tbuckley/cabot-search huggingface dataset:
Phosphoinositide phosphatases in cancer cell dynamics—Beyond PI3K and PTEN
Authors: Takeshi Ijuin
Journal: Seminars in Cancer Biology (2019)

Phosphoinositides are a group of lipids that regulate intracellular signaling and subcellular biological events. The signaling by phosphatidylinositol-3,4,5-trisphosphate and Akt mediates the action of growth factors that are essential for cell proliferation, gene transcription, cell migration, and polarity. The hyperactivation of this signaling has been identified in different cancer cells; and, it has been implicated in oncogenic transformation and cancer cell malignancy. Recent studies have argued the role of phosphoinositides in cancer cell dynamics, including actin cytoskeletal rearrangement at the plasma membrane and the organization of intracellular compartments. The focus of this review is to summarize the impact of the activities of phosphoinositide phosphatases on intracellular signaling related to cancer cell dynamics and to discuss how the abnormalities in the activities of the enzymes alter the levels of phosphoinositides in cancer cells.
Abstract P2-06-21: Endogenous expression of ERβ variants contributes towards chemotherapy-resistance in the triple negative breast cancer cell line HCC-1806
Authors: M Faria, J-A Gustafsson, A Strom
Journal: Cancer Research (2019)

Abstract Triple negative breast cancer (TNBC) still remains a challenge to treat in the clinic due to a lack of good targets for treatment. Although TNBC lacks expression of ERα, the expression of ERβ and its variants are detected quite frequently in this cancer type and can represent an avenue for treatment. We show that the variants of ERβ, namely ERβ1, ERβ2, ERβ4, and ERβ5, contributes to aggressiveness of the TNBC cell line HCC1806 by affecting E-Cadherin expression and chemotherapy sensitivity. We have previously shown that the HCC1806 cell line expresses all the ERβ variants. To investigate their function we used the recently developed dCas9-KRAB system with Guide RNA for both ERβ promoters 0N and 0K, using 3 guide RNA's for each promoter and we found that expression of panERβ decreased from a ct. of 28 to 33 indicating loss of total ERβ. Treatment of HCC1806 cells with chemotherapy in combination with an ERβ agonist, LY500307, is more effective in reducing cancer cell viability. Knockdown of total ERβ in HCC1806 cells using CRISPR-Cas9 technology, decreased the proliferation and increased chemo-sensitivity to docetaxel agent in cells with the 0K promoter knock down, while cells with the 0N promoter knock down were less affected. Furthermore, after ERβ knockdown, the cell morphology of HCC-1806 changed to a more epithelial phenotype and there was increase in the expression of the classical epithelial marker, E-cadherin. N-Cadherin was unchanged in the cells with the 0K promoter knock down, while E-Cadherin was slightly decreased in cells with the 0N promoter knock down. We also found that cells with the 0K promoter knock down migrated less than control cells in a migration assay, while cells with the 0N promoter knock down were less affected. These findings are in agreement with reports showing that the 0K promoter is responsible for expression of the variants ERβ2 and ERβ5, while the 0N promoter expresses more ERβ1. Furthermore, we have earlier shown that ERβ2 and ERβ5 increase aggressiveness of TNBC via several oncogenic signaling pathways. In conclusion, knockdown of ERβ variants in HCC-1806 indicated that the variants may be responsible for conferring oncogenic properties to TNBC such as EMT, cancer cell proliferation and chemo-resistance. Therefore, treating TNBC patients with combination therapy including ERβ agonists, may prove to be extremely beneficial for securing better treatment responses and future pre-clinical studies should design appropriate experiments to confirm these findings in vivo. Citation Format: Faria M, Gustafsson J-A, Strom A. Endogenous expression of ERβ variants contributes towards chemotherapy-resistance in the triple negative breast cancer cell line HCC-1806 [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-06-21.
Paternally Expressed Imprinted Genes under Positive Darwinian Selection in Arabidopsis thaliana
Authors: Reetu Tuteja, Peter C McKeown, Pat Ryan, Claire C Morgan, Mark T A Donoghue, Tim Downing, Mary J O’Connell, Charles Spillane
Journal: Molecular Biology and Evolution (2019)

