tbuckley/cabot-search huggingface dataset:
Effects of Material–Tissue Interactions on Bone Regeneration Outcomes Using Baghdadite Implants in a Large Animal Model
Authors: Jiao Jiao Li, Austin Akey, Colin R. Dunstan, Martin Vielreicher, Oliver Friedrich, David C. Bell, Hala Zreiqat
Journal: Advanced Healthcare Materials (2018)

Abstract Extensive bone loss due to trauma or disease leads to impaired healing. Current bone grafts and substitutes have major drawbacks that limit their effectiveness for treating large bone defects. A number of bone substitutes in development are undergoing preclinical testing, but few studies specifically investigate the in vivo material–tissue interactions that provide an important indicator to long‐term implant safety and efficacy. This study is the first of its kind to specifically investigate in vivo material–tissue interactions at the bone–implant interface. Baghdadite scaffolds implanted in critical‐sized segmental defects in sheep tibia for 26 weeks are analyzed by focused ion beam scanning electron microscopy, multiphoton microscopy, and histology. The scaffolds are seen to induce extensive bone formation that directly abut the implant surfaces with no evidence of chronic inflammation or fibrous capsule formation. Bone remodeling is influenced by slow in vivo degradation around and within the implant, causing portions of the implant to be incorporated into the newly formed bone. These findings have important implications for predicting the long‐term effects of baghdadite ceramics in promoting defect healing, and support the translation of baghdadite scaffolds as a new generation of bone graft substitutes with improved properties for the repair of large bone defects.
Long noncoding RNA AFAP1-AS1 predicts a poor prognosis and regulates non–small cell lung cancer cell proliferation by epigenetically repressing p21 expression
Authors: Dandan Yin, Xiyi Lu, Jun Su, Xuezhi He, Wei De, Jinsong Yang, Wei Li, Liang Han, Erbao Zhang
Journal: Molecular Cancer (2018)

Mounting evidence indicates that long noncoding RNAs (lncRNAs) could play a pivotal role in cancer biology. However, the role and molecular mechanism and global genes that were mediated by lncRNA AFAP1-AS1 in non–small cell lung cancer (NSCLC) remain largely unknown. Expression of AFAP1-AS1 was analyzed in 92 NSCLC tissues and cell lines by Quantitative real time polymerase chain reaction (qRT-PCR). The effect of AFAP1-AS1 on proliferation was evaluated by function assays both in in vitro and in vivo. RNA-seq assays were performed after knockdown AFAP1-AS1. RNA immunoprecipitation (RIP) was performed to confirm the interaction between AFAP1-AS1 and EZH2. Chromatin immunoprecipitation (ChIP) was used to study the promoter region of p21. AFAP1-AS1 expression was increased in NSCLC tissues and was correlated with clinical outcomes of NSCLC. Further experiments revealed that inhibition of its expression in NSCLC cells resulted in diminished cell growth in vitro and in vivo. RNA-seq revealed that knockdown of AFAP1-AS1 could induce the expression of p21. Mechanistic investigations found that AFAP1-AS1 could interact with EZH2 and recruit EZH2 to the promoter regions of p21, thus epigenetically repressing p21 expression. Together, these results suggest that lncRNA AFAP1-AS1 may serve as a candidate prognostic biomarker and target for new therapies in human NSCLC.
The Detroit Research on Cancer Survivors (ROCS) study: A focus on outcomes after cancer in a racially diverse patient population.
Authors: Jennifer Lynn Beebe-Dimmer, Terrance Lynn Albrecht, Julie J. Ruterbusch, Tara Baird, Theresa A. Hastert, Felicity W. K. Harper, Kendra L. Schwartz, Michael S. Simon, Ann G. Schwartz
Journal: Journal of Clinical Oncology (2018)

