tbuckley/cabot-search huggingface dataset:
Versatile and Finely Tuned Albumin Nanoplatform based on Click Chemistry
Authors: Ji Yong Park, Myung Geun Song, Kyu Wan Kim, Nadeem Ahmed Lodhi, Jin Yeong Choi, Young Ju Kim, Jung Young Kim, Hyewon Chung, Chiwoo Oh, Yun-Sang Lee, Keon Wook Kang, Hyung-Jun Im, Seung Hyeok Seok, Dong Soo Lee, Edmund E. Kim, Jae Min Jeong
Journal: Theranostics (2019)

Albumin is one of the most attractive nanoplatforms for targeted imaging and drug delivery due to its biocompatibility and long circulation half-life.However, previously reported albumin-based nanoplatforms have shown inconsistent blood circulation half-life according to the modified methods, and the affecting factors were not well evaluated, which could hamper the clinical translation of albumin-based nanoplatforms.Herein, we developed a finely tuned click-chemistry based albumin nanoplatform (CAN) with a longer circulation half-life and an efficient tumor targeting ability.Methods: CAN was synthesized in two steps.First, albumin was conjugated with ADIBO-NHS (albumin-ADIBO) by reacting albumin with various molar ratios of ADIBO.The number of attached ADIBO moieties was determined using matrix-assisted laser desorption ionization time of flight (MALDI-TOF).Second, the desired modalities including azide-functionalized chelator, a fluorescence dye, and folate were incorporated into albumin-ADIBO using strain-promoted alkyne-azide cycloaddition reaction (SPAAC reaction).The biodistribution and targeting efficiency of functionalized CANs were demonstrated in mice. Results:The degree of functionalization (DOF) and resulting in vivo biodistribution was controlled precisely using the click chemistry approach.Specifically, the numbers of attached azadibenzocyclooctyne (ADIBO) moieties on albumin, the DOF, were optimized by reacting albumin with varying molar ratios of ADIBO with a high reproducibility.Furthermore, we developed a simple and efficient method to estimate the DOF using UV-visible spectrophotometry (UV-vis), which was further validated by matrix-assisted laser desorption ionization time of flight (MALDI-TOF).The biodistribution of CAN could be controlled by DOF, and CAN with an optimized DOF showed a long circulation half-life (> 18 h).CAN was further functionalized using a simple click chemistry reaction with an azide functionalized chelator, a fluorescence dye, and folate. 64Cu-and folate-labeled CAN ( 64 Cu-CAN-FA) showed effective and specific folate receptor targeting in vivo, with an over two-fold higher uptake than the liver at 24 h post-injection.Conclusions: Our development from the precisely controlled DOF demonstrates that an optimized CAN can be used as a multifunctional nanoplatform to obtain a longer half-life with radioisotopes and ligands, and provides an effective method for the development of albumin-based tumor theranostic agents.
Cycling is associated with a lower incidence of cardiovascular diseases and death: Part 1 – systematic review of cohort studies with meta-analysis
Authors: Solveig Nordengen, Lars Bo Andersen, Ane K Solbraa, Amund Riiser
Journal: British Journal of Sports Medicine (2019)

Objectives Physical inactivity is a risk factor for cardiovascular disease (CVD). Cycling as a physical activity holds great potential to prevent CVD. We aimed to determine whether cycling reduces the risk of CVD and CVD risk factors and to investigate potential dose-response relationships. Design Systematic review and meta-analysis of quantitative studies. Eligibility criteria for selecting studies We searched four databases (Web of Science, MEDLINE, SPORTDiscus and Scopus). All quantitative studies, published until August 2017, were included when a general population was investigated, cycling was assessed either in total or as a transportation mode, and CVD incidence, mortality or risk factors were reported. Studies were excluded when they reported continuous outcomes or when cycling and walking were combined in them. We pooled adjusted relative risks (RR) and OR. Heterogeneity was investigated using I. Results The search yielded 5174 studies; 21 studies which included 1,069,034 individuals. We found a significantly lower association in combined CVD incidence, mortality and physiological risk factors with total effect estimate 0.78 (95% CI (CI): 0.74–0.82; P&lt;0.001; I 2 =58%). Separate analyses for CVD incidence, mortality and risk factors showed estimates of RR 0.84 (CI, 0.80 to 0.88; P&lt;0.001; I 2 =29%), RR 0.83 (CI, 0.76 to 0.90; P&lt;0.001; I 2 =0%), and OR 0.75 (CI, 0.69 to 0.82; P&lt;0.001; I 2 =66%), respectively. We found no dose-response relationship or sex-specific difference. Conclusions Any form of cycling seems to be associated with lower CVD risk, and thus, we recommend cycling as a health-enhancing physical activity. Systematic review registration Prospero CRD42016052421.
A comprehensive meta-analysis of endocrine immune-related adverse events of immune checkpoint inhibitors and outcomes in head and neck cancer and lung cancer.
Authors: Cristiane Jeyce Gomes-Lima, John Kwagyan, Fred King, Stephen J Fernandez, Kenneth D Burman, Irina Veytsman
Journal: Journal of Clinical Oncology (2019)

