tbuckley/cabot-search huggingface dataset:
A DOWNWARD HEAD POSTURE LEADS TO HIGHER CERVICAL SPINE LOADING DURING HEAD-FIRST IMPACTS IN SIMULATED RUGBY TACKLES
Authors: Elena Seminati, Ezio Preatoni, Grant Trewartha, Keith Stokes, Sean Williams, Dario Cazzola
Journal: British Journal of Sports Medicine (2017)

Background A rugby tackle is an open and unpredictable event, which can lead to intentional or unintentional head-first impacts rather than the preferred ‘shoulder first’ technique. Objective To identify the effect of head-neck orientation as well as collision speed on the loads experienced at the upper cervical spine and the relevance in terms of injury risk from head-first impacts. Design Repeated ‘tackles’ were simulated using a 40 kg punch bag (simulated ball carrier) making contact against a fixed instrumented head and neck anthropometric test device (ATD). Setting Biomechanics laboratory. Patients (or Participants) A single head-neck ATD was used to complete all the trials. Interventions (or Assessment of Risk Factors) 10 repetitions were recorded in each of two speed ranges (low and high) and 3 ATD sagittal plane orientations (head-up [+20°], neutral [0°], and head-down [-20°]), 60 trials in total. Main Outcome Measurements Forces experienced at the equivalent of the C1 vertebra were measured by a load cell at the head joint of the ATD. ANCOVA (covariate=punch bag speed) and effect sizes were used to assess differences between tackle conditions. Results Low speed (2.34±0.18 m/s) tackles resulted in 37% lower peak impact forces compared with high speed (3.43±0.17 m/s) tackles. Total force on neck acted in multiple directions (75% in compression; magnitude of total force was 2.37±0.18 kN in neutral high speed condition) and it was substantially higher in the head-down orientation compared with the neutral (13%) and head-up orientation (17%). Conclusions Our findings support the idea that: 1) collision speed during a tackle affects the load experienced by the head-neck structures; 2) a neutral or head-up orientation of the head is preferred to a head-down orientation in the event of head-first impacts during simulated rugby tackle, which aligns with current Rugby Union coaching recommendations.
Clinical characteristics and outcome of mucinous breast cancer: A retrospective analysis of 10-year study.
Authors: Lei Lei, Xingfei Yu, Bo Chen, zhan-Hong Chen, Xiaojia Wang
Journal: Journal of Clinical Oncology (2016)

e13095 Background: Mucinous breast carcinoma (MC) is a special type of breast cancer, comprising approximately 4% of all invasive breast cancers. Pathologically, it is divided into two main subtypes, the pure type and the mixed type. In this study, we aimed to report the last 10-year experience of the Zhejiang Cancer Hospital in China regarding MC with its clinical characteristics and outcome. Methods: We used consecutive ten years of data that were collected at Zhejiang Cancer Hospital from January 2001 to January 2011.All patients were divided into three groups: patial mixed mucinous breast carcinoma (pMMC) was defined as less than 50% mucinous component; main mixed mucinous breast carcinoma (mMMC) was defined as mucinous component accounted from 50% to 90%; PMC was defined as mucinouscomponent accounted more than 90%.The clinical pathological characteristics included age at diagnosed, menopausal status, tumor size, clinical stage, lymph node metastasis(LN+), estrogen receptor (ER), prostrogen receptor (PR), human epidermal growth factor receptor-2 (HER2) and P53. Disease free survival(DFS) and overall suvival(OS) were collected in 79 patients.The medium follow-up time is 84 months(24-168 months). Results: We identified 48 cases diagnosed PMC ,58 cases with pMMC and 19 cases with mMMC. The tumor size was larger in mMMC than PMC (p = 0.031). The pMMC group had more III-IV stages patients than the other groups (p = 0.005). The LN+ was more frequent in pMMC either than mMMC and PMC (p = 0.003). PMC had much less P53 expression than other two groups (p = 0.007). Tumor size, P53 and the proportion of mucinous component might impact LN+. LN+ and clinical stage appeared to have worse impact on DFS (HR = 5.234, p = 0.008;HR = 3.402,p = 0.008,respectively).Adjusted for age, HER-2, P53 and LN metastasis, COX proportional hazard regression model shows no impact of pathologic grouping on MC patients survival. Conclusions: LN+, higher clinical stages,P53 mutation were presented more often in MMC patients than in PMC patients. The amount of mucinous component in MC patients should be considered in diagnosis. LN metastasis and clinical stage are potential negative prognostic factors for MC patients.
Characterization of potential predictive biomarkers of response to nivolumab in CheckMate-141 in patients with squamous cell carcinoma of the head and neck (SCCHN).
Authors: Robert L. Ferris, Fernando Concha-Benavente, George R. Blumenschein, Kevin J. Harrington, Jerome Fayette, A. Dimitrios Colevas, Lisa F. Licitra, Stefan Kasper, Caroline Even, Maura L. Gillison, Francis Worden, Nabil F. Saba, