tbuckley/cabot-search huggingface dataset:
Single Agent Daratumumab in Advanced Multiple Myeloma: Specific Healthcare Program in the Czech Republic
Authors: Jiri Minarik, Ludek Pour, Vladimir Maisnar, Ivan Spicka, Alexandra Jungova, Hana Plonkova, Lucie Brozova, Petra Krhovska, Tomas Pika, Jaroslav Bacovsky, Sabina Sevcikova, Jakub Radocha, Vlastimil Scudla, Roman Hájek
Journal: Blood (2017)
Network Analysis of Genome-Wide Association Studies for Chronic Obstructive Pulmonary Disease in the Context of Biological Pathways
Authors: Sarah Mount, Elisa Cirillo, Kelly Stewart, Susan Coort, Chris T. Evelo, Anke Wesselius, Maurice P. Zeegers, Annemie M. W. J. Schols
Journal: American Journal of Respiratory and Critical Care Medicine (2019)
Synergistic and selective inhibition of NSCLC cell growth via a caspase-independent cell death pathway by tumor suppressor 101F6 nanoparticles plus vitamin C <i>in vitro and in vivo</i>
Authors: S. Ohtani, K. Ueda, G. Jayanchandran, K. Xu, J. D. Minna, J. A. Roth, L. Ji
Journal: Journal of Clinical Oncology (2006)

13086 Background: 101F6 is a candidate tumor suppressor gene on chromosome 3p21.3, a site of allele loss and genomic alterations were frequently found in many human cancers. We previously showed that enforced expression of wt-101F6 by adenoviral virus significantly inhibited tumor cell growth in 3p21.3-deficient NSCLC cells in vitro and in vivo. How 101F6 exerts this effect is largely unknown. Using a computer-aided structural and functional modeling, we recently identified 101F6 as a member of cytochrome b-561 protein family, which is involved in the regeneration of vitamin C. We hypothesized that under normal physiologic conditions, 101F6 protects cells from oxidative damage by regenerating antioxidant vitamin C and that in 101F6-deficient tumor cells, exogenous 101F6 facilitates vitamin C-mediated cytotoxic H 2 O 2 formation. Methods and Results: We examined endogenous 101F6 expression in human NSCLC cell lines and tissue samples. All normal lung bronchial epithelial cells and fibroblasts but few lung cancers expressed 101F6. We investigated the combined effect of 101F6 and vitamin C on the cell growth: a nanoparticle-mediated wt-101F6 gene transfer plus a sub-pharmacologic concentration of vitamin C synergistically inhibited 3p21.3-deficient NSCLC cell growth but did not affect normal cell growth. We also used a human NSCLC H322 orthotopic lung tumor xenograft mouse model to evaluate the therapeutic efficacy of systemic injection of 101F6 nanoparticles and intraperitoneal injection of vitamin C. The growth of lung tumors was synergistically inhibited by the combination treatment (p&lt;0.001). Furthermore, exogenous 101F6 promoted intracellular vitamin C uptake, leading to the vitamin C-mediated accumulation of H 2 O 2 in the tumor cells, and these two agents synergistically killed the cells through caspase-independent apoptosis and autophagy cell death pathways. Conclusions: The synergistic and selective antitumor effect of 101F6 nanoparticles plus vitamin C may offer a useful tool for lung cancer prevention and intervention. This abstract is supported by grants from NCI (SPORE P50CA70907) and DOD (TARGET, DAMD17002–1-0706). No significant financial relationships to disclose.
Hierarchy of mono- and biallelic TP53 alterations in multiple myeloma cell fitness
Authors: Umair Munawar, Leo Rasche, Nicole Müller, Cornelia Vogt, Matteo Da-Via, Larissa Haertle, Panagiota Arampatzi, Sascha Dietrich, Markus Roth, Andoni Garitano-Trojaola, Maximilian Johannes Steinhardt, Susanne Strifler, Miguel Gallardo, Joaquin Martinez-Lopez, Ralf C. Bargou, Tobias Heckel, Hermann Einsele, Thorsten Stühmer, K. Martin Kortüm, Santiago Barrio
Journal: Blood (2019)
Endothelial life discontinues without Erk
Authors: Yihai Cao
Journal: The Journal of Experimental Medicine (2019)