e14096 Background: Immune checkpoint inhibitors (ICPi) have emerged as an effective treatment for a variety of cancers. However, important immune-related adverse events (irAEs) can occur. The aim of this study was to determine the prevalence of endocrine irAEs in patients with head and neck cancer and lung cancer that have used a ICPi and outcomes. Methods: A systematic literature review was performed within PubMed and EMBASE databases. Search terms included “durvalumab”, “atezolizumab”, “nivolumab”, “pembrolizumab”, “ipilimumab”, “head &amp; neck cancer”, “lung cancer”. Studies published before September 2018 were included. The search was limited to randomized controlled trials (RCTs) phase III written in English. Data were extracted about patient characteristics, interventions, overall survival (OS), progression free survival (PFS), and endocrine irAEs. A summary hazard ratio (HR) and 95% confidence interval were calculated using the software Comprehensive Meta-Analysis and a scatter plot was generated. Results: Twelve RCTs comprising 7060 patients were reviewed; 3815 used an ICPi (treatment arm). The mean follow-up time of 12.2 months ± 7.1 SD. The survival rate of the treatment arm was enhanced (HR, 0.75; 95% CI, 0.70-0.80), compared to the alternate arm. Similarly, the PFS of the treatment arm was improved (HR, 0.77; 95% CI, 0.72-0.81) but with a higher incidence of endocrine irAEs. The most common endocrine irAE reported was hypothyroidism;193 patients in the treatment arm vs. 29 in the alternate arm (p &lt; 0.001); grade 3/4 AE was observed in 10 patients vs. 1 patient, respectively. Other endocrine irAEs were reported in 168 patients in the treatment arm vs. 26 patients in the alternate arm (p &lt; 0.001); grade 3/4 AE was observed in 28 patients vs. 3 patients, respectively. A significant positive correlation between endocrine irAEs and OS was observed (p = 0.019). Conclusions: ICPi are a powerful tool in the treatment of cancer. The prevalence of endocrine irAEs in this meta-analysis was 9%. There is evidence of improved overall survival in patients who developed endocrine irAEs. Further studies are needed to correlate the development of irAEs and OS advantage.
Role of tropomyosin 4 gene misregulation in colon epithelial cell tumorigenesis.
Authors: Mony Pheachnak Son, Michael Papetti
Journal: Journal of Clinical Oncology (2019)