Genomic imprinting is an epigenetic phenomenon where autosomal genes display uniparental expression depending on whether they are maternally or paternally inherited. Genomic imprinting can arise from parental conflicts over resource allocation to the offspring, which could drive imprinted loci to evolve by positive selection. We investigate whether positive selection is associated with genomic imprinting in the inbreeding species Arabidopsis thaliana. Our analysis of 140 genes regulated by genomic imprinting in the A. thaliana seed endosperm demonstrates they are evolving more rapidly than expected. To investigate whether positive selection drives this evolutionary acceleration, we identified orthologs of each imprinted gene across 34 plant species and elucidated their evolutionary trajectories. Increased positive selection was sought by comparing its incidence among imprinted genes with nonimprinted controls. Strikingly, we find a statistically significant enrichment of imprinted paternally expressed genes (iPEGs) evolving under positive selection, 50.6% of the total, but no such enrichment for positive selection among imprinted maternally expressed genes (iMEGs). This suggests that maternally- and paternally expressed imprinted genes are subject to different selective pressures. Almost all positively selected amino acids were fixed across 80 sequenced A. thaliana accessions, suggestive of selective sweeps in the A. thaliana lineage. The imprinted genes under positive selection are involved in processes important for seed development including auxin biosynthesis and epigenetic regulation. Our findings support a genomic imprinting model for plants where positive selection can affect paternally expressed genes due to continued conflict with maternal sporophyte tissues, even when parental conflict is reduced in predominantly inbreeding species.
Follow-up survey of oral health status of children enrolled in UNRWA schools: a cross-sectional study
Authors: Majed Hababeh, Amjad Matooq, Abdalla Odattalla, Asa'ad Na'jeh, Hanan diab, Imad Burbara, Amjad khoury, Zaki Saleh, Ayoub Ayoub, Mohammad Salameh, Mohammad Hadi Saleh, Ali Khader, Akihiro Seita, Patricia Di Caccamo, Lilia Biscaglia, Mari Antonietta Arrica, Cristiana Zerosi, Guglielmo Campus
Journal: The Lancet (2019)
QIM19-142: Development of a Low Resource Tool for Improving Head and Neck Cancer Treatment Delivery Within an Integrated Health Care Delivery System
Authors: Vlad Sandulache, Anita Sabichi, George Chen, Scott Charnitsky
Journal: Journal of the National Comprehensive Cancer Network (2019)

Background: The Veterans Health Administration (VHA) is the only nationally integrated healthcare delivery system in the United States. The vertical and horizontal integration of the VHA make it an ideal environment for development of tools designed to streamline cancer diagnosis and treatment. Head and neck cancer (HNC) remains a difficult disease to diagnose and treat. Delivery of multimodality treatment for advanced HNC is challenging at both academic centers and in the community setting. This problem is magnified by the increased incidence of HNC, powered by an epidemic increase in the incidence of human papilloma virus (HPV)–associated oropharyngeal cancer (OPC). Objective: To develop a non–resource-intensive approach to improving: (1) time to treatment initiation and (2) compliance with optimal treatment package time for HNC patients. Methods: Retrospective analysis of 300 patients with a diagnosis of HNC from the Michael E. DeBakey VA Medical Center (MEDVAMC) was used to generate baseline data (2000–2010) for: (1) time to treatment (surgery, 24 days; radiation, 48 days) and (2) treatment package time &lt;100 days compliance (68%). We developed a tool available to providers and clinic staff to prospectively track patients from initial referral, through diagnosis and treatment, along with completion of ancillary studies (modified barium swallow) and completion of the survivorship care plan. Between June 2016 and October 2018, 350 patients were tracked using this tool; 275 patients were new HNC diagnoses. Results: Implementation of the tracking tool reduced diagnosis to treatment start (mean, 44 days; median, 26 days). Compliance with treatment package time &lt;100 days was increased to 95%; compliance with initiation of adjuvant radiation within 6 weeks of surgery was increased to 75%. Utilization of the tool allowed for streamlined surgical care, particularly through integration of dental extractions into the oncologic resection, and facilitated timely initiation of adjuvant radiation for advanced HNC. Conclusions: It is possible to improve: (1) time to diagnosis, (2) time to treatment initiation, and (3) treatment completion rates for complex HNC requiring multimodality treatment without additional resource utilization. However, appropriate implementation requires a robust multidisciplinary treatment team, with appropriate “buy in” from all participants and is facilitated by the presence of a fully integrated health care delivery system.
Niche Heterogeneity Impacts Evolution of Myeloproliferative Neoplasms Driven By the Same Oncogenic Pathway
Authors: Claudia Korn, Justyna Rak, Andrés García-García, Claire Fielding, Reema Khorshed, Sara González-Antón, Juan Li, Ruggiero Norfo, E Joanna Baxter, Thomas McKerrell, Thomas Roberts, Hesham Eldaly, Anna L Godfrey, Aracely Castillo-Venzor, Anjali Kusumbe, Adam J. Mead, Anthony R Green, David Kent, Cristina Lo Celso, Simon Mendez-Ferrer
Journal: Blood (2018)
BPI19-018: Cancer Screening Rates and Adherence of Uninsured Cancer Patients in Free Clinics
Authors: Katherine Robinson, Amber Todd, Abu-Sayeef Mirza, Madeline Macdonald, Noura Ayoubi, Rahul Mhaskar, Richard Roetzheim, Laurie Woodard, Smitha Pabbathi
Journal: Journal of the National Comprehensive Cancer Network (2019)