177 Background: Although we continue to make progress in reducing the incidence and mortality for most cancers in the United States, African Americans (AA) continue to experience higher cancer incidence rates and have worse survival than other populations. The causes of these poorer outcomes, from higher mortality to poorer quality of life, in AA cancer survivors are not well understood. The Detroit ROCS study was initiated to improve our understanding of the experience of AAs living with cancer. Methods: 1,000 AA and non-Hispanic white (NHW) patients with primary lung, female breast, prostate or colorectal cancer diagnosed on or after January 1, 2013, and/or treated at the Karmanos Cancer Institute in Detroit, MI were recruited to participate in a cohort study with planned follow-up for 4 years. At baseline, participants completed a web-based survey to gather information about their medical history, family history of cancer, treatment and medication use, behavioral risk factors and self-assessed quality of life. Statistical analyses were performed to examine racial differences in the distribution of patient characteristics including comorbid conditions, stage at diagnosis, first course treatment and reported health-related quality of life (HRQOL). Results: The majority of patients were AA (60%) and female (61%), with a median age at diagnosis of 60 years. AAs were older, more likely to report use of cigarettes and alcohol and report a greater number of comorbidities compared with NHW patients; they were less educated and less likely to be employed full time or married (all p-values &lt; 0.001). AA patients reported poorer overall HRQOL compared with NHW patients (p-value &lt; 0.001). Controlling for marital status and employment attenuated the observed racial differences in mean HRQOL scores across all measured domains. Conclusions: We observed significantly lower self-reported HRQOL among AA cancer survivors compared with NHW, which could be partially explained by differences in specific socioeconomic factors but interestingly, not the presence of multiple comorbidities. Future research efforts will evaluate the relative contribution of social and financial support to HRQOL in AAs.
Correlates of anxiety and depression in chronic lymphocytic leukemia (CLL) survivors.
Authors: AnnaLynn Williams, Rina Yarosh, Jackson Clark, Carla Casulo, Paul M. Barr, Charles Stewart Kamen, Edwin van Wijngaarden, Clive Zent, Michelle Christine Janelsins
Journal: Journal of Clinical Oncology (2018)

153 Background: CLL is an indolent lymphoma effecting aging populations. Early stage patients are assigned to active surveillance and only 10% of patients require treatment at diagnosis. Active surveillance for CLL may increase susceptibility to anxiety and depression, resulting in enhanced comorbidities and reduced quality of life. However, little is known about the prevalence and risk factors of anxiety and depression in CLL. Methods: 125 CLL patients that were treatment naïve (n = 86) or previously chemotherapy-treated (n = 39) completed anxiety and depression questionnaires (State Trait Anxiety Index (STAI) and Center for Epidemiologic Studies Depression (CES-D)). Multivariable linear regression was used to examine associations with STAI/CES-D score. Logistic regression was used to examine clinically meaningful anxiety and depression, using validated cut points of 40 for the STAI and 16 (or on antidepressants) for the CES-D. All models included treatment status (treatment naïve vs. treated), age, gender, ECOG grade, time since diagnosis, education, &amp; disease stage. Results: Patients had a median age of 65, were mostly male (60.8%), Caucasian (96%), well educated (55% ≥ college), and had low stage CLL (66% stage 0) and good performance status (67% ECOG 0). 20 and 24% of patients had clinically meaningful anxiety or depression (11% had both). Treatment and time since diagnosis were not associated with anxiety or depression. Older age was associated with better STAI and CES-D scores (STAI β = -0.34 (95%CI -0.52, -0.17) CES-D β = -0.27 (95%CI -0.42, -0.12)), and each 1 year increase in age was associated with a 9% decrease in odds of anxiety and a 7% decrease in odds of depression (OR 0.91(95%CI 0.86, 0.96) OR 0.93 (95%CI 0.88, 0.98) respectively). An ECOG grade of 3 or 4 was a significant predictor of increased depression risk (OR 2.84 (95%CI 1.03, 7.82)) and worse CES-D scores (β = 4.69 (95%CI 8.09, 1.29)) but not of anxiety. Conclusions: Anxiety and depression are common among CLL patients. Poor performance status was associated with more depression while older age was associated with less anxiety and depression. Future studies should investigate potential interventions for anxiety and depression in younger CLL patients.
Role of Epstein-Barr virus infection in SLE: gene-environment interactions at the molecular level
Authors: David S Pisetsky
Journal: Annals of the Rheumatic Diseases (2018)

A paper by Harley et al in Nature Genetics provides an important new perspective on the mechanisms by which infection with Epstein-Barr virus (EBV) can promote autoimmunity and, in particular, systemic lupus erythematosus (SLE).1 An interest in the role of EBV in lupus pathogenesis has a long history beginning in the 1970s with observations that patients with SLE have increased titres of anti-EBV antibodies.2 Subsequent studies have strengthened the link between EBV and SLE as well as other diseases such as rheumatoid arthritis (RA) and multiple sclerosis (MS).3 To many investigators, the question has not been whether EBV infection can lead to autoimmunity but rather how since the evidence for causality appears high.