The mechanism of maintaining vascular endothelial identity and integrity is largely unknown. In this issue of JEM, Ricard et al. (https://doi.org/10.1084/jem.20182151) discover essential roles of ERK1/2 in maintaining endothelial homeostasis and its deletion-related serious defects in multiple tissues and organs.
Global fitness in adult survivors of childhood acute lymphoblastic leukemia (ALL).
Authors: Kirsten K. Ness, Sujuan Huang, Webb A Smith, Ching-Hon Pui, Jennifer Lanctot, Carrie R Howell, Robyn Karlage, Kyla C Shelton, Leslie L. Robison, Melissa M. Hudson
Journal: Journal of Clinical Oncology (2013)

10022 Background: The extent to which adult survivors of childhood ALL may have impaired fitness has not been well documented. This study compared clinically assessed fitness between childhood ALL survivors and matched controls, and examined risk factors for impaired fitness among survivors. Methods: 365 survivors of childhood ALL diagnosed from 1980-2002, treated at St. Jude Children’s Research Hospital (SJCRH), 10+ years from diagnosis, and 18+ years old completed questionnaires, fitness testing and physical activity assessment (accelerometry). 365 friends/relatives of current SJCRH patients, frequency matched on age, race and sex, were recruited as controls. Data from fitness measures were combined into a composite (SJFIT) using factor analysis. Individual measures and SJFIT scores were compared between survivors and controls with two sample t-tests. Among survivors, associations between demographic, lifestyle, treatment variables and poor fitness, i.e. scoring in the lowest 10th percentile of controls on the SJFIT, were evaluated with logistic regression. Results: Survivors were 52% male (mean age 28±7 years, mean diagnosis age 6±5 years, mean survival 21±5 years), and scored lower than controls on individual fitness measures (Table) and the SJFIT composite. Female sex (OR 9.4, 95%CI 3.4-26.1) and fewer daily minutes of moderate and vigorous physical activity (OR 0.95, 95% CI 0.92-0.99) were associated with poor fitness after adjusting for diagnosis age, current age, cranial radiation, body fat and smoking. Conclusions: Childhood ALL survivors, particularly females, have fitness impairments when compared to matched controls. Poor fitness is associated with physical activity levels. Interventions to address impairments need to be tested and implemented. [Table: see text]
Abstract 3965: Association of Obesity and Weight-Change with Long-Term Mortality in the Elderly
Authors: John S Pantazopoulos, Alan C Wilson, Nora M Cosgrove, John B Kostis
Journal: Circulation (2006)

Background: The epidemic of obesity in the USA raises fears of increasing death rates in the overweight. However age may be a modifying factor, and it is important to clarify the impact of weight a...
PAG1 limits allergen‐induced type 2 inflammation in the murine lung
Authors: Md Ashik Ullah, Cristina T. Vicente, Natasha Collinson, Bodie Curren, Md Al Amin Sikder, Ismail Sebina, Jennifer Simpson, Antiopi Varelias, Jonathan A. Lindquist, Manuel A. R. Ferreira, Simon Phipps
Journal: Allergy (2019)