Background: There are limited studies documenting the prevalence of malignancies and the cancer screening practices of the uninsured population. Cancer survivors require continued cancer surveillance and screening for recurrence and second primaries. However, screening may be suboptimal among the uninsured. Our objective was to identify and document the screening rates and adherence to ACS guidelines in our local uninsured community. Methods: Demographic data, cancer history and associated cancer screening measures were extracted from electronic medical records of patients managed in 8 free clinics between January 2016 and December 2017 in the Tampa Bay Area. Frequencies, proportions, and Pearson correlation coefficients were used to describe the population and statistically significant relationships. Using the ACS cancer screening recommendations, the charts were reviewed for appropriate cancer screening. Results: From manual chart review, 6,958 charts were reviewed and 201 (2.89%) patients had a diagnosis of cancer. The average age was 55.58 years and 134 (66.67%) were women. Most common malignancies included breast cancer (49, 24.38%), prostate (18, 8.96%), colorectal (13, 6.47%), leukemia/lymphoma (11, 5.47%), cervical (10, 4.98%), melanoma (10, 4.98%), ovarian (9, 4.48%), thyroid (9, 4.48%), renal (6, 2.99%), bladder (5, 2.49%), and uterine (5, 2.49%). Of the 201 patients diagnosed with cancer, 104 (51.74%) met the guidelines for a screening mammogram; however, only 49 (47.12%) had this completed. 115 (57.21%) met the guidelines for a screening Papanicolaou smear; 28 (24.35%) had it completed. 145 (72.14%) met the guidelines for a screening colonoscopy; 23 (15.86%) had it completed. 39 (19.4%) met the guidelines for prostate screening; 3 (7.69%) had it completed. Of the 201 patients, 14 (6.97%) reported a greater than 30 pack smoking history but no patients were screened with a low-dose CT of the thorax. Of the 10 patients with melanoma, 3 (30%) mentioned having routine skin exams. Conclusions: The uninsured population have many barriers to obtaining health care and appropriate screening for malignancies. This retrospective chart review highlights the need for easier access to screening. Increasing screening rates in the uninsured population will decrease cancer mortality as well as being cost effective to the community. It is important for free clinic providers to emphasize guideline-directed cancer screening at every visit.
Prophylactic Intravenous Administration of Standard Immune Globulin as Compared with Core-Lipopolysaccharide Immune Globulin in Patients at High Risk of Postsurgical Infection
Authors: Alain Cometta, Jean-Daniel Baumgartner, Martin L Lee, Geneviève Hanique, Michel-Pierre Glauser
Journal: New England Journal of Medicine (1992)

Original Article from The New England Journal of Medicine — Prophylactic Intravenous Administration of Standard Immune Globulin as Compared with Core-Lipopolysaccharide Immune Globulin in Patients at High Risk of Postsurgical Infection
CLO19-034: The Clinical Outcomes of Next-Generation Sequencing Testing at a Community Oncology Practice
Authors: Christie Hancock, Jacob Bitran
Journal: Journal of the National Comprehensive Cancer Network (2019)