Like other autoimmune diseases, SLE is likely the outcome of an encounter of a genetically susceptible individual with an environmental trigger such as an infection. With EBV, classic epidemiology faces a major challenge since infection with this virus, a member of the herpes family, is almost invariable in the adult population.3 While the study of disease associations in children can be informative because of their lower infection rate,4 it is difficult if not impossible to sort adults into infected and uninfected bins to investigate disease associations. Furthermore, it is always possible that abnormalities that predispose to autoimmunity also predispose to infection with EBV, complicating the situation further.

Given the limitations of epidemiology, investigators have explored other mechanisms by which EBV can trigger disease. One of the …
Tailored neoadjuvant epirubicin and cyclophosphamide and nanoparticle albumin bound (<i>nab</i>)-paclitaxel for newly diagnosed breast cancer.
Authors: Mustafa Khasraw, Linda West, Wei Duan, Violet Mukaro, Sandra Harvey, Robert Spokes, Conrad Brandt, Gregory Mitchell, Kimberley Prince, Theresa M. Hayes, Sally E. Baron-Hay, Anne Maree Woollett, Inger Helen Olesen, Karen White, Susan Bowles, Shu Fen Wong, David M. Ashley, Sujata Patil
Journal: Journal of Clinical Oncology (2014)

TPS1135 Background: Neoadjuvant chemotherapy for breast cancer allows response to be assessed depending on subtype, and to judge impact of response to therapy on progression-free survival (PFS). Methods: This study enrols women with breast tumours > 2cm and high likelihood of response, to receive Epirubicin 90mg/m2 and Cyclophosphamide 600mg/m2 Q3 weeks x 4 followed by nab-Paclitaxel (125mg/m2 IV days 1, 8, 15 Q4 weeks) for 12 weeks. Trastuzumab Q3 weeks, will be added to nab-paclitaxel in HER2 positive patients. Forty women; 15 HER2 positive, 15 triple negative and 10 patients with Oncotype DX assay Recurrence Score (RS) >25 will be evaluated for response. We will screen 50 hormone positive women to identify 10 with Oncotype DX assay RS ≥25 and the patients with RS <25 will be included as an exploratory cohort to receive neoadjuvant hormonal treatment. The primary endpoint is rate of pathologic Complete Response (pCR) in the breast. In previous studies, Response Rate (RR) ranged from 12 to 30%. Accordingly, we set RR rate for the null hypothesis (uninteresting) at 30% and for the alternative (worthy of further study) at 50% (CI 95%). Forty patients will be evaluated to discern between RR of 30% and 50% (6% type I error and 87% power). If at the end of the study, 17 or more patients achieve pCR, the regimen will be deemed worthy of further study. Secondary end points include rate of breast conservation, safety and tolerability, PFS and a number of translational endpoints using pre- and post-chemotherapy MRIs and tissue. Translational endpoints include determination of NQO1*2 genotype (P187S) status that may predict anthracycline resistance, isolating cancer stem cells, passing fresh tumour to xenograft, implanting tumours, using aptamers to target implanted tumours and targeting breast cancer stem cells with novel agents including cyclin D and histone deacetylatase inhibitors. Current status: Recruitment began April 2013. A total of 20 patients have been enrolled on to the study as of Feb 2014. Clinical trial information: NCT01830244.
Spinal surgeon was negligent in giving patient heparin too early and leaving her disabled
Authors: Clare Dyer
Journal: BMJ (2018)

A college lecturer has been left with permanent neurological injury as a result of a consultant neurosurgeon’s decision to give her anti-thrombotic medication too soon after spinal surgery, a High Court judge has ruled.1

Mr Justice Martin Spencer concluded that Christos Tolias was negligent in giving Yvonne Lesforis low molecular weight heparin (LMWH) only three hours after her operation, and that this caused her injury.

Tolias has applied for permission to appeal but if the judgment stands, Lesforis is expected to receive more than £1m (€1.13m; $1.34m) in damages.

Lesforis, now 61, had been having lower back problems off and on with pain radiating down her legs since 2007. In 2012 and 2013 she consulted Tolias at Kings College Hospital in London.