e15184 Background: Ordered migration of colon epithelial cells from the bottom to the top of the crypt is required for their differentiation. Because aberrant colon cell migration may contribute to early stages of colon tumorigenesis, elucidation of how this migration is regulated provides insight into how colon cancer can be prevented and treated before malignancy. Certain actin-binding tropomyosins, including tropomyosin 4 (TPM4), regulate cytoskeletal contractility and migration in many different cell types. Methods: To determine whether aberrant TPM4 regulation may be an early event in colon cell tumorigenesis, we measured TPM4 RNA expression in uninvolved, grossly normal colon tissue from 10 human familial adenomatous polyposis (FAP) patients genetically predisposed to colon cancer versus 7 patients not genetically predisposed (normal). We also examined TPM4 expression in a colon adenocarcinoma cell line (Caco2). These are highly proliferative, undifferentiated cells but can be induced to growth arrest and differentiate, thus acquiring many characteristics of normal absorptive colon epithelial cells. Reporter assays were used to identify sequences that regulate TPM4 gene expression in Caco2 cells. Results: Average TPM4 RNA expression is 2.59 fold higher in the FAP versus normal tissue. TPM4 RNA and protein are highly expressed in proliferating, undifferentiated Caco2 cells but are severely reduced in growth arrested, differentiated cells. Reporter assays have identified genetic regions, near the TPM4 transcriptional start site, that may regulate TPM4 gene expression in proliferating Caco2 cells. Conclusions: This data suggests that aberrantly upregulated TPM4 may be an early event in colon tumorigenesis and that normal TPM4 expression, by fostering ordered colon epithelial cell migration, may promote normal cell differentiation and mitigate adoption of a premalignant state.
Correlations between multiple molecular markers' expression and survival in patients with glioblastoma multiforme treated with the current standard treatment
Authors: Daniela A Bota, Kathy L Newell, Marsha Danley, Marilyn Davis, Richard Dubinsky, Sarah A Taylor
Journal: Neuro-Oncology (2006)

Author(s): Bota, Daniela A; Newell, Kathy L; Danley, Marsha; Davis, Marilyn; Dubinsky, Richard; Taylor, Sarah A
Ethical and Regulatory Considerations for Using Social Media Platforms to Locate and Track Research Participants
Authors: Ananya Bhatia-Lin, Alexandra Boon-Dooley, Michelle K. Roberts, Caroline Pronai, Dylan Fisher, Lea Parker, Allison Engstrom, Leah Ingraham, Doyanne Darnell
Journal: The American Journal of Bioethics (2019)

As social media becomes increasingly popular, human subjects researchers are able to use these platforms to locate, track, and communicate with study participants, thereby increasing participant retention and the generalizability and validity of research. The use of social media; however, raises novel ethical and regulatory issues that have received limited attention in the literature and federal regulations. We review research ethics and regulations and outline the implications for maintaining participant privacy, respecting participant autonomy, and promoting researcher transparency when using social media to locate and track participants. We offer a rubric that can be used in future studies to determine ethical and regulation-consistent use of social media platforms and illustrate the rubric using our study team's experience with Facebook. We also offer recommendations for both researchers and institutional review boards that emphasize the importance of well-described procedures for social media use as part of informed consent.
Gaining insights into the DICER1 syndrome: An early report from the Italian DICER1 registry.
Authors: Arcangela De Nicolo, Daniela Turchetti, Fulvia Brugnoletti, Lisa Elefanti, Amanda Field, Giovanni Innella, Rossella Tita, Irene Feroce, Maria Grazia Pomponi, Roberta Zuntini, Alessandra Renieri, Bernardo Bonanni, Chrysi Kanellopoulou, Maria Teresa Landi, D. Ashley Hill, Chiara Menin, Maurizio Genuardi
Journal: Journal of Clinical Oncology (2019)

1519 Background: DICER1 is a key endoribonuclease in the microRNA pathway that modulates gene expression. Germline loss of function variants in DICER1, first found in pleuropulmonary blastoma, have been subsequently linked to a variety of cancerous (and non) conditions referred to as DICER1 syndrome. In 2018, the Italian Society of Human Genetics launched an initiative aimed at establishing a national registry of DICER1 germline sequence variants. Methods: Centers involved in genetic testing for cancer predisposition were asked to report any identified DICER1 germline variants and related clinical information. Five University and/or research institutes filled-in the electronic survey. Informed consent was obtained from patients or their legal guardians prior to DNA testing by NGS and/or Sanger sequencing. Results: Six DICER1 sequence variants were identified in 11 individuals. Three missense variants are secondary results of NGS panels for cancer predisposition and lack definitive categorization in online databases. Three previously unreported variants are predicted to be protein truncating and, hence, likely pathogenic. Of these, DICER1 c.4844delA p.(Lys1615Argfs*5) and c.4886C &gt; G p.(Ser1629*) result from ad hoc testing offered to probands based on a history of early onset follicular thyroid carcinoma and botryoid-type embryonal rhabdomyosarcoma of the cervix and of pleuropulmonary blastoma 2nd type, respectively. DICER1 c.4643T &gt; A p.(Leu1548*), instead, results from whole exome sequencing in two siblings with malignant melanoma who tested non informative for alterations in the CDKN2A and CDK4 melanoma predisposing genes. Further investigation unearthed thyroid disease in the family and identified two other young carrier individuals, one unaffected and one thyroidectomized due to multinodular goiter. A DICER1 somatic hot spot sequence variant was detected in goiter specimens. Conclusions: Via the newly established national registry we uncovered novel DICER1 germline sequence variants and uncommon genotype-phenotype associations. Our joint effort will help us to refine our knowledge of the rare DICER1 syndrome , to inform research studies, and to improve testing and clinical management strategies.
The Global Workspace Needs Metacognition
Authors: Nicholas Shea, Chris D. Frith
Journal: Trends in Cognitive Sciences (2019)