Background: The value of next-generation sequencing (NGS) tests is dependent on how it changes clinical management, if at all. There are not any guidelines on when a physician should obtain testing; what certain genetic variations can be clinically, meaningfully intervened on; and if this active drug is financially practical. A NGS test ideally should identify a targetable mutational profile that leads to a treatment that can be obtained and produces lasting responses. We reviewed the NGS testing practices at our community hospital. Methods: Patients in our oncology clinic that underwent NGS testing of their tumor were reviewed. Specifically, the patient’s age, gender, diagnosis, date of diagnosis, previous lines of treatment, date of NGS testing, and reported molecular targets were recorded. Details of the changes in clinical management based on the NGS and survival time after the NGS test was ordered were also analyzed. Results: Forty-three patient cases were reviewed that had NGS testing obtained between the years 2014–2015 and 2017. Eighteen patients were males and 25 were females. Median age was 60 years. Most common tumor type was breast; 3 were triple-negative and 6 were only hormone-receptor positive. Second most common type was colorectal. NGS changed management in 12 cases. Two patients were able to enter a clinical trial and the other 10 had therapeutic changes based on protein or mRNA overexpression. Median time of change in management to survival in these patients was 7 months. Thirty-seven patients died; overall time from ordering of test to death was 7 months. Overall time of ordering test to survival for all patients was 8 months. Conclusions: NGS gathers a significant amount of information of a patient’s cancer, but this information is difficult to interpret in the clinical setting. Twenty-eight percent of our patients had a change in treatment, but this did not translate into lasting responses compared to other patients. Furthermore, the responses that were seen may have not been related to the therapeutic interventions, but intrinsic tumor biology. It is important to be aware of the clinical utility in ordering these tests for both the physician and patient.
A Role of Drd2 Hippocampal Neurons in Context-Dependent Food Intake
Authors: Estefania P. Azevedo, Lisa Pomeranz, Jia Cheng, Marc Schneeberger, Roger Vaughan, Sarah A. Stern, Bowen Tan, Katherine Doerig, Paul Greengard, Jeffrey M. Friedman
Journal: Neuron (2019)
Initiation of Thrombus Formation: Novel Role for Thiol Isomerases
Authors: Bruce Furie
Journal: Circulation (2011)

A fundamental component of protein biosynthesis is the intracellular generation or isomerization of disulfide bonds by thiol isomerases. Nature has apparently borrowed, or more accurately, hijacked this enzymatic machinery to regulate the extracellular initiation of thrombus formation in injured blood vessels. Protein disulfide isomerase, a prototypic thiol isomerase, is of critical import during in vivo arterial thrombus formation. This enzyme is secreted by the stimulated endothelium and activated platelets and is captured within the growing thrombus by b3 integrins, specifically aIIbb3 on platelets and avb3 on the endothelium. Inhibition of PDI blocks both platelet thrombus formation by preventing integrin activation and fibrin generation by preventing the expression of tissue factor activity. High throughput screening of chemical libraries has identified a series of flavonoids, including quercetin, isoquercetin and quercetin rutinoside, that are potent low molecular weight inhibitors of PDI in vitro. ERp5, a PDI-like thiol isomerase, is similarly secreted by platelets and plays a role in thrombus formation in vivo. Low molecular weight thiol isomerase inhibitors block platelet thrombus formation and fibrin generation in vivo and offer a novel target for anti-thrombotic therapy. The precise mechanism by which thiol isomerases control thrombus initiation remains to be unraveled.
A man with fever and breathlessness
Authors: David Hamilton, Karen Lipscomb
Journal: BMJ (2019)

A 42 year old man, born in Zimbabwe and living in the UK, presented with a two week history of fever, vomiting, and diarrhoea on a background of six months of increasing exertional dyspnoea.

His temperature was 38°C, heart rate 96 beats/min, respiratory rate 24 breaths per minute, blood pressure 82/57 mmHg, and saturations 100% on room air. On examination there was a loud first heart sound and mid-diastolic murmur. Blood results are shown in the table.

View this table:

Relevant abnormal blood results



He underwent chest radiography (fig 1).



Fig 1 
Chest radiograph



He was treated for septic shock of unknown origin with piperacillin-tazobactam and 4000 mL intravenous fluid, after which he developed bilateral coarse crepitations on auscultation and marked type 1 respiratory failure. He improved after 12 hours of ventilation on the intensive care unit and was successfully extubated. Blood cultures were later positive for Streptococcus oralis .