She agreed to have decompression surgery to treat stenosis at the L3 and L4 levels in her …
Pin1 inhibition exerts potent activity against acute myeloid leukemia through blocking multiple cancer-driving pathways
Authors: Xiaolan Lian, Yu-Min Lin, Shingo Kozono, Megan K. Herbert, Xin Li, Xiaohong Yuan, Jiangrui Guo, Yafei Guo, Min Tang, Jia Lin, Yiping Huang, Bixin Wang, Chenxi Qiu, Cheng-Yu Tsai, Jane Xie, Ziang Jeff Gao, Yong Wu, Hekun Liu, Xiao Zhen Zhou, Kun Ping Lu, Yuanzhong Chen
Journal: Journal of Hematology & Oncology (2018)

The increasing genomic complexity of acute myeloid leukemia (AML), the most common form of acute leukemia, poses a major challenge to its therapy. To identify potent therapeutic targets with the ability to block multiple cancer-driving pathways is thus imperative. The unique peptidyl-prolyl cis-trans isomerase Pin1 has been reported to promote tumorigenesis through upregulation of numerous cancer-driving pathways. Although Pin1 is a key drug target for treating acute promyelocytic leukemia (APL) caused by a fusion oncogene, much less is known about the role of Pin1 in other heterogeneous leukemia.The mRNA and protein levels of Pin1 were detected in samples from de novo leukemia patients and healthy controls using real-time quantitative RT-PCR (qRT-PCR) and western blot. The establishment of the lentiviral stable-expressed short hairpin RNA (shRNA) system and the tetracycline-inducible shRNA system for targeting Pin1 were used to analyze the biological function of Pin1 in AML cells. The expression of cancer-related Pin1 downstream oncoproteins in shPin1 (Pin1 knockdown) and Pin1 inhibitor all-trans retinoic acid (ATRA) treated leukemia cells were examined by western blot, followed by evaluating the effects of genetic and chemical inhibition of Pin1 in leukemia cells on transformed phenotype, including cell proliferation and colony formation ability, using trypan blue, cell counting assay, and colony formation assay in vitro, as well as the tumorigenesis ability using in vivo xenograft mouse models.First, we found that the expression of Pin1 mRNA and protein was significantly increased in both de novo leukemia clinical samples and multiple leukemia cell lines, compared with healthy controls. Furthermore, genetic or chemical inhibition of Pin1 in human multiple leukemia cell lines potently inhibited multiple Pin1 substrate oncoproteins and effectively suppressed leukemia cell proliferation and colony formation ability in cell culture models in vitro. Moreover, tetracycline-inducible Pin1 knockdown and slow-releasing ATRA potently inhibited tumorigenicity of U937 and HL-60 leukemia cells in xenograft mouse models.We demonstrate that Pin1 is highly overexpressed in human AML and is a promising therapeutic target to block multiple cancer-driving pathways in AML.
Impact of residual nodal disease burden on sentinel node mapping and accuracy of intraoperative frozen section in node positive (cN1) breast cancer patients treated with neoadjuvant chemotherapy (NAC).
Authors: Alison Laws, Melissa E Hughes, Jiani Hu, William Thomas Barry, Laura Stewart Dominici, Faina Nakhlis, Thanh Barbie, Margaret M. Duggan, Anna Weiss, Esther Rhei, Katharine Carter, Katherina Calvillo, Suniti Nimbkar, Stuart J. Schnitt, Tari A. King
Journal: Journal of Clinical Oncology (2018)

