tbuckley/cabot-search huggingface dataset:
Evaluating patient out-of-pocket (OOP) costs associated with attendance at a prostate cancer supportive care program.
Authors: Eugenia Wu, Lindsay Hedden, Sterling Bryan, Olga Arsovska, Michaela Vivar, Monita Sundar, Larry Goldenberg, Celestia S. Higano
Journal: Journal of Clinical Oncology (2019)

108 Background: The Prostate Cancer Supportive Care (PCSC) Program at the Vancouver Prostate Centre (VPC) services address the physical and psychological needs of men and their partners from the time of PC diagnosis onwards. The study objective was to assess the level of patient out-of-pocket (OOP) expenditure associated with attending the PCSC services, which are otherwise free of charge, and determine whether OPP varies by specific clinical or sociodemographic characteristics. Methods: All men with PC seen at the VPC are invited to enroll in this study. Before or after any clinic and/or education appointment, pts completed a cost evaluation survey. Demographic data was collected from the PCSC Program registration forms and VPC electronic medical records. Results: Between 16-Apr-18 and 06-Sep-18, 207 men enrolled in the study and completed the survey. OOP expenses were highly skewed, with the majority of study participants spending less than $20 for each visit to the program, median (median $10, SD 80.0). Majority (93.6%) experienced either no or minimal financial burden, while 5.3% experienced moderate and 1.1% experienced substantial financial burden associated with their attendance at the program. Forty-four participants (22.1%) had to take time away from work to attend a PCSC service, on average this was 275 minutes, and 13.6% of them (2.9% of the total study sample) considered not participating because of difficulty getting the necessary time off. The average travel time (72.9 minutes) associated with a visit to the program was also highly skewed (median 45.0, SD 210.6). Using a simple linear regression, longer travel was associated with higher cost (t=8.30, p&lt;0.0001), however, longer travel was unrelated to cost burden (F=0.35, p=0.79). Conclusions: OOP expenditure as well as associated burden is very minimal for the majority of participants. From a programmatic standpoint, a reasonable number of participants (22%) had to take time away from work. Bi-variate results show no relationship with personal income, OOP expenditure and financial burden.
Use of composite outcomes facilitate core outcome set uptake in rheumatoid arthritis trials
Authors: Jamie Kirkham, Robin Christensen, Maarten Boers
Journal: Annals of the Rheumatic Diseases (2019)

The WHO and the International League of Associations for Rheumatology set of core outcomes for rheumatoid arthritis (hereafter RA-COS) was adopted in 1993; it comprises eight individual outcomes which aim to assess disease activity, patient-reported outcome and damage.1 2 In addition, several validated composite outcome measures are available for use in clinical trials to measure both disease activity and state. The two key indices used in RA, the American College of Rheumatology (ACR) 20% and the Disease Activity Score (DAS) 28, represent combined subsets of the core outcome set (COS); they have been widely adopted as primary endpoints, and reporting of one of these, as well as the RA-COS, is recommended in regulatory guidance.3 4 Non-reporting of the individual core outcomes restricts meta-analyses, might lead to relevant information being missed, to exaggerated perceptions on how well an intervention works, and could lead to suspicion of intentional …
A randomized, phase II study comparing irinotecan versus amrubicin as maintenance therapy after first-line induction therapy for extensive disease small cell lung cancer (HOT1401/NJLCG1401)
Authors: K. Baba, H. Tanaka, Y. Fujita, A. Nakamura, E. Kikuchi, Y. Kawai, T. Harada, N. Watanabe, H. Yokouchi, K. Usui, R. Saito, H. Watanabe, T. Masuda, T. Fukuhara, K. Kudo, R. Honda, S. Oizimi, M. Maemondo, A. Inoue, N. Morikawa
Journal: Annals of Oncology (2019)
Chimeric antigen receptor T cell therapies for multiple myeloma
Authors: Chao Wu, Lina Zhang, Qierra R. Brockman, Fenghuang Zhan, Lijuan Chen
Journal: Journal of Hematology & Oncology (2019)

Multiple myeloma (MM) is the second most common hematologic malignancy and remains incurable despite the advent of numerous new drugs such as proteasome inhibitors (PIs), immunomodulatory agents (IMiDs), and monoclonal antibodies. There is an unmet need to develop novel therapies for refractory/relapsed MM. In the past few years, chimeric antigen receptor (CAR)-modified T cell therapy for MM has shown promising efficacy in preclinical and clinical studies. Furthermore, the toxicities of CAR-T cell therapy are manageable. This article summarizes recent developments of CAR-T therapy in MM, focusing on promising targets, new technologies, and new research areas. Additionally, a comprehensive overview of antigen selection is presented along with preliminary results and future directions of CAR-T therapy development.
Biomimetic Decoy Inhibits Tumor Growth and Lung Metastasis by Reversing the Drawbacks of Sonodynamic Therapy
Authors: Hongjuan Zhao, Beibei Zhao, Li Li, Kaili Ding, Huifang Xiao, Cuixia Zheng, Lingling Sun, Zhenzhong Zhang, Lei Wang
Journal: Advanced Healthcare Materials (2019)

Abstract Sonodynamic therapy (SDT) shows tremendous potential to induce immunogenic cell death (ICD) and activate antitumor immunity. However, it can aggravate hypoxia and release platelet (PLT)‐associated danger‐associated molecular patterns (DAMPs), which impede therapeutic efficacy and promote tumor metastasis. In order to solve these problems, a biomimetic decoy (designated as Lipo‐Ce6/TPZ@M H ) is constructed to reverse the drawbacks of SDT by loading sonosensitizer chlorin e6 (Ce6) and hypoxia‐activated tirapazamine (TPZ) in the red blood cells–PLTs hybrid membrane (M H )‐camouflaged pH‐sensitive liposome. After administration, the decoy exhibits enhanced cancer accumulation and retention abilities due to the immune escape and specific targeting behaviors by biomimetic surface coating. Upon local ultrasound, Ce6 produces toxic reactive oxygen species for SDT, and the resulting hypoxia microenvironment activates TPZ, which can realize a high‐effective synergistic therapy. Meanwhile, DAMPs‐mediated tumor metastasis is significantly inhibited, because the decoy retains platelet binding functions but is incapable of platelet‐mediated metastasis. In addition, ICD‐mediated strong antitumor immunities further prevent the growth and metastasis of the residual tumors left behind after synergistic treatment. Taken together, this study highlights the potential of using this cascade therapeutic therapy plus biomemitic decoy in one nanosystem to both eliminate melanoma in situ and suppress lung metastasis.
In Vitro Human Liver Model of Nonalcoholic Steatohepatitis by Coculturing Hepatocytes, Endothelial Cells, and Kupffer Cells
Authors: Ceri‐Anne E. Suurmond, Soufian Lasli, Floor W. van den Dolder, Aly Ung, Han‐Jun Kim, Praveen Bandaru, KangJu Lee, Hyun‐Jong Cho, Samad Ahadian, Nureddin Ashammakhi, Mehmet R. Dokmeci, Junmin Lee, Ali Khademhosseini
Journal: Advanced Healthcare Materials (2019)

