tbuckley/cabot-search huggingface dataset:
Development of novel superficial bladder cancer model in rabbit to facilitate endoscopic diagnosis and treatment
Authors: Canan Agartan, Catherine Whitbeck, Tipu Nazeer, Robert Levin, Badar M. Mian
Journal: Cancer Research (2004)

1533   Most bladder cancers are superficial at diagnosis, and require multiple endoscopic procedures or intravesical therapies. While animal models of advanced bladder cancer are available, no reliable animal models have been reported that mimic the disease process similar to that of humans, i.e. recurrence, intravesical therapy and progression. There are no reliable bladder cancer models that allow us to diagnose, or treat the cancers in a manner similar to the clinical practice. Our previous studies demonstrated that acute bladder overdistention results in the overexpression of bFGF, VEGF, HIF-1 alpha, as well as c-myc and ras family of oncogenes. These changes are also noted in bladder cancer of various grades and stages. We hypothesized that exposure of the overdistended rabbit urothelium, while it is undergoing the above-stated cellular and molecular changes, to a carcinogen will convert the rabbit urothelium to a malignant phenotype, that will yield spontaneous tumors ranging from superficial to deeply invasive. Four adult male NZW rabbits were anesthetized and the bladder was overdistended for 30 minutes. Then nitrosomethylurea 2.5 mg in 25 ml of normal saline was instilled into the bladder, once/week for 5 weeks. A 10 French size pediatric cystoscope was used prior to each instillation to inspect the urothelium and obtain biopsies from abnormal appearing areas. The control group included 2 rabbits without distention or instillation. The rabbits did not experience any untoward effects from cystoscopy or biopsy. The animals were sacrificed after 5 weeks, and full thickness bladder walls were sectioned and formalin-fixed for pathologic review. The specimens were reviewed by a pathologist and a urologist, who were blinded to the experiments. At 4 weeks, the urothelium appeared to develop lesions that cystoscopically appeared similar to human papillary TCC. In 3 of 4 animals, the biopsies revealed presence of pre-malignant and early malignant lesions such as papillary hyperplasia, intestinal metaplasia, squamous metaplasia and low-grade dysplasia. The full thickness bladder wall specimens revealed presence of mild to marked papillary hyperplasia, focal to diffuse atypia, and low-grade dysplasia in all 4 animals. The findings of this preliminary study suggest that exposing the urothelium to a carcinogen at a time when it is undergoing specific cellular and molecular changes, can result in a malignant phenotype. This model allows us to perform serial cystoscopic examinations to assess disease progression or response to therapy, without sacrificing the animals. In order to develop a more reliable and reproducible range of tumors, further experiments with modifications in the overdistention/instillation schedules, or carcinogen doses are currently ongoing.
Parallel Interdigitated Distributed Networks within the Individual Estimated by Intrinsic Functional Connectivity
Authors: Rodrigo M. Braga, Randy L. Buckner
Journal: Neuron (2017)

Certain organizational features of brain networks present in the individual are lost when central tendencies are examined in the group. Here we investigated the detailed network organization of four individuals each scanned 24 times using MRI. We discovered that the distributed network known as the default network is comprised of two separate networks possessing adjacent regions in eight or more cortical zones. A distinction between the networks is that one is coupled to the hippocampal formation while the other is not. Further exploration revealed that these two networks were juxtaposed with additional networks that themselves fractionate group-defined networks. The collective networks display a repeating spatial progression in multiple cortical zones, suggesting that they are embedded within a broad macroscale gradient. Regions contributing to the newly defined networks are spatially variable across individuals and adjacent to distinct networks, raising issues for network estimation in group-averaged data and applied endeavors, including targeted neuromodulation.
Training load and structure-specific load: applications for sport injury causality and data analyses
Authors: Rasmus Oestergaard Nielsen, Michael Lejbach Bertelsen, Merete Møller, Adam Hulme, Johann Windt, Evert Verhagen, Mohammad Ali Mansournia, Martí Casals, Erik Thorlund Parner
Journal: British Journal of Sports Medicine (2017)

### Definitions

#### Training load

Training load represents step count, throws, distance run and/or time spent practising sport. This can be used to calculate a change in training load over time (eg, acute:chronic workload ratio or week-to-week changes), which has been used as a time-varying exposure to sports injury recently.