1.  What does the chest radiograph show?

2.  What is the most likely underlying diagnosis?

3.  What is the most likely cause of the rapid deterioration and improvement of respiratory function?

### 1. What does the chest radiograph show?

It shows evidence of pulmonary oedema with perihilar congestion, fluid in …
CLO19-027: Assessment of Metastatic Invasive Lobular Carcinoma Management and Outcomes From 2004-2014: A Single Institution Experience
Authors: Hinda Boutrid, Maryam Lustberg, Jeffrey Vandeusen, Sagar Sardesai, Daniel Stover, Robert Wesolowski, Mathew Cherian, Julie Stephens, Marilly Palettas, Evan Morgan, Mohmoud Kassem, Michael Berger, Craig A. Vargo, Bhuvaneswari Ramaswamy, Nicole Williams
Journal: Journal of the National Comprehensive Cancer Network (2019)

Background: Invasive lobular carcinoma (ILC) accounts for 5%–15% of all invasive breast cancer cases. ILC has the propensity for distant late recurrence with widespread metastatic disease. To our knowledge, there is limited data on the clinical outcomes and treatment strategies of metastatic ILC. This retrospective study evaluates the overall survival (OS) and progression-free survival (PFS) in the metastatic ILC population at a single institution, focusing on first line treatment received in the metastatic setting. Methods: A retrospective chart review was performed on patients (Pts) diagnosed with metastatic ILC diagnosed at The Ohio State University Comprehensive Cancer Center between January 1, 2004 and December 31, 2014 using an IRB approved protocol. Patient demographics, clinical characteristics, and treatment modalities were summarized with descriptive statistics. OS (time from metastasis to death or last known follow-up) and PFS (time from diagnosis of metastasis to progression) were compared between types of first-line treatment: endocrine therapy (ET), chemotherapy (chemo), chemo followed by ET, ET plus CDK 4/6 inhibitor, or other treatments. OS and PFS estimates were generated using Kaplan Meier methods and compared using Log-rank tests. Results: 60 female pts were included in this study. The median age was 59 years (24–78). 45 (75%) pts were postmenopausal, 44 (73%) ER+/PR+, 14 (23%) ER+/PR-, and 2 (3%) ER-PR-, 28 (47%) with only bone metastases, 19 (32%) with visceral and bone metastases, and 13 (22%) with liver metastases. Twenty-eight (47%) pts received first line ET therapy, 12 (20%) received ET + CDK 4/6 inhibitor, 7 (12%) received chemo alone, 4 (7%) received chemo followed by ET, and 9 (15%) received other types of first line therapy. The median OS was 3.0 years, and the median PFS was 1.4 years. No difference in the Kaplan-Meier curves was found between first-line treatment groups in OS or PFS (OS: P =.247; PFS: P =.436). Discussion: ILC is a histologically distinct disease from invasive ductal cancer. It has been previously shown that invasive lobular cancer may not be as sensitive to adjuvant chemotherapy. We showed that in the metastatic setting there was no difference in PFS and OS among first line treatment groups. ET remains preferred treatment option; however, based on our data, chemotherapy can be considered in patient with metastatic ILC in the appropriate clinical context such as visceral crisis.
Withholding and Withdrawing Life-Sustaining Treatment: Ethically Equivalent?
Authors: Lars Øystein Ursin
Journal: The American Journal of Bioethics (2019)

Withholding and withdrawing treatment are widely regarded as ethically equivalent in medical guidelines and ethics literature. Health care personnel, however, widely perceive moral differences between withholding and withdrawing. The proponents of equivalence argue that any perceived difference can be explained in terms of cognitive biases and flawed reasoning. Thus, policymakers should clear away any resistance to accept the equivalence stance by moral education. To embark on such a campaign of changing attitudes, we need to be convinced that the ethical analysis is correct. Is it? In this article, I take a closer look at the moral relation between withholding and withdrawing. My conclusion is that withholding and withdrawing are not in general ethically equivalent. Thus, medical guidelines should be rewritten, and rather than being "educated" away from their sound judgments, medical professionals and patients should have nuanced medico-ethical discussions regarding withholding and withdrawing treatment.
Abstract 15176: Incremental Utility of Echocardiographic Strain for Assessment of Myocardial Infarct Size and Thrombus as Assessed via Cardiac Magnetic Resonance Tissue Characterization
Authors: Jiwon Kim, Aparna Srinivasan, Sara Rodriguez-Diego, Rachel M Brown, Antonino Di Franco, Jonathan Y Siden, Samantha R Goldburg, Chaitanya Medicherla, Richard B Devereux, Jonathan W Weinsaft
Journal: Circulation (2017)

Background: Myocardial strain provides a novel means of quantifying subtle alterations in LV function; utility of strain as a marker of MI size and stratification index for post MI thrombus (LVT) i...