Phosphoprotein associated with glycosphingolipid-enriched microdomains 1 (PAG1) is a transmembrane adaptor protein that affects immune receptor signaling in T and B cells. Evidence from genome-wide association studies of asthma suggests that genetic variants that regulate the expression of PAG1 are associated with asthma risk. However, it is not known whether PAG1 expression is causally related to asthma pathophysiology. Here, we investigated the role of PAG1 in a preclinical mouse model of house dust mite (HDM)-induced allergic sensitization and allergic airway inflammation.Pag1-deficient (Pag1-/- ) and wild-type (WT) mice were sensitized or sensitized/challenged to HDM, and hallmark features of allergic inflammation were assessed. The contribution of T cells was assessed through depletion (anti-CD4 antibody) and adoptive transfer studies.Type 2 inflammation (eosinophilia, eotaxin-2 expression, IL-4/IL-5/IL-13 production, mucus production) in the airways and lungs was significantly increased in HDM sensitized/challenged Pag1-/- mice compared to WT mice. The predisposition to allergic sensitization was associated with increased airway epithelial high-mobility group box 1 (HMGB1) translocation and release, increased type 2 innate lymphoid cells (ILC2s) and monocyte-derived dendritic cell numbers in the mediastinal lymph nodes, and increased T-helper type 2 (TH 2)-cell differentiation. CD4+ T-cell depletion studies or the adoptive transfer of WT OVA-specific CD4+ T cells to WT or Pag1-/- recipients demonstrated that the heightened propensity for TH 2-cell differentiation was both T cell intrinsic and extrinsic.PAG1 deficiency increased airway epithelial activation, ILC2 expansion, and TH 2 differentiation. As a consequence, PAG1 deficiency predisposed toward allergic sensitization and increased the severity of experimental asthma.
Impact of naturally forming human α/β-tryptase heterotetramers in the pathogenesis of hereditary α-tryptasemia
Authors: Quang T. Le, Jonathan J. Lyons, Andrea N. Naranjo, Ana Olivera, Robert A. Lazarus, Dean D. Metcalfe, Joshua D. Milner, Lawrence B. Schwartz
Journal: The Journal of Experimental Medicine (2019)

Both α-tryptase and β-tryptase are preferentially expressed by human mast cells, but the purpose of α-tryptase is enigmatic, because its tetramers lack protease activity, whereas β-tryptase tetramers are active proteases. The monogenic disorder called hereditary α-tryptasemia, due to increased α-tryptase gene copies and protein expression, presents with clinical features such as vibratory urticaria and dysautonomia. We show that heterotetramers composed of 2α- and 2β-tryptase protomers (α/β-tryptase) form naturally in individuals who express α-tryptase. α/β-Tryptase, but not homotetramer, activates protease-activated receptor-2 (PAR2), which is expressed on cell types such as smooth muscle, neurons, and endothelium. Also, only α/β-tryptase makes mast cells susceptible to vibration-triggered degranulation by cleaving the α subunit of the EGF-like module-containing mucin-like hormone receptor-like 2 (EMR2) mechanosensory receptor. Allosteric effects of α-tryptase protomers on neighboring β-tryptase protomers likely result in the novel substrate repertoire of α/β-tryptase tetramers that in turn cause some of the clinical features of hereditary α-tryptasemia and of other disorders involving mast cells.
Coalescent Theory of Migration Network Motifs
Authors: Nicolas Alcala, Amy Goldberg, Uma Ramakrishnan, Noah A Rosenberg
Journal: Molecular Biology and Evolution (2019)

