tbuckley/cabot-search huggingface dataset:
The Relationship of Retinal Vessel Geometric Characteristics to the Incidence and Progression of Diabetic Retinopathy
Authors: Ronald Klein, Kristine E. Lee, Lorraine Danforth, Michael Y. Tsai, Ronald E. Gangnon, Stacy E. Meuer, Tien Y. Wong, Carol Y. Cheung, Barbara E.K. Klein
Journal: Ophthalmology (2018)
Phase Ib trial of pembrolizumab and XL888 in patients with advanced gastrointestinal malignancies.
Authors: Mehmet Akce, Olatunji B. Alese, Walid Labib Shaib, Christina Sing-Ying Wu, Gregory B Lesinski, Bassel F. El-Rayes
Journal: Journal of Clinical Oncology (2018)

TPS526 Background: Heat shock protein 90 (HSP90) has a central role in modulating tumor microenvironment, inflammatory signaling pathways (NF-κB, HIF-1α and Jak-STAT), tumor antigen presentation and expression, PD-L1 expression and macrophage migration inhibitory factor (MIF) as well as cytokine production. Inhibitors of HSP90 have been shown in preclinical studies and in patient samples to exert anti-tumor effects and modulate signaling pathways. XL888 is a selective inhibitor of HSP90. Based on this preclinical rationale, we have developed a phase Ib/II trial to determine the recommended phase II dose, evaluate the safety, toxicity profile, preliminary antitumor activity, and immunogenicity of the XL888 and Pembrolizumab combination in previously treated patients with advanced gastrointestinal tumors. Methods: The phase Ib trial design is standard 3+3. XL888 is administered orally (PO) in three dose levels of 45 (DL1), 90 (DL2), 60 (only if DLT on DL2) mg twice weekly with pembrolizumab at 200 mg IV on day 1, in 21-day cycles. Eligible patients must have stage IV or locally advanced unresectable gastrointestinal adenocarcinomas who have failed at least one prior therapy (patients with colorectal adenocarcinoma must have previously received oxaliplatin, irinotecan, and fluoropyrimidine), age ≥18 years, ECOG PS 0-1, no prior anti PD-1 or anti-PD-L1 agent. After recommended phase II dose is established, an expansion phase will enroll 16 patients with pancreatic adenocarcinoma (Arm A) and 16 patients with colorectal adenocarcinoma (Arm B). Primary endpoint response rate. In the expansion phase patients will receive initial cycle (3 weeks) treatment with either pembrolizumab or pembrolizumab plus XL888 and then starting cycle 2 all patients receive the combination. Blood will be collected pre-treatment, post 1 st and 2 nd cycle. Eight patients in each arm will undergo pre and post treatment tumor biopsies. This design will enable us to evaluate the effects of pembrolizumab alone versus the combination. This study was activated in June 2017 and to date 4 patients were enrolled in dose escalation phase. The dose expansion phase is expected to start accrual in December 2017. Clinical trial information: NCT03095781.
Identifying potential barriers to sperm cryopreservation among Pakistani male cancer patients.
Authors: Nida Latif, Natasha Ali
Journal: Journal of Clinical Oncology (2017)