#### Structure-specific cumulative load

Can be viewed as the sum of step-specific or throw-specific loads that a certain musculoskeletal structure is exposed to during a training session. Estimation of the structure-specific cumulative load per training session involves stepwise or throw-wise quantification of the load distribution and the load magnitude.

#### Structure-specific load capacity

Can be defined as a certain structure’s ability to withstand structure-specific cumulative load.

How should I schedule my training? How much is too much? Coaches and sports medicine clinicians commonly face such questions when considering training and injury risk. These are highly relevant inquiries, as training load is a necessary cause of sports injury.1 2 To provide answers, our analytical approaches should align with causal frameworks. Changes in training load (eg, acute:chronic workload ratio) has been used as an interesting exposure to injury lately3–5 and promoted as proximal in the causal chain to sports injury.2 6 However, the aetiology behind sports injury development is multifactorial.1 Therefore, more variables (eg, body mass, alignment, diet, strength) than training load are necessary to robustly identify ‘how much is too much’.7 Accordingly, the purpose of this editorial is to describe the differences among the concepts ‘training-load’, ‘structure-specific load’ and ‘load capacity’, including the varied exposures that define them.

Sports injury prevention scientists should carefully consider how best to phrase their research questions in aetiological …
Erratum: Cilostazol or pentoxifylline for claudication? (Circulation (October 27, 1998) 98:17 (I1-I1016))
Authors: D. L. Dawson, H. G. Beebe, M. H. Davidson, D. A. Chinoy, J. A. Herd, W. R. Hiatt, J. D. Heckman, E. B. Bortey, W. P. Forbes
Journal: Circulation (1999)
ASSESSMENT OF RISK FACTORS INVOLVED WITH CONTACT AND NON-CONTACT INJURIES IN US RUGBY-7S
Authors: Victor Lopez, Richard Ma, Meryle Weinstein, Patria Hume, Robert Cantu, Christian Victoria, Samuel Haleem, Jessica Delallo, Allen Answorth
Journal: British Journal of Sports Medicine (2017)

Background Rugby-7s is growing in popularity, however there is a comparative lack of injury data. Objective To report incidence of contact and non-contact causes of US Rugby-7s injuries. Design Prospective descriptive epidemiology study. Setting The study encompassed U19 to elite players in USA Rugby tournaments (2010–2014). Participants A total of 24,418 US players (Men=17,770; Women=6.768; age: 13–49 years) were included over 57 tournaments (72 days) of 4,448 matches (Men=3,238; Women=1,261) in 2,038 teams (Men=1,474; Women=564). Assessment of Risk Factors Contact and non-contact causes of match injuries. Main measurement outcome Injury incidence (per 1000 player-hour (ph)) and mechanism, captured using Rugby Injury Survey &amp; Evaluation ( RISE ) Report. Time-loss injuries=players who did not return to play the day of their injury. Medical attention injuries=players who had injuries evaluated with no absence from play. Severity=days absent before return to training/competition (including post tournament). Results Contact injuries (54%; n=823) occurred more often than non-contact (46%; n=697) (P&lt;0.001). Medical attention injuries occurred more often (contact=30.4/1000 ph; non-contact=29.2/1000 ph; P&lt;0.001), than time-loss injuries (contact=23.8/1000 ph; non-contact=16.7/1000 ph; P&lt;0.001). Non-contact causes encountered no differences (men=48.1/1000 ph; women=46.95/1000 ph; P=0.621). Non-contact causes occurred in 20–25 year olds at 54% (n=354). Days absent were frequent among 63% with follow-up data (contact=34 days; CI: 26.5–41.3; non-contact=32 days; CI: 26.6–39.3). New acute match injuries (94%) were most common (contact 57%; non-contact 43%; P&lt;0.001) with tackles (contact=77%; non-contact=52%), followed by open play (non-contact=32%). Ligament injuries were most common among causes (non-contact =23%; contact=30%). Similar rates among non-contact causes were found with field types (grass=46.1/1000 ph; artificial=52.4/1000 ph; P=0.467). Conclusions Due to the frequency of contact injuries, tackling techniques must be evaluated as an area for injury prevention in Rugby 7s. The cause of non-contact injuries with increased open-play needs attention for injury prevention and management.
Defining the path: lung cancer CT screening in Europe
Authors: Matthew E Callister, Sam M Janes
Journal: Thorax (2017)