Abstract The liver has a complex and unique microenvironment with multiple cell–cell interactions and internal vascular networks. Although nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease with multiple phases, no proper model could fully recapitulate the in vivo microenvironment to understand NAFLD progression. Here, an in vitro human liver model of NAFLD by coculturing human hepatocytes, umbilical vein endothelial cells (HUVECs), and Kupffer cells (KCs) into spheroids is presented. Analysis of indirect cross‐talk using conditioned media between steatotic spheroids—composed of hepatocellular carcinoma‐derived cells (HepG2) and HUVECs—and mouse KCs reveals that the latter can be activated showing increased cell area, elevated production of reactive oxygen species (ROS), and proinflammatory cytokines. Spheroids incorporating human KCs (HKCs) can also be induced into steatotic stage by supplementing fat. Steatotic spheroids with/without HKCs show different levels of steatotic stages through lipid accumulation and ROS production. Steatotic spheroids made from an immortalized hepatic progenitor cell line (HepaRG) compared to those made from HepG2 cells display similar trends of functionality, but elevated levels of proinflammatory cytokines, and improved reversibility of steatosis. The in vitro human liver system proposed makes strides in developing a model to mimic and monitor the progression of NAFLD.
Statin Use Is Associated with Lower Risk of PTEN-Null and Lethal Prostate Cancer
Authors: Emma H. Allott, Ericka M. Ebot, Konrad H. Stopsack, Amparo G. Gonzalez-Feliciano, Sarah C. Markt, Kathryn M. Wilson, Thomas U. Ahearn, Travis A. Gerke, Mary K. Downer, Jennifer R. Rider, Stephen J. Freedland, Tamara L. Lotan, Philip W. Kantoff, Elizabeth A. Platz, Massimo Loda, Meir J. Stampfer, Edward Giovannucci, Christopher J. Sweeney, Stephen P. Finn, Lorelei A. Mucci
Journal: Clinical Cancer Research (2019)

Abstract Purpose: Statins are associated with lower risk of aggressive prostate cancer, but lethal prostate cancer is understudied and contributing mechanisms are unclear. We prospectively examined statins and lethal prostate cancer risk in the Health Professionals Follow-up Study (HPFS), tested associations with molecular subtypes, and integrated gene expression profiling to identify putative mechanisms. Experimental Design: Our study included 44,126 men cancer-free in 1990, followed for prostate cancer incidence through 2014, with statin use recorded on biennial questionnaires. We used multivariable Cox regression to examine associations between statins and prostate cancer risk overall, by measures of clinically significant disease, and by ERG and PTEN status. In an exploratory analysis, age-adjusted gene set enrichment analysis identified statin-associated pathways enriched in tumor and adjacent normal prostate tissue. Results: During 24 years of follow-up, 6,305 prostate cancers were diagnosed and 801 (13%) were lethal (metastatic at diagnosis or metastatic/fatal during follow-up). Relative to never/past use, current statin use was inversely associated with risk of lethal prostate cancer [HR, 0.76; 95% confidence interval (CI), 0.60–0.96] but not overall disease. We found a strong inverse association for risk of PTEN-null cancers (HR, 0.40; 95% CI, 0.19–0.87) but not PTEN-intact cancers (HR, 1.18; 95% CI, 0.95–1.48; P heterogeneity = 0.01). Associations did not differ by ERG. Inflammation and immune pathways were enriched in normal prostate tissue of statin ever (n = 10) versus never users (n = 103). Conclusions: Molecular tumor classification identified PTEN and inflammation/immune activation as potential mechanisms linking statins with lower lethal prostate cancer risk. These findings support a potential causal association and could inform selection of relevant biomarkers for statin clinical trials.
Genetically Engineered Cell-Derived Nanoparticles for Targeted Breast Cancer Immunotherapy
Authors: Xiaojing Shi, Qinqin Cheng, Tianling Hou, Menglu Han, Goar Smbatyan, Julie E. Lang, Alan L. Epstein, Heinz-Josef Lenz, Yong Zhang
Journal: Molecular Therapy (2019)

Exosomes are nanosized membranous vesicles secreted by a variety of cells. Due to their unique and pharmacologically important properties, cell-derived exosome nanoparticles have drawn significant interest for drug development. By genetically modifying exosomes with two distinct types of surface-displayed monoclonal antibodies, we have developed an exosome platform termed synthetic multivalent antibodies retargeted exosome (SMART-Exo) for controlling cellular immunity. Here, we apply this approach to human epidermal growth factor receptor 2 (HER2)-expressing breast cancer by engineering exosomes through genetic display of both anti-human CD3 and anti-human HER2 antibodies, resulting in SMART-Exos dually targeting T cell CD3 and breast cancer-associated HER2 receptors. By redirecting and activating cytotoxic T cells toward attacking HER2-expressing breast cancer cells, the designed SMART-Exos exhibited highly potent and specific anti-tumor activity both in vitro and in vivo. This work demonstrates preclinical feasibility of utilizing endogenous exosomes for targeted breast cancer immunotherapy and the SMART-Exos as a broadly applicable platform technology for the development of next-generation immuno-nanomedicines.
Targeted disruption of dual leucine zipper kinase and leucine zipper kinase promotes neuronal survival in a model of diffuse traumatic brain injury
Authors: Derek S. Welsbie, Nikolaos K. Ziogas, Leyan Xu, Byung-Jin Kim, Yusong Ge, Amit K. Patel, Jiwon Ryu, Mohamed Lehar, Athanasios S. Alexandris, Nicholas Stewart, Donald J. Zack, Vassilis E. Koliatsos
Journal: Molecular Neurodegeneration (2019)