Natural populations display a variety of spatial arrangements, each potentially with a distinctive impact on genetic diversity and genetic differentiation among subpopulations. Although the spatial arrangement of populations can lead to intricate migration networks, theoretical developments have focused mainly on a small subset of such networks, emphasizing the island-migration and stepping-stone models. In this study, we investigate all small network motifs: the set of all possible migration networks among populations subdivided into at most four subpopulations. For each motif, we use coalescent theory to derive expectations for three quantities that describe genetic variation: nucleotide diversity, FST, and half-time to equilibrium diversity. We describe the impact of network properties on these quantities, finding that motifs with a high mean node degree have the largest nucleotide diversity and the longest time to equilibrium, whereas motifs with low density have the largest FST. In addition, we show that the motifs whose pattern of variation is most strongly influenced by loss of a connection or a subpopulation are those that can be split easily into disconnected components. We illustrate our results using two example data sets-sky island birds of genus Sholicola and Indian tigers-identifying disturbance scenarios that produce the greatest reduction in genetic diversity; for tigers, we also compare the benefits of two assisted gene flow scenarios. Our results have consequences for understanding the effect of geography on genetic diversity, and they can assist in designing strategies to alter population migration networks toward maximizing genetic variation in the context of conservation of endangered species.
Identification of a Novel Icotinib-Sensitive EGFR-SEPTIN14 Fusion Variant in Lung Adenocarcinoma by Next-Generation Sequencing
Authors: You-Cai Zhu, Wen-Xian Wang, Xing-Liang Li, Chun-Wei Xu, Gang Chen, Wu Zhuang, Tangfeng Lv, Yong Song
Journal: Journal of Thoracic Oncology (2019)
Varicella Zoster Virus Encephalitis Mimicking Nivolumab-Induced Autoimmune Neuropathy in a Patient with Lung Cancer
Authors: Yusuke Watanabe, Ryota Kikuchi, Yuki Iwai, Masayuki Ito, Hiroshi Tsukamoto, Kaoru Yamazaki, Hiroyuki Nakamura, Kazutetsu Aoshiba
Journal: Journal of Thoracic Oncology (2019)
The effect of moving to East Village, the former London 2012 Olympic and Paralympic Games Athletes' Village, on physical activity and adiposity (ENABLE London): a cohort study
Authors: Claire M Nightingale, Elizabeth S Limb, Bina Ram, Aparna Shankar, Christelle Clary, Daniel Lewis, Steven Cummins, Duncan Procter, Ashley R Cooper, Angie S Page, Anne Ellaway, Billie Giles-Corti, Peter H Whincup, Alicja R Rudnicka, Derek G Cook, Christopher G Owen
Journal: The Lancet Public Health (2019)

BackgroundThe built environment can affect health behaviours, but longitudinal evidence is limited. We aimed to examine the effect of moving into East Village, the former London 2012 Olympic and Paralympic Games Athletes' Village that was repurposed on active design principles, on adult physical activity and adiposity.MethodsIn this cohort study, we recruited adults seeking new accommodation in East Village and compared physical activity and built environment measures with these data in control participants who had not moved to East Village. At baseline and after 2 years, we objectively measured physical activity with accelerometry and adiposity with body-mass index and bioimpedance, and we assessed objective measures of and participants' perceptions of change in their built environment. We examined the change in physical activity and adiposity between the East Village and control groups, after adjusting for sex, age group, ethnicity, housing tenure, and household (as a random effect).FindingsWe recruited participants for baseline assessment between Jan 24, 2013, and Jan 7, 2016, and we followed up the cohort after 2 years, between Feb 24, 2015, and Oct 24, 2017. At baseline, 1819 households (one adult per household) consented to initial contact by the study team. 1278 adults (16 years and older) from 1006 (55%) households participated at baseline; of these participants, 877 (69%) adults from 710 (71%) households were assessed after 2 years, of whom 441 (50%) participants from 343 (48%) households had moved to East Village. We found no effect associated with moving to East Village on daily steps, the time spent doing moderate-to-vigorous physical activity (either in total or in 10-min bouts or more), daily sedentary time, body-mass index, or fat mass percentage between participants who had moved to East Village and those in the control group, despite sizeable improvements in walkability and neighbourhood perceptions of crime and quality among the East Village group relative to their original neighbourhood at baseline.InterpretationDespite large improvements in neighbourhood perceptions and walkability, we found no clear evidence that moving to East Village was associated with increased physical activity. Improving the built environment on its own might be insufficient to increase physical activity.FundingNational Institute for Health Research and National Prevention Research Initiative.
LncRNA PCNAP1 modulates hepatitis B virus replication and enhances tumor growth of liver cancer
Authors: Jinyan Feng, Guang Yang, Yunxia Liu, Yuen Gao, Man Zhao, Yanan Bu, Hongfeng Yuan, Ying Yuan, Haolin Yun, Mingming Sun, Hongwei Gao, Shuqin Zhang, Zixian Liu, Ming Yin, Xijun Song, Zhenchuan Miao, Zhongqing Lin, Xiaodong Zhang
Journal: Theranostics (2019)