e18223 Background: Cancer survivor rates have increased over the past few decades leading to a growing interest in research related to quality of life. The American society of clinical oncology’s updated guidelines of 2013 recommend that health care providers discuss the possibility of infertility with patients and present fertility preservation options to those who express interest. We attempted to explore the unique barriers that might prevent adult male cancer patients from accessing sperm cryopreservation in Pakistan Methods: We conducted semi-structured interviews of male cancer patients aged 18-45 years, diagnosed with cancer of any stage or type. The interviews were audio-recorded in Urdu and translated to English, following which they were transcribed ad verbatim. The topics included quality of information received regarding the risk of infertility following chemotherapy, future reproductive choices and barriers to sperm cryopreservation Results: Out of the 25 patients interviewed, there were n = 10 cases of Leukemia, n = 3 of Lymphoma, n = 2 cases each of colorectal carcinoma and Multiple Myeloma, n = 1 case each of Neuroblastoma and Osteosarcoma, and solitary cases involving the lung, breast, thymus, brain, jaw and testis. Only n = 4 patients knew about the potential for infertility due to cancer chemotherapy, all of whom were also aware of the option of sperm cryopreservation. Two patients had their sperm preserved prior to the initiation of chemotherapy. Perceived treatment related expenses appeared to be the biggest barrier to sperm cryopreservation for n = 9 patients (36%). This was followed by lack of information which was cited by n = 8 patients (32%) and religious reasons (n = 2 patients, 8.3%). Other barriers were identified as family wishes, female gender of the doctor and patient’s preferences. Four patients stated there are no barriers. Conclusions: There is a significant lack of awareness among male cancer patients regarding threat to fertility following cancer treatment. It is imperative that physicians inform them of this and discuss treatment options, along with addressing potential barriers.
Tuberculous meningitis: a roadmap for advancing basic and translational research
Authors: Sanjay K. Jain, David M. Tobin, Elizabeth W. Tucker, Vishwanath Venketaraman, Alvaro A. Ordonez, Lakshmi Jayashankar, Omar K. Siddiqi, Dima A. Hammoud, Nemani V. Prasadarao, Matyas Sandor, Richard Hafner, Zsuzsanna Fabry
Journal: Nature Immunology (2018)
Synergetic Combinations of Dual‐Targeting Ligands for Enhanced In Vitro and In Vivo Tumor Targeting
Authors: Yun Liu, Yue Hui, Rui Ran, Guang‐Ze Yang, David Wibowo, Hao‐Fei Wang, Anton P. J. Middelberg, Chun‐Xia Zhao
Journal: Advanced Healthcare Materials (2018)

Abstract The concept of dual‐ligand targeting has been around for quite some time, but remains controversial due to the intricate interplay between so many different factors such as the choice of dual ligands, their densities, ratios and length matching, etc. Herein, the synthesis of a combinatorial library of single and dual‐ligand nanoparticles with systematically varied properties (ligand densities, ligand ratios, and lengths) for tumor targeting is reported. Folic acid (FA) and hyaluronic acid (HA) are used as two model targeting ligands. It is found that the length matching and ligand ratio play critical roles in achieving the synergetic effect of the dual‐ligand targeting. When FA is presented on the nanoparticle surface through a 5K polyethylene glycol (PEG) chain, the dual ligand formulations using the HA with either 5K or 10K length do not show any targeting effect, but the right length of HA (7K) with a careful selection of the right ligand ratio do enhance the targeting efficiency and specificity significantly. Further in vitro 3D tumor spheroid models and in vivo xenograft mice models confirm the synergetic targeting efficiency of the optimal dual‐ligand formulation (5F2H 7K ). This work provides a valuable insight into the design of dual‐ligand targeting nanosystems.
Brain Activity Associated With Attention Deficits Following Chemotherapy for Childhood Acute Lymphoblastic Leukemia
Authors: Slim Fellah, Yin T Cheung, Matthew A Scoggins, Ping Zou, Noah D Sabin, Ching-Hon Pui, Leslie L Robison, Melissa M Hudson, Robert J Ogg, Kevin R Krull
Journal: JNCI Journal of the National Cancer Institute (2018)

The impact of contemporary chemotherapy treatment for childhood acute lymphoblastic leukemia on central nervous system activity is not fully appreciated.Neurocognitive testing and functional magnetic resonance imaging (fMRI) were obtained in 165 survivors five or more years postdiagnosis (average age = 14.4 years, 7.7 years from diagnosis, 51.5% males). Chemotherapy exposure was measured as serum concentration of methotrexate following high-dose intravenous injection. Neurocognitive testing included measures of attention and executive function. fMRI was obtained during completion of two tasks, the continuous performance task (CPT) and the attention network task (ANT). Image analysis was performed using Statistical Parametric Mapping software, with contrasts targeting sustained attention, alerting, orienting, and conflict. All statistical tests were two-sided.Compared with population norms, survivors demonstrated impairment on number-letter switching (P < .001, a measure of cognitive flexibility), which was associated with treatment intensity (P = .048). Task performance during fMRI was associated with neurocognitive dysfunction across multiple tasks. Regional brain activation was lower in survivors diagnosed at younger ages for the CPT (bilateral parietal and temporal lobes) and the ANT (left parietal and right hippocampus). With higher serum methotrexate exposure, CPT activation decreased in the right temporal and bilateral frontal and parietal lobes, but ANT alerting activation increased in the ventral frontal, insula, caudate, and anterior cingulate.Brain activation during attention and executive function tasks was associated with serum methotrexate exposure and age at diagnosis. These findings provide evidence for compromised and compensatory changes in regional brain function that may help clarify the neural substrates of cognitive deficits in acute lymphoblastic leukemia survivors.
Recognizing young investigators at Frontiers in Cardiovascular Biology 2018
Authors: Heather Y Small
Journal: Cardiovascular Research (2018)