Abstract Background Traumatic brain injury (TBI) is a major cause of CNS neurodegeneration and has no disease-altering therapies. It is commonly associated with a specific type of biomechanical disruption of the axon called traumatic axonal injury (TAI), which often leads to axonal and sometimes perikaryal degeneration of CNS neurons. We have previously used genome-scale, arrayed RNA interference-based screens in primary mouse retinal ganglion cells (RGCs) to identify a pair of related kinases, dual leucine zipper kinase (DLK) and leucine zipper kinase (LZK) that are key mediators of cell death in response to simple axotomy. Moreover, we showed that DLK and LZK are the major upstream triggers for JUN N-terminal kinase (JNK) signaling following total axonal transection. However, the degree to which DLK/LZK are involved in TAI/TBI is unknown. Methods Here we used the impact acceleration (IA) model of diffuse TBI, which produces TAI in the visual system, and complementary genetic and pharmacologic approaches to disrupt DLK and LZK, and explored whether DLK and LZK play a role in RGC perikaryal and axonal degeneration in response to TAI. Results Our findings show that the IA model activates DLK/JNK/JUN signaling but, in contrast to axotomy, many RGCs are able to recover from the injury and terminate the activation of the pathway. Moreover, while DLK disruption is sufficient to suppress JUN phosphorylation, combined DLK and LZK inhibition is required to prevent RGC cell death. Finally, we show that the FDA-approved protein kinase inhibitor, sunitinib, which has activity against DLK and LZK, is able to produce similar increases in RGC survival. Conclusion The mitogen-activated kinase kinase kinases (MAP3Ks), DLK and LZK, participate in cell death signaling of CNS neurons in response to TBI. Moreover, sustained pharmacologic inhibition of DLK is neuroprotective, an effect creating an opportunity to potentially translate these findings to patients with TBI.
Long-Term Hydroxyurea Use Is Associated with Lower Levels of Hematopoietic Stem and Progenitor Cells in Patients with Sickle Cell Disease
Authors: Seda S. Tolu, Kai Wang, Zi Yan, Andrew Crouch, Gracy Sebastian, Mark Chaitowitz, Eric Fornari, Evan Schwechter, Joan Uehlinger, Deepa Manwani, Caterina P. Minniti, Eric E. Bouhassira
Journal: Blood (2019)
A phase I and extension study of S-1 and carboplatin for previously untreated patients aged 75 years or more with advanced non-small cell lung cancer
Authors: H. Imai, T. Kasai, K. Mori, K. Kishi, T. Kaburagi, M. Yomota, T. Sugano, Y. Hosomi, Y. Yamada, S. Moriguchi, K. Minato, A. Gemma
Journal: Annals of Oncology (2019)
Effect of Delayed vs Immediate Umbilical Cord Clamping on Maternal Blood Loss in Term Cesarean Delivery
Authors: Stephanie E. Purisch, Cande V. Ananth, Brittany Arditi, Logan Mauney, Barouyr Ajemian, Amy Heiderich, Tina Leone, Cynthia Gyamfi-Bannerman
Journal: JAMA (2019)