584 Background: Recent trials have demonstrated the feasibility of SLN biopsy in cN1 patients who become cN0 after NAC. We sought to evaluate success of SLN mapping and accuracy of intraop frozen section (FS) by residual nodal disease burden. Methods: cT1-3 cN1 patients receiving NAC and surgery (1/2016 to 5/2017) were identified from a prospective database. Pts who converted to cN0 and had SLN biopsy with dual-tracer were included. Adequate mapping (defined as ≥3 SLN) and false negative rate (FNR) of intraop FS were assessed by residual nodal disease burden (ypN0, ypNmi+ITC, ypN1-3). Results: Among 137 cT1-3 cN1 pts, 76 met inclusion criteria. Median age 45 yrs [27-82]; median tumor size 4.3cm [0.8-15.0]. 32 (42%) pts were ER+HER2-, 24 (32%) HER2+ and 20 (26%) ER-HER2-. Adequate mapping was achieved in 50 (66%) pts; 14 (18%) failed to map and 12 (16%) had < 3 SLN identified. Adequate mapping was not associated with residual node burden (table, p = 0.21). Among 48 pts with adequate mapping and FS, 16 were ypN+ on FS and 28 were ypN+ on final pathology; FNR of 12/28 (43%). Smaller residual node burden was associated with false negative FS (table, p = 0.005). 28/76 (37%) pts achieved axillary pCR, of whom 20 (71%) had ≥3 negative SLN and were spared ALND. Of 36 pts with successful mapping and positive SLN, 22 (61%) underwent ALND, of whom 8 (36%) had additional nodal disease; the remaining 14 (39%) had axillary radiation. Conclusions: Among pre-NAC cN1 pts, SLN biopsy was technically adequate in 66%. Of these, 40% achieved axillary pCR and avoided ALND. The FNR of intraop FS was 43%. Residual nodal disease burden was not associated with adequate mapping; micrometastases and ITCs were associated with higher likelihood of false negative FS. Preoperative counseling for SLN biopsy should include realistic assessment of the limitations of SLN mapping and intraop FS and the potential need for ALND. Volume of residual nodal disease in 76 patients with attempted SLN biopsy ypN0 (n = 28, 37%) ypNmi / ITCs (n = 11, 14%) ypN1-3 (n = 37, 49%) p-value Adequate SLN mapping* 20/28 (71%) 9/11 (82%) 21/37 (57%) 0.21 FNR of FS in pts with ≥3 SLN -- 8/9 (89%) 5/20 (25%) 0.005 *≥3 SLN
Ethics and the Legalization of Physician-Assisted Suicide
Authors: Christie Reimer
Journal: Annals of Internal Medicine (2018)

Letters5 June 2018Ethics and the Legalization of Physician-Assisted SuicideChristie Reimer, MDChristie Reimer, MDFort Collins, Colorado (C.R.)Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/L18-0080 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail TO THE EDITOR:I read Sulmasy and colleagues' position paper (1) with interest. In Colorado, my patients—the voters—legalized physician-assisted death (PAD). We are concerned that the American College of Physicians (ACP) is taking such a firm stance on an issue that affects the heart of what the ACP has traditionally prioritized: the value of the physician–patient relationship. Although Sulmasy and colleagues' recommendations for end-of-life care are helpful and appropriate, they do not address the real-life situation when the patient, family, care team, and physician thoughtfully come to an educated decision that PAD may be best. Because we internists promote the ...Reference1. Snyder Sulmasy L, Mueller PS; Ethics, Professionalism and Human Rights Committee of the American College of Physicians. Ethics and the legalization of physician-assisted suicide: an American College of Physicians position paper. Ann Intern Med. 2017;167:576-8. [PMID: 28975242]. doi:10.7326/M17-0938 LinkGoogle Scholar Author, Article, and Disclosure InformationAffiliations: Fort Collins, Colorado (C.R.)Disclosures: The author has disclosed no conflicts of interest. The form can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=L18-0080. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetailsSee AlsoEthics and the Legalization of Physician-Assisted Suicide: An American College of Physicians Position Paper Lois Snyder Sulmasy , Paul S. Mueller , and Ethics and the Legalization of Physician-Assisted Suicide Allen H. Roberts II Ethics and the Legalization of Physician-Assisted Suicide Timothy L. Gieseke Ethics and the Legalization of Physician-Assisted Suicide Lois Snyder Sulmasy and Paul S. Mueller Ethics and the Legalization of Physician-Assisted Suicide E. Wesley Ely Ethics and the Legalization of Physician-Assisted Suicide Banu E. Symington Metrics 5 June 2018Volume 168, Issue 11Page: 833KeywordsConflicts of interestDisclosureEnd of life careHeartPatientsSuicide ePublished: 5 June 2018 Issue Published: 5 June 2018 Copyright & PermissionsCopyright © 2018 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
Sterol profiles are valuable biomarkers for phenotype expression of Conradi-Hünermann-Happle syndrome with <i>EBP</i> mutations
Authors: T. Takeichi, A. Honda, Y. Okuno, D. Kojima, M. Kono, Y. Nakamura, M. Tohyama, T. Tanaka, Y. Aoyama, M. Akiyama
Journal: British Journal of Dermatology (2018)