The Frontiers in CardioVascular Biology Meeting 2018 was held in Vienna, Austria on 20th to 22nd April. 1 One of the central aims of the meeting was to provide young investigators with a platform to disseminate their research and interact with world-leaders in the cardiovascular field. 2 An example of such an initiative was the Young Investigators Award session.Finalists were selected from more than 500 abstracts for oral presentation and presented their research in two sessions, specialized into Cardiac and Vascular Biology.The two sessions had a truly international flair bringing together 12 presenters from 10 countries.Cardiovascular Research Onlife was present during the session and had the opportunity to talk to some of the young investigators about their work.To find out more about the benefits for young investigators for attending the FCVB meeting, watch our interview with conference organiser
Why Are We Failing to Address the Issue of Access to Insulin? A National and Global Perspective
Authors: David Beran, Irl B. Hirsch, John S. Yudkin
Journal: Diabetes Care (2018)

Insulin was discovered in 1921 and soon became widely available in high-income countries. However, many people currently in need of this life-saving medicine are unable to access it. This is a global phenomenon, impacting not only populations of low- and middle-income countries but low-income populations in the U.S. In the U.S., the rate of diabetic ketoacidosis remains high in certain subpopulations, the cost of insulin being the main precipitating factor. On a global level the main cause of mortality for a child with type 1 diabetes is a lack of access to insulin, and in sub-Saharan Africa the life expectancy of a child with type 1 diabetes can be as low as 1 year. One lens for considering the issue of access to health and medicines is to consider society as a three-legged stool. In this paradigm, the role of the public sector is to provide “protections” to the population it serves; the private sector is made up of “responsible businesses” that supply many of the goods and services people need; and the plural sector comprises communities and not-for-profits providing the “social affiliations” that are needed. For HIV/AIDS, each of these “legs” played a role in improving access. Civil society raised awareness of the issue and advocated for access to treatment. Governments provided funding and responses both nationally and globally. Finally, the private sector played its role, under pressure from civil society and governments, in lowering the price of medicines and developing programs to expand access. Here, we use this framework to describe the shortcomings in access to insulin from a U.S. and global perspective.
The long non-coding RNA PTTG3P promotes cell growth and metastasis via up-regulating PTTG1 and activating PI3K/AKT signaling in hepatocellular carcinoma
Authors: Jin-lan Huang, Shun-wang Cao, Qi-shui Ou, Bin Yang, Shi-hao Zheng, Jing Tang, Jing Chen, Yan-wei Hu, Lei Zheng, Qian Wang
Journal: Molecular Cancer (2018)