<h3>Importance</h3> The American College of Obstetricians and Gynecologists recommends a delay in umbilical cord clamping in term neonates for at least 30 to 60 seconds after birth. Most literature supporting this practice is from low-risk vaginal deliveries. There are no published data specific to cesarean delivery. <h3>Objective</h3> To compare maternal blood loss with immediate cord clamping vs delayed cord clamping in scheduled cesarean deliveries at term (≥37 weeks). <h3>Design, Setting, and Participants</h3> Randomized clinical trial performed at 2 hospitals within a tertiary academic medical center in New York City from October 2017 to February 2018 (follow-up completed March 15, 2018). A total of 113 women undergoing scheduled cesarean delivery of term singleton gestations were included. <h3>Interventions</h3> In the immediate cord clamping group (n = 56), cord clamping was within 15 seconds after birth. In the delayed cord clamping group (n = 57), cord clamping was at 60 seconds after birth. <h3>Main Outcomes and Measures</h3> The primary outcome was change in maternal hemoglobin level from preoperative to postoperative day 1, which was used as a proxy for maternal blood loss. Secondary outcomes included neonatal hemoglobin level at 24 to 72 hours of life. <h3>Results</h3> All of the 113 women who were randomized (mean [SD] age, 32.6 [5.2] years) completed the trial. The mean preoperative hemoglobin level was 12.0 g/dL in the delayed and 11.6 g/dL in the immediate cord clamping group. The mean postoperative day 1 hemoglobin level was 10.1 g/dL in the delayed group and 9.8 g/dL in the immediate group. There was no significant difference in the primary outcome, with a mean hemoglobin change of −1.90 g/dL (95% CI, −2.14 to −1.66) and −1.78 g/dL (95% CI, −2.03 to −1.54) in the delayed and immediate cord clamping groups, respectively (mean difference, 0.12 g/dL [95% CI, −0.22 to 0.46];<i>P</i> = .49). Of 19 prespecified secondary outcomes analyzed, 15 showed no significant difference. The mean neonatal hemoglobin level, available for 90 neonates (79.6%), was significantly higher with delayed (18.1 g/dL [95% CI, 17.4 to 18.8]) compared with immediate (16.4 g/dL [95% CI, 15.9 to 17.0]) cord clamping (mean difference, 1.67 g/dL [95% CI, 0.75 to 2.59];<i>P</i> &lt; .001). There was 1 unplanned hysterectomy in each group. <h3>Conclusions and Relevance</h3> Among women undergoing scheduled cesarean delivery of term singleton pregnancies, delayed umbilical cord clamping, compared with immediate cord clamping, resulted in no significant difference in the change in maternal hemoglobin level at postoperative day 1. <h3>Trial Registration</h3> ClinicalTrials.gov Identifier:NCT03150641
Appraising appraisal
Authors: W. Riley
Journal: BMJ (1998)

You are a consultant with responsibility for supervising the training of at least one specialist registrar. With that goes the responsibility for conducting appraisals. What should you be doing? What should you not be doing?

You are a newly appointed specialist registrar, and the consultant assigned as your educational supervisor has arranged a date for an appraisal meeting. What should you expect?

Increasingly, appraisal is recognised as performing a central role in the training of tomorrow's doctors. With this recognition has come an appreciation that it is not easy and requires a professional approach. What exactly is appraisal? And how does it differ from assessment, which, at least since the Calman reforms, is often mentioned in the same breath?

### Successful appraisers…

The Guide to Specialist Registrar Training(1) distinguishes between assessment, a process “to measure progress against defined criteria based on relevant curricula,” and appraisal, which provides “a complementary or parallel approach focussing on the trainee and his or her personal and professional needs.”(1) The process will enable educational supervisors to offer trainees “feedback on performance and assistance in career progression” by means of confidential “constructive and regular dialogue.” Homage duly paid, the orange book declines to give any guidance on appraisal and instead moves swiftly on to discuss assessment. So what guidance is there?