Since the publication of the National Lung Screening Trial (NLST) in 2011 demonstrating a 20% reduction in lung cancer-specific mortality by annual low-dose CT (LDCT),1 implementation of screening has continued apace in the USA. Other developed nations, perhaps mindful of the potential cost implications of national screening programmes, have been more reticent, with many awaiting the final outcome data from the largest European randomised trial—the Dutch-Belgian Lung Cancer Screening trial (NELSON)  study which remains in follow-up.2 

Despite the convincing mortality reduction in NLST, questions remain about implementation of LDCT screening for lung cancer. Unresolved issues include how to best identify high-risk individuals for screening, what is the most appropriate screening interval to achieve an optimal balance between mortality reduction and cost-effectiveness and how to minimise possible harms associated with screening—particularly overdiagnosis. This issue of Thorax includes two papers which provide important additions to accumulating evidence in this field.

Paci and colleagues3 report lung cancer incidence and mortality rates from the Italian Lung Cancer Screening Trial (ITALUNG) randomised lung cancer screening trial conducted in Tuscany, Italy, commencing in 2004. From an invited population of over 71 232 subjects aged 55–69 years, 1613 were randomised to four rounds of annual LDCT screening and 1593 to usual care. Like many of the other European screening studies, ITALUNG was not powered to demonstrate mortality reduction in isolation, and pooled analysis with other similarly designed randomised trials is planned.

As expected, lung cancer incidence was higher in the intervention group during the 4-year screening period (55% excess diagnoses vs usual care group). However, this was followed by a compensatory reduction in diagnoses during the 5-year follow-up period, such that there was no significant difference in incidence rates between the groups at the end of the study. After a median follow-up of 9 years, the authors report …
An Essential Role for the Tumor-Suppressor Merlin in Regulating Fatty Acid Synthesis
Authors: Dina S. Stepanova, Galina Semenova, Yin-Ming Kuo, Andrew J. Andrews, Sylwia Ammoun, C. Oliver Hanemann, Jonathan Chernoff
Journal: Cancer Research (2017)

Neurofibromatosis type 2 (NF2) is an autosomal dominant disorder characterized by the development of multiple tumors in the central nervous system, most notably schwannomas, and meningiomas. Mutational inactivation of the NF2 gene encoding the protein Merlin is found in most sporadic and inherited schwannomas, but the molecular mechanisms underlying neoplastic changes in schwannoma cells remain unclear. We report here that Nf2-deficient cells display elevated expression levels of key enzymes involved in lipogenesis and that this upregulation is caused by increased activity of Torc1. Inhibition or knockdown of fatty acid synthase (FASN), the enzyme that catalyzes the formation of palmitic acid from malonyl-CoA, drove NF2-deficient cells into apoptosis. Treatment of NF2-mutant cells with agents that inhibit the production of malonyl-CoA reduced their sensitivity to FASN inhibitors. Collectively, these results suggest that the altered lipid metabolism found in NF2-mutant cells renders them sensitive to elevated levels of malonyl-CoA, as occurs following blockade of FASN, suggesting new targeted strategies in the treatment of NF2-deficient tumors. Cancer Res; 77(18); 5026-38. ©2017 AACR.
Down-regulation of Akt/PKB by siRNA increases chemosensitivity of non-small cell lung cancer cells
Authors: Myoung Woo Lee, Na Young Min, Heung Tae Kim
Journal: Cancer Research (2006)