Dysfunctions of long non-coding RNA (lncRNAs) have been associated with the initiation and progression of hepatocellular carcinoma (HCC), but the clinicopathologic significance and potential role of lncRNA PTTG3P (pituitary tumor-transforming 3, pseudogene) in HCC remains largely unknown.We compared the expression profiles of lncRNAs in 3 HCC tumor tissues and adjacent non-tumor tissues by microarrays. In situ hybridization (ISH) and quantitative real-time polymerase chain reaction (qRT-PCR) were applied to assess the level of PTTG3P and prognostic values of PTTG3P were assayed in two HCC cohorts (n = 46 and 90). Artificial modulation of PTTG3P (down- and over-expression) was performed to explore the role of PTTG3P in tumor growth and metastasis in vitro and in vivo. Involvement of PTTG1 (pituitary tumor-transforming 1), PI3K/AKT signaling and its downstream signals were validated by qRT-PCR and western blot.We found that PTTG3P was frequently up-regulated in HCC and its level was positively correlated to tumor size, TNM stage and poor survival of patients with HCC. Enforced expression of PTTG3P significantly promoted cell proliferation, migration, and invasion in vitro, as well as tumorigenesis and metastasis in vivo. Conversely, PTTG3P knockdown had opposite effects. Mechanistically, over-expression of PTTG3P up-regulated PTTG1, activated PI3K/AKT signaling and its downstream signals including cell cycle progression, cell apoptosis and epithelial-mesenchymal transition (EMT)-associated genes.Our findings suggest that PTTG3P, a valuable marker of HCC prognosis, promotes tumor growth and metastasis via up-regulating PTTG1 and activating PI3K/AKT signaling in HCC and might represent a potential target for gene-based therapy.
Diagnostic Yield of Genetic Testing in Young Athletes With T-Wave Inversion
Authors: Nabeel Sheikh, Michael Papadakis, Mathew Wilson, Aneil Malhotra, Carmen Adamuz, Tessa Homfray, Lorenzo Monserrat, Elijah R. Behr, Sanjay Sharma
Journal: Circulation (2018)

T-wave inversion (TWI) is common in patients with cardiomyopathy. However, up to 25% of athletes of African/Afro-Caribbean descent (black athletes) and 5% of white athletes also have TWI of unclear clinical significance despite comprehensive clinical evaluation and long-term follow-up. The aim of this study was to determine the diagnostic yield from genetic testing, beyond clinical evaluation, when investigating athletes with TWI.We investigated 50 consecutive asymptomatic black and 50 white athletes 14 to 35 years of age with TWI and a normal echocardiogram who were referred to a UK tertiary center for cardiomyopathy and sports cardiology. Subjects underwent exercise testing, 24-hour ambulatory ECG, signal-averaged ECG, cardiac magnetic resonance imaging, and a blood-based analysis of a comprehensive 311-gene panel for cardiomyopathies and ion channel disorders associated with TWI, including hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, dilated cardiomyopathy, left ventricular noncompaction, long-QT syndrome, and Brugada syndrome.In total, 21 athletes (21%) were diagnosed with cardiac disease on the basis of comprehensive clinical investigations. Of these, 8 (38.1%) were gene positive (myosin binding protein C[ MYBPC3], myosin heavy chain 7 [ MYH7], galactosidase alpha [ GLA], and actin alpha, cardiac muscle 1 [ ACTC1] genes) and 13 (61.9%) were gene negative. Of the remaining 79 athletes (79%), 2 (2.5%) were gene positive (transthyretin [ TTR] and sodium voltage-gated channel alpha subunit 5 [ SCN5A] genes) in the absence of a clinical phenotype. The prevalence of newly diagnosed cardiomyopathy was higher in white athletes compared with black athletes (30.0% versus 12%; P=0.027). Hypertrophic cardiomyopathy accounted for 90.5% of all clinical diagnoses. All black athletes and 93.3% of white athletes with a clinical diagnosis of cardiomyopathy or a genetic mutation capable of causing cardiomyopathy exhibited lateral TWI as opposed to isolated anterior or inferior TWI; the genetic yield of diagnoses from lateral TWI was 12.3%.Up to 10% of athletes with TWI revealed mutations capable of causing cardiac disease. Despite the substantial cost, the positive diagnostic yield from genetic testing was one half that from clinical evaluation (10% versus 21%) and contributed to additional diagnoses in only 2.5% of athletes with TWI in the absence of a clear clinical phenotype, making it of negligible use in routine clinical practice.
Precision Communication—A Path Forward to Improve Goals-of-Care Communication
Authors: Joanna Paladino, Rachelle Bernacki
Journal: JAMA Internal Medicine (2018)

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Association of Exposure to Diethylstilbestrol During Pregnancy With Multigenerational Neurodevelopmental Deficits
Authors: Marianthi-Anna Kioumourtzoglou, Brent A. Coull, Éilis J. O’Reilly, Alberto Ascherio, Marc G. Weisskopf
Journal: JAMA Pediatrics (2018)