The two leading cognitive accounts of consciousness currently available concern global workspace (a form of working memory) and metacognition. There is relatively little interaction between these two approaches and it has even been suggested that the two accounts are rival and separable alternatives. Here, we argue that the successful function of a global workspace critically requires that the broadcast representations include a metacognitive component.
Exploiting DNA repair alterations in metastatic pancreatic cancer (mPAC): Is MGMT methylation a new therapeutic target?
Authors: Monica Niger, Federica Morano, Sara Manglaviti, Alessandra Raimondi, Federica Perrone, Elena Tamborini, Matteo Marcuzzo, Federico Nichetti, Giorgia Peverelli, Filippo Pagani, Giovanni Randon, Arianna Ottini, Martina Torchio, Michele Prisciandaro, Maria Antista, Filippo Pietrantonio, Sara Pusceddu, Giancarlo Pruneri, Maria Di Bartolomeo, Filippo G. De Braud
Journal: Journal of Clinical Oncology (2019)

e15770 Background: Metastatic pancreatic cancer (mPAC) has a poor prognosis, with few therapeutic options and an overall survival (OS) at 5 years &lt; 5%. O6-methylguanine-DNA methyltransferase ( MGMT) is a key DNA repair gene, responsible of alkyl groups’ elimination from the O6-position of guanine. Its promoter methylation results in diminished DNA-repair of O6-alkylguanine adducts and enhanced sensitivity to alkylating agents, such as temozolomide (TMZ). Of note, both reductions in MGMT expression and MGMT promoter methylation are described in a variety of gastrointestinal malignancies, including colorectal cancer (CRC). Here we present data on MGMT methylation tested in mPAC pts treated at our center. Methods: Formalin-fixed paraffin-embedded (FFPE) tissue samples were examined using Next Generation Sequencing (50 genes “Hotspot Cancer Panel, Ion Torrent®” and “Oncomine BRCA Research Assay”) and PCR analysis of microsatellite instability (MSI). Furthermore, the exploratory analysis of MGMT status was performed via methyl specific PCR (EZ DNA Methylation-Gold™ KIT) to assess promoter methylation, and immunohistochemistry (IHC) was done to assess protein expression. Results: Archived FFPE tissue sections obtained from 60 pts treated at Fondazione IRCCS Istituto Nazionale dei Tumori of Milan from October 2017 to December 2018 were analyzed. 47 samples (78%) had adequate tissue for extended analyses. As expected, 44 (93%) pts had KRAS mutations, while ATM, CDKN2A mutations and microsatellite instability (MSI) were found in 3 pts (6%), respectively. MGMT promoter methylation was identified in 14 pts (29%), with low/negative MGMT protein expression in 7 (14%). Interestingly, amongst MGMT methylated pts, there were 3 (21%) BRCA1/2 somatic mutant and 1 (7%) MSI, suggesting possible genomic instability. Conclusions: MGMT is a prognostic and predictive marker in glioblastomas and there is an increasing evidence in its role in metastatic CRC, with phase II studies showing a response rate of 10% in chemorefractory pts with MGMT methylation treated with TMZ. In our single center experience, MGMT methylation was found in 29% of patients with mPAC. This data warrant further prospective confirmation, but there is definitely a growing interest in the role of MGMT methylation as a predictive and prognostic biomarker in mPAC.
Impact of timing of palliative care team consults in patients with advanced cancer.
Authors: Thomas Bemis, Praneeth Baratam, Dawn Seiders, Kristine Marie Ward, Michael Styler
Journal: Journal of Clinical Oncology (2019)