In other sectors, such as the university sector in which I work, appraisal is widely used to enable us, as employees, to develop effectively in our work and careers. Here a distinction is drawn between reviewing an individual's potential, in the context of that person's own career history, and reviewing it in relation to fixed criteria …
Zn<sup>2+</sup> Doped Ultrasmall Prussian Blue Nanotheranostic Agent for Breast Cancer Photothermal Therapy under MR Imaging Guidance
Authors: Pingbo Shou, Zhangsen Yu, Yiting Wu, Qiang Feng, Bangyi Zhou, Jie Xing, Chuang Liu, Jinqing Tu, Ozioma Udochukwu Akakuru, Zhiqiu Ye, Xiaojuan Zhang, Zhenbo Lu, Luyun Zhang, Aiguo Wu
Journal: Advanced Healthcare Materials (2019)

Prussian blue nanoprobes are widely studied and applied in tumor photothermal therapy (PTT) and magnetic resonance imaging (MRI), due to their low toxicity and excellent in vivo performance. However, the sizes of hitherto reported Prussian blue nanoprobes are generally larger than 50 nm, which greatly influence cell phagocytosis, in vivo circulation, and biodistribution. In this work, a novel method of doping zinc ions is used to control the size of Prussian blue nanoprobes. Consequently, the performances of the nanoprobes in PTT and MRI are both significantly improved. The results show that the minimum size of Prussian blue nanoprobes achieved by doping 10% zinc ions (abbreviated as SPBZn(10%)) is 3.8 ± 0.90 nm, and the maximum specific absorption coefficient, photothermal conversion efficiency, and longitudinal relaxation rates are 1.78 L g-1 cm-1 , 47.33%, and 18.40 mm-1 s-1 , respectively. In addition, the SPBZn(10%) nanoprobes provide excellent PTT efficacy on 4T1 tumor cells (killing rate: 90.3%) and breast cancer model (tumor inhibition rate: 69.4%). Toxicological experiment results show that the SPBZn(n%) nanoprobes exhibit no obvious in vitro cytotoxicity and they can be used safely in mice at doses below 100 mg kg-1 . Therefore, SPBZn(10%) nanoprobes can potentially be used for effective cancer theranostics.
Author Correction: Noradrenergic signaling in the wakeful state inhibits microglial surveillance and synaptic plasticity in the mouse visual cortex
Authors: Rianne D. Stowell, Grayson O. Sipe, Ryan P. Dawes, Hanna N. Batchelor, Katheryn A. Lordy, Brendan S. Whitelaw, Mark B. Stoessel, Jean M. Bidlack, Edward Brown, Mriganka Sur, Ania K. Majewska
Journal: Nature Neuroscience (2019)
Cross‐reactivities of non‐homologous allergens
Authors: Merima Bublin, Heimo Breiteneder
Journal: Allergy (2019)

Abstract Allergen cross‐reactivities occur when IgE antibodies, originally raised against a specific allergen, bind to identical or highly similar surface areas of another related allergen. It is a commonly held view that cross‐reactivity requires more than 70% sequence identity, while proteins that share &lt;50% sequence identity are rarely cross‐reactive. This also implies that cross‐reactive proteins have a similar 3D fold and belong to the same protein family. At first, the existence of cross‐reactivity between non‐homologous allergens was not expected because it was contrary to the above described concepts. Now, several lines of evidence demonstrate that IgE cross‐reactivity also exists between unrelated allergens. In this Editorial, we aim to summarize the existing literature on IgE cross‐reactivity between non‐homologous allergens.
Suicide and Ambient Temperature: A Multi-Country Multi-City Study
Authors: Yoonhee Kim, Ho Kim, Antonio Gasparrini, Ben Armstrong, Yasushi Honda, Yeonseung Chung, Chris Fook Sheng Ng, Aurelio Tobias, Carmen Íñiguez, Eric Lavigne, Francesco Sera, Ana M. Vicedo-Cabrera, Martina S. Ragettli, Noah Scovronick, Fiorella Acquaotta, Bing-Yu Chen, Yue-Liang Leon Guo, Xerxes Seposo, Tran Ngoc Dang, Micheline de Sousa Zanotti Stagliorio Coelho, Paulo Hilario Nascimento Saldiva, Anna Kosheleva, Antonella Zanobetti, Joel Schwartz, Michelle L. Bell, Masahiro Hashizume
Journal: Environmental Health Perspectives (2019)

Previous literature suggests that higher ambient temperature may play a role in increasing the risk of suicide. However, no multi-country study has explored the shape of the association and the role of moderate and extreme heat across different locations.