<h3>Importance</h3> Animal evidence suggests that endocrine disruptors affect germline cells and neurodevelopment. However, to date, the third-generation neurodevelopmental outcomes in humans have not been examined. <h3>Objective</h3> To explore the potential consequences of exposure to diethylstilbestrol or DES across generations—specifically, third-generation neurodevelopment. <h3>Design, Setting, and Participants</h3> This cohort study uses self-reported health information, such as exposure to diethylstilbestrol during pregnancy and attention-deficit/hyperactivity disorder (ADHD) diagnosis, from 47 540 participants enrolled in the ongoing Nurses’ Health Study II. The 3 generations analyzed in this study were the participants (F1 generation), their mothers (F0 generation), and their live-born children (F2 generation). <h3>Main Outcomes and Measures</h3> Participant- and mother-reported exposure to diethylstilbestrol during pregnancy and physician-diagnosed child ADHD. <h3>Results</h3> The total number of women included in this study was 47 540. Of the 47 540 F0 mothers, 861 (1.8%) used diethylstilbestrol and 46 679 (98.2%) did not while pregnant with the F1 participants. Use of diethylstylbestrol by F0 mothers was associated with an increased risk of ADHD among the F2 generation: 7.7% vs 5.2%, adjusted odds ratio (OR), 1.36 (95% CI, 1.10-1.67) and an OR of 1.63 (95% CI, 1.18-2.25) if diethylstilbestrol was taken during the first trimester of pregnancy. No effect modification was observed by the F2 children’s sex. <h3>Conclusions and Relevance</h3> This study provides evidence that diethylstilbestrol exposure is associated with multigenerational neurodevelopmental deficits. The doses and potency level of environmental endocrine disruptors to which humans are exposed are lower than those of diethylstilbestrol, but the prevalence of such exposure and the possibility of cumulative action are potentially high and thus warrant consideration.
Sixty seconds on . . . the daily mile
Authors: Nigel Hawkes
Journal: BMJ (2018)

It was invented by a Scottish headteacher, Elaine Wyllie, who in 2012 had the idea that it would be good for the children in her primary school to run or walk a mile a day at their own pace.

It makes sense, and it has spread fast. There are now 778 schools in Scotland, 1292 in England, and 217 …
Abstract B46: Varying the inoculation site of mouse syngeneic tumors can result in aberrant inclusion of lymph node tissue at tumor harvest
Authors: Renee Clift, Barbara Blouw, Susan Zimmerman, Sanna Rosengren, Curt Thompson, Benjamin Thompson
Journal: Cancer Research (2018)

Abstract In recent years, growing interest in immunotherapies for the treatment of cancer has led to increased reliance on murine syngeneic tumor models for preclinical study in immunocompetent animals. These studies typically examine changes in the quantities and phenotypes of tumor-infiltrating immune cells; thus, it is crucial to distinguish between these cells and extratumoral immune cells during tumor harvest. Here, we show that 4T1 breast tumors inoculated in mammary fat pads (MFP) numbers 4 or 9 (4/9) contained greater frequencies of B cells and naïve T cells than tumors inoculated in MFP numbers 5 or 10 (5/10). Immunohistochemical analysis for B-cell presence demonstrated that MFP 4/9 tumors encroached on, and often encapsulated, inguinal lymph nodes, such that lymph node tissue was unknowingly collected during tumor harvest. This prevented accurate enumeration and phenotyping of infiltrating immune cells by flow cytometry, as the majority of lymphocytes in the affected samples derived from lymph nodes, and had not infiltrated the tumor per se. We observed the same phenomenon in peritibial tumors using immunohistochemical analysis, which began to encapsulate popliteal lymph nodes at large tumor volumes (&amp;gt;1500 mm3). Our data highlight the importance of choosing an appropriate inoculation site for obtaining accurate and consistent results when evaluating immune cell infiltration in syngeneic tumor models. Citation Format: Renee Clift, Barbara Blouw, Susan Zimmerman, Sanna Rosengren, Curt Thompson, Benjamin Thompson. Varying the inoculation site of mouse syngeneic tumors can result in aberrant inclusion of lymph node tissue at tumor harvest [abstract]. In: Proceedings of the AACR Special Conference: Advances in Modeling Cancer in Mice: Technology, Biology, and Beyond; 2017 Sep 24-27; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(10 Suppl):Abstract nr B46.