e18182 Background: The 2018 ASCO palliative care guidelines recommend palliative care team (PCT) involvement within 8 weeks for patients with an advanced cancer diagnosis. However, the optimal timing of PCT consults in the inpatient setting has not been established. We investigated whether early PCT involvement for in-patients with an advanced cancer diagnosis affected discharge outcomes. Methods: We queried the Hahnemann University Hospital’s Palliative Care In-patient database between 2015 and 2018 for patients with advanced cancer and an estimated life expectancy of &lt; 6 months. Dates of admission, initial PCT consult and discharge were examined. PCT consults within 7 days of admission were defined as early consults and those &gt; 7 days as late consults. Chi square analysis was used to determine differences in LOS and time from PCT consult to discharge between the two groups. Cost-savings estimates were based on the Kaiser State Health Facts, which list an average cost per inpatient day in US hospitals of $2,289 in nonprofit and $1,791 in for-profit hospitals. Results: The majority of cases (69.7%) had PCT involvement &lt; 7 days from admission and were associated with an overall shorter LOS of 12 days compared to 30 days with consults called &gt; 7 days (p = &lt; 0.001). Furthermore, early PCT involvement led to a 2-day shorter time to discharge (p = &lt; 0.02) for an average cost-savings of at least $4,578 at a non-profit hospital and $3,582 at a for-profit hospital. Conclusions: Our findings show that the majority of patients at our institution with advanced cancer had early PCT involvement, which was associated with reduced hospital length of stay. These findings suggest that PCT involvement may expedite hospital discharge and by extension lead to increased cost-savings and patient quality of life. Future studies will aim to investigate the impact of early PCT involvement on hospital readmission rates and discharge to hospice care among other indicators of improved patient well-being.[Table: see text]
Community-based lung cancer screening program: A five-year comprehensive review.
Authors: Ari Hakimian, Axel Joob, Jennifer Aversano, Michael Vercillo, Michael Oconnor, Yangyang Liu
Journal: Journal of Clinical Oncology (2019)

e13080 Background: Low-dose chest CT for lung cancer screening has been shown to have a significant impact on the early diagnosis of lung cancer. Initial trials have shown an approximate 20% decrease in overall lung cancer mortality (NLST, 2011). This study incorporates all patients who were evaluated by the Center for Thoracic Disease in a community-based lung cancer screening program from 2013 to 2018. Over the course of the study, thoracic surgeons have evaluated these patients with subsequent interval-based scans to monitor the progression of suspicious nodules. Methods: Eligibility criteria for the program included patients within the age range of 55-80, with a &gt; 30 pack year smoking history, and that were current smokers or quit tobacco less than 15 years ago. Individuals between 50-55 years old were also included if they had &gt; 20 pack year smoking history and at least one additional lung cancer risk factor. All patients included in this analysis completed an initial lung cancer screening consultation and recommended follow-up evaluations with thoracic surgeons from March 2013 to December 2018. All patients with suggestive abnormalities were discussed at a multidisciplinary conference prior to embarking on any invasive procedures. Patient data was collected on REDCap. Descriptive statistics for all continuous (mean ± SD) and categorical [N (%)] variables were calculated on patients. Results: 470 patients were included in the final analysis. The majority of the patients were males (56.4%), mean age was 64 years old (range: 50-81), and 55.3% were current smokers. The average smoking history was 42.3 pack years. 223 (47.6%) patients had a family history of cancer and 70 (14.5%) patients had a personal history of cancer. 25 patients (5.3%) had a diagnosis of primary lung cancer, among whom, 16 patients (64%) had early stage lung cancer (stage 1 and stage 2), 5 patients (20%) had stage 3, and 4 patients (16%) had stage 4 lung cancer. The cancer distribution included 17 adenocarcinomas (68%), 3 squamous cell carcinomas (12%), 3 small cell cancers (12%), 1 large cell cancer (4%) and 1 carcinoid tumor (4%). Conclusions: This study has demonstrated the value of enrolling patients in a community-based lung cancer screening program. Our results have reiterated the prevalence of discovering early staged lung cancer in high risk patients. This comprehensive five-year review indicates the importance of physician coordinated follow-up and evaluation in lung cancer screening patients.