Rationale: Hepatitis B virus (HBV) is a major risk factor for liver cancer, in which HBV covalently closed circular DNA (cccDNA) plays crucial roles.However, the effect of pseudogene-derived long noncoding RNAs (lncRNAs) acting as functional regulators of their ancestral gene expression on HBV replication and hepatocellular carcinoma (HCC) remains unclear.In this study, we speculated that the pseudogene-derived lncRNA PCNAP1 and its ancestor PCNA might modulate HBV replication and promote hepatocarcinogenesis. Methods: We investigated the roles of lncRNA PCNAP1 in contribution of HBV replication through modulating miR-154/PCNA/HBV cccDNA signaling in hepatocarcinogenesis by using CRISPR/Cas9, Southern blot analysis, confocal assays, et al. in primary human hepatocytes (PHH), HepaRG cells, HepG2-NTCP cells, hepatoma carcinoma cells, human liver-chimeric mice model, transgenetic mice model, in vitro tumorigenicity and clinical patients.Results: Interestingly, the expression levels of PCNAP1 and PCNA were significantly elevated in the liver of HBV-infectious human liver-chimeric mice.Clinically, the mRNA levels of PCNAP1 and PCNA were increased in the liver of HBV-positive/HBV cccDNA-positive HCC patients.Mechanistically, PCNA interacted with HBV cccDNA in a HBc-dependent manner.PCNAP1 enhanced PCNA through sponging miR-154 targeting PCNA mRNA 3′UTR.Functionally, PCNAP1 or PCNA remarkably enhanced HBV replication and accelerated the growth of HCC in vitro and in vivo. Conclusion:We conclude that lncRNA PCNAP1 enhances the HBV replication through modulating miR-154/PCNA/HBV cccDNA signaling and the PCNAP1/PCNA signaling drives the hepatocarcinogenesis.Our finding provides new insights into the mechanism by which lncRNA PCNAP1 enhances HBV replication and hepatocarcinogenesis.
First-in-human phase 1 study of IT1208, a defucosylated humanized anti-CD4 depleting antibody, in patients with advanced solid tumors
Authors: Kohei Shitara, Satoshi Ueha, Shigeyuki Shichino, Hiroyasu Aoki, Haru Ogiwara, Tetsuya Nakatsura, Toshihiro Suzuki, Manami Shimomura, Toshiaki Yoshikawa, Kayoko Shoda, Shigehisa Kitano, Makiko Yamashita, Takayuki Nakayama, Akihiro Sato, Sakiko Kuroda, Masashi Wakabayashi, Shogo Nomura, Shoji Yokochi, Satoru Ito, Kouji Matsushima, Toshihiko Doi
Journal: Journal for ImmunoTherapy of Cancer (2019)