727  The Akt/protein kinase B (PKB) signaling is very important for cancer cell survival and growth when cells are exposed to various apoptotic stimuli. Akt, which is constitutively activated in non-small cell lung cancer (NSCLC) cells, is an attractive target for enhancing cytotoxicity to chemotherapeutic agents in NSCLC. In the current study, we have investigated whether inhibiting Akt using siRNA can increase the apoptotic death of NSCLC cells and increase the chemosensitivity of NSCLC cells. In NSCLC cell line H460, siRNAs (scramble siRNA or effective siRNA) targeting Akt were transfected by lipofectamine and then basal and knockdown levels of Akt were determined by quantitative reverse transcriptase-polymerase chain reaction and western blotting. To elucidate the effect of Akt knockdown on cisplatin-induced apoptosis in NSCSL cells, various biochemical analyses were performed. We observed that mRNA and protein level of Akt were significantly decreased in siRNA-transfected cells at 12 hr after post-incubation. In addition, cisplatin treatment in these cells induced more apoptotic cell death. When the siRNA transfected cells were exposed to 20 uM cisplatin, apoptotic cell death increased, compared with the control cells (31% versus 12% apoptotic cell death in 24 hr cisplatin-treated cells). These data suggest that down-regulation of Akt by siRNA can increase the chemosensitivity of NSCLC cells, providing the rationale of combined therapy with siRNA targeting Akt signaling and chemotherapy for the treatment of NSCLC.
Temperature-Controlled Radiofrequency Ablation for Pulmonary Vein Isolation in Patients With Atrial Fibrillation
Authors: Jin Iwasawa, Jacob S. Koruth, Jan Petru, Libor Dujka, Stepan Kralovec, Katerina Mzourkova, Srinivas R. Dukkipati, Petr Neuzil, Vivek Y. Reddy
Journal: Journal of the American College of Cardiology (2017)
Interventions to Improve Infant Safe Sleep Practices
Authors: Carrie K. Shapiro-Mendoza
Journal: JAMA (2017)

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Abstract P195: Nuclear Translocation of GRK5 Following Hypertrophic Stimuli Is a Calmodulin-Dependent Process
Authors: Jessica I Gold, Jeffrey S Martini, J Kurt Chuprun, Walter J Koch
Journal: Circulation Research (2011)

Maladaptive ventricular hypertrophy often precedes the pathological endpoint of Heart Failure (HF). G protein Coupled Receptors (GPCRs), such as the β-adrenergic receptor, play a crucial role in the development of cardiac hypertrophy. GPCR Kinase 5 (GRK5) is a primary GRK expressed in cardiomyocytes. Traditionally, it phosphorylates and desensitizes agonist-bound GPCRs. Recent, exciting data from our lab shows that GRK5 translocates into the nucleus and phosphorylates Histone Deacetylase 5 (HDAC5) in response to hypertrophic stimuli. This novel kinase activity of GRK5 causes nuclear export of HDAC5, enhancing transcription of hypertrophic genes regulated by myocyte elongation factor 2 (MEF2). We hypothesize that that nuclear GRK5 activity plays a critical role in cardiomyocytes, facilitating pathological hypertrophy and HF, and that hypertrophic GPCR signaling induces GRK5 nuclear translocation. To test this hypothesis, we utilized neonatal rat ventricular cardiomyocytes (NRVMs) to determine GRK5 localization following the hypertrophic stimulus of phenylephrine (PE) treatment. To determine the mechanism causing nuclear translocation, we analyzed the effects targeted inhibition of key post-GPCR hypertrophic signaling pathways on GRK5 cellular localization. Treatment of NRVMs with PE for 1 hour increases nuclear GRK5 accumulation by 100%. Chronic infusion of PE also lead to a 50% increase in nuclear GRK5 in the hearts of mice overexpressing cardiac-specific GRK5. Calmodulin inhibition (CaM) in NRVMs via calmidizolium chloride decreases nuclear GRK5 accumulation, while inhibition of PKC and PKD shows no significant effect. Using a luciferase assay, we have shown that overexpression of CaM increases MEF2 activity 3-fold and causes increased nuclear accumulation of GRK5. Further, overexpression of a GRK5 mutant that lacks CaM binding activity, results in a lack of PE- and CaM-induced nuclear translocation. We have now found that hypertrophic stimuli increases myocyte GRK5 nuclear translocation via a CaM-dependent process. Defining the role of CaM signaling in pathological GRK5 nuclear localization may offer a new therapeutic target for maladaptive hypertrophy and HF.
Abstract 216: Sex Chromosome Protection Again Myocardial Ischemia/reperfusiong Injury In Mice: One X Is Better Than Two
Authors: Jingyuan Li, Rebecca McClusky, Xuqi Chen, Arthur P. Arnold, Mansoureh Eghbali
Journal: Circulation Research (2013)

