 95% CI 1.13-1.71). sICAM-1 and P-selectin were associated with lower forced vital capacity (44 mL, 95% CI 12-76 mL and 29 mL, 95% CI 8-49 mL, respectively). sVCAM-1 and P-selectin were associated with increased risk of ILD death (HR 2.15, 95% CI 1.26-3.64 and 3.61, 95% CI 1.54-8.46, respectively).Higher levels of circulating sICAM-1, sVCAM-1 and P-selectin are independently associated with CT and spirometric measures of subclinical ILD, and increased rate of adjudicated ILD events among community-dwelling adults.
Epidemiology and health outcomes of sarcoidosis in a universal healthcare population: a cohort study
Authors: Lee M. Fidler, Meyer Balter, Jolene H. Fisher, Teresa To, Matthew B. Stanbrook, Andrea Gershon
Journal: European Respiratory Journal (2019)

Sarcoidosis-related mortality appears to be rising in North America, with increasing rates in females and the elderly. We aimed to estimate trends in sarcoidosis incidence, prevalence and mortality in Ontario, Canada.We performed a cohort study using health administrative data from Ontario between 1996 and 2015. International Classification of Diseases and Ontario Health Insurance Plan codes were used for case detection. Three disease definitions were created: 1) sarcoidosis, two or more physician claims within 2 years; 2) chronic sarcoidosis, five or more physician claims within 3 years; and 3) sarcoidosis with histology, two or more physician claims with a tissue biopsy performed between claims.Overall, 18 550, 9199 and 3819 individuals with sarcoidosis, chronic sarcoidosis and sarcoidosis with histology, respectively, were identified. The prevalence of sarcoidosis was 143 per 100 000 in 2015, increasing by 116% (p<0.0001) from 1996. The increase in age-adjusted prevalence was higher in males than females (136% versus 99%; p<0.0001). The incidence of sarcoidosis declined from 7.9 to 6.8 per 100 000 between 1996 and 2014 (15% decrease; p=0.0009). A 30.3% decrease in incidence was seen among females (p<0.0001) compared with a 5.5% increase in males (p=0.47). Age- and sex-adjusted mortality rates of patients with sarcoidosis rose from 1.15% to 1.47% between 1996 and 2015 (28% increase; p=0.02), with the overall trend being nonsignificant (p=0.39). Mortality rates in patients with chronic sarcoidosis increased significantly over the study period (p=0.0008).The prevalence of sarcoidosis is rising in Ontario, with an apparent shifting trend in disease burden from females to males. Mortality is increasing in patients with chronic sarcoidosis.
6-Phosphofructo-2-Kinase/Fructose-2,6-Biphosphatase-2 Regulates TP53-Dependent Paclitaxel Sensitivity in Ovarian and Breast Cancers
Authors: Hailing Yang, Zhang Shu, Yongying Jiang, Weiqun Mao, Lan Pang, Abena Redwood, Sabrina L. Jeter-Jones, Nicholas B. Jennings, Argentina Ornelas, Jinhua Zhou, Cristian Rodriguez-Aguayo, Geoffrey Bartholomeusz, LaKesla R. Iles, Niki M. Zacharias, Steven W. Millward, Gabriel Lopez-Berestein, Xiao-Feng Le, Ahmed A. Ahmed, Helen Piwnica-Worms, Anil K. Sood, Robert C. Bast, Zhen Lu
Journal: Clinical Cancer Research (2019)

Paclitaxel is an integral component of primary therapy for breast and epithelial ovarian cancers, but less than half of these cancers respond to the drug. Enhancing the response to primary therapy with paclitaxel could improve outcomes for women with both diseases.Experimental Design: Twelve kinases that regulate metabolism were depleted in multiple ovarian and breast cancer cell lines to determine whether they regulate sensitivity to paclitaxel in Sulforhodamine B assays. The effects of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 2 (PFKFB2) depletion on cell metabolomics, extracellular acidification rate, nicotinamide adenine dinucleotide phosphate, reactive oxygen species (ROS), and apoptosis were studied in multiple ovarian and breast cancer cell lines. Four breast and ovarian human xenografts and a breast cancer patient-derived xenograft (PDX) were used to examine the knockdown effect of PFKFB2 on tumor cell growth in vivo.Knockdown of PFKFB2 inhibited clonogenic growth and enhanced paclitaxel sensitivity in ovarian and breast cancer cell lines with wild-type TP53 (wtTP53). Silencing PFKFB2 significantly inhibited tumor growth and enhanced paclitaxel sensitivity in four xenografts derived from two ovarian and two breast cancer cell lines, and prolonged survival in a triple-negative breast cancer PDX. Transfection of siPFKFB2 increased the glycolysis rate, but decreased the flow of intermediates through the pentose-phosphate pathway in cancer cells with wtTP53, decreasing NADPH. ROS accumulated after PFKFB2 knockdown, which stimulated Jun N-terminal kinase and p53 phosphorylation, and induced apoptosis that depended upon upregulation of p21 and Puma.PFKFB2 is a novel target whose inhibition can enhance the effect of paclitaxel-based primary chemotherapy upon ovarian and breast cancers retaining wtTP53.