<h3>Background</h3> Transient CD4<sup>+</sup> T cell depletion led to the proliferation of tumor-specific CD8<sup>+</sup> T cells in the draining lymph node and increased infiltration of PD-1<sup>+</sup>CD8<sup>+</sup> T cells into the tumor, which resulted in strong anti-tumor effects in tumor-bearing mice. This is a first-in-human study of IT1208, a defucosylated humanized anti-CD4 monoclonal antibody, engineered to exert potent antibody-dependent cellular cytotoxicity. <h3>Methods</h3> Patients with advanced solid tumors were treated with intravenous IT1208 at doses of 0.1 or 1.0 mg/kg. The first patient in each cohort received a single administration, and the other patients received two administrations of IT1208 on days 1 and 8. <h3>Results</h3> Eleven patients were enrolled in the 0.1 mg/kg (<i>n</i>&nbsp;= 4) and 1.0 mg/kg cohorts (<i>n</i>&nbsp;= 7). Grade 1 or 2 infusion-related reactions was observed in all patients. Decreased CD4<sup>+</sup> T cells in peripheral blood due to IT1208 were observed in all patients and especially in those receiving two administrations of 1.0 mg/kg. CD8<sup>+</sup> T cells increased on day 29 compared with baseline in most patients, resulting in remarkably decreased CD4/8 ratios. One microsatellite-stable colon cancer patient achieved durable partial response showing increased infiltration of both CD4<sup>+</sup> and CD8<sup>+</sup> T cells into tumors after IT1208 administration. Moreover, transcriptomic profiling of the liver metastasis of the patient revealed upregulation of the expression of interferon-stimulated genes, T cell activation-related genes, and antigen presentation-related genes after IT1208 administration. Two additional patients with gastric or esophageal cancer achieved stable disease lasting at least 3 months. <h3>Conclusions</h3> IT1208 monotherapy successfully depleted CD4<sup>+</sup> T cells with a manageable safety profile and encouraging preliminary efficacy signals, which warrants further investigations, especially in combination with immune checkpoint inhibitors.
Johnson and Johnson under criminal investigation in US over asbestos in talcum powder
Authors: Owen Dyer
Journal: BMJ (2019)

A federal grand jury in Washington DC is examining company documents as part of a criminal probe by the US justice department into what executives at Johnson and Johnson may have known or concealed about asbestos in their talcum products, according to a Bloomberg news report that cites “people with knowledge of the matter.”1

The company is facing around 14 000 lawsuits over Johnson’s Baby Powder and other talcum products such as Shower to Shower, which plaintiffs say caused mesotheliomas and ovarian cancers. But this is the first news of a criminal investigation, which if it leads to charges could set a new …
A randomized controlled trial (RCT) of long-term follow-up for early stage breast cancer comparing family physician to specialist care: A report of secondary outcomes
Authors: E. Grunfeld, J. Julian, M. Levine, K. Pritchard, D. Coyle, S. Dent, S. Verma, D. Mirsky, C. Sawka, D. Ginsburg, M. Wood
Journal: Journal of Clinical Oncology (2006)

6003 Background: Breast cancer patients usually receive follow-up in specialist cancer clinics. We have reported that family physician follow-up of breast cancer patients is a safe and acceptable alternative to specialist follow-up as measured by the primary clinical outcome of the rate of serious clinical events (Grunfeld et al, JCO 2006;24(6)). We report here the secondary outcomes of this trial: quality of life domains, patient satisfaction and patients’ costs. Methods: Women with early stage breast cancer who had completed adjuvant therapy (patients may have continued on adjuvant hormonal therapy), who were disease free and between 9 and 15 months after diagnosis, were allocated to receive follow-up in a cancer clinic according to usual practice (CC arm) or follow-up from their own family physician (FP arm). For patients without recurrence, quality of life (QL) measured by the SF36, patient satisfaction, and patients’ costs were measured every 6 months. For patients with recurrence QL measured by the EORTC QLQ C-30 was measured at the time of recurrence. Results: 483 patients were allocated to the FP arm and 485 to the CC arm. Median follow-up was 3.5 years. There were no significant differences between groups on change scores for SF36 subscales to 24 months, or EORTC functional subscale scores at the time of recurrence. Patients’ costs of follow-up (travel costs, out-of-pocket expenses, and lost earnings) were significantly less to 24 months (p &lt; 0.02) in the FP arm. Although costs were less between 36 and 48 months, these were not significant. Conclusions: Family physician follow-up of breast cancer patients does not have a negative impact on clinical or QL outcomes and is less costly for patients. No significant financial relationships to disclose.