Sex differences in susceptibility to ischemia/reperfusion (I/R) injury have been demonstrated both in basic and clinical settings. Female hearts show better functional recovery after I/R injury compared with males. Most of these sex differences in the I/R injury model have been attributed to sex hormones. Here we used a unique mouse model (XY*) to investigate the role of sex chromosomes on cardiac I/R injury. The XY* model produces the equivalent of XX and XO gonadal females, and XY and XXY gonadal males. A comparison between mice with one X chromosome (XO or XY) to those with two X chromosomes (XX or XXY) reveals an effect of X chromosome number, whereas comparing mice with a Y chromosome (XY, XXY) with those without Y (XO, XX) shows the effect of presence/absence of the Y chromosome. Four to six weeks before the experiment, mice were gonadectomized (GDX) to eliminate the effects of gonadal hormones. Isolated mouse hearts were subjected to 30 min global normothermic ischemia followed by 60 min reperfusion. Hemodynamic parameters were continuously recorded with a catheter (1.4F Millar SPR-671) connected to a pressure transducer (Power Lab, ADInstruments). At the end of reperfusion, the hearts were cut into four transverse slices and myocardial necrosis was assessed by measurement of the infarct size using triphenyltetrazolium chloride (TTC) staining. The cardiac function was similar among all 4 groups of XY* mice before ischemia. However, postischemic functional recovery of mice with two copies of the X chromosome was significantly lower than mice with a single copy, irrespective of gonadal sex. Rate pressure product (RPP) recovery was markedly lower in XX gonadal females (34.0±10.3%, n=6) and XXY gonadal males (28.0±12.1%, n=5) compared to XO females (60.3±13.5%, n=4) and XO males (60.5±13.8%, n=5, p&lt;0.05). Infarct size was also markedly larger in mice with two X chromosomes (41.4±8.9% in XX gonadal females (n=6) and 46.3±9.5% in XXY gonadal males (n=5)) than mice with one X chromosome (23.7±3.9% in XO females, n=4 and 26.6±6.9% in XO males, n=5, p&lt;0.05). In conclusion, the number of X chromosomes in gonadectomized mice plays a key role in susceptibility to myocardial ischemia/reperfusion injury regardless of the presence or absence of the Y chromosome.
Testing Novel Anti - Multiple Myeloma (MM) Agents in a Suitable Three-Dimensional (3D) Co-Culture Platform
Authors: Stefan J. Müller, Johannes M. Waldschmidt, Johanna Senger, Dagmar Wider, Andreas R. Thomsen, Gabriele Ihorst, Justus Duyster, Martin J. Hug, Manfred Jung, Ralph Wäsch, Monika Engelhardt
Journal: Blood (2016)
The noncoding RNA HOXD-AS1 is a critical regulator of the metastasis and apoptosis phenotype in human hepatocellular carcinoma
Authors: Shan Lu, Jiansheng Zhou, Yimin Sun, Nan Li, Mingyong Miao, Binghua Jiao, Huan Chen
Journal: Molecular Cancer (2017)

Despite accumulating evidence that long noncoding RNAs (lncRNAs) are associated with cancer development in multiple types of cancer, the biological roles of many lncRNAs in human hepatocellular carcinoma (HCC) metastasis have not been well characterized. A lncRNA+ mRNA human gene expression microarray analysis was used to identify differentially expressed lncRNAs in metastatic HCC tissues compared to non-metastatic tissue. We observed remarkable overexpression of HOXD-AS1 in metastatic cancer tissues. In vitro and in vivo gain- or loss-of-function studies re-affirmed that HOXD-AS1 is able to facilitate cancer metastasis and inhibit apoptosis. Moreover, we identified that HOXD-AS1 upregulated the Rho GTPase activating protein 11A (ARHGAP11A) by competitively binding to microRNA-19a (miR19a), resulting in induced metastasis. Interestingly, the regulator of G-protein signaling 3 (RGS3), a potential inhibitor of the MEK-ERK1/2 signaling axis, was also found to be downregulated by ectopic HOXD-AS1 overexpression, leading to a remarkably reduced apoptotic effect. The present investigation strongly indicates that HOXD-AS1 is an oncogenic lncRNA that promotes HCC metastasis and that its pro-metastatic phenotype can partially be attributed to the HOXD-AS1/miR19a/ARHGAP11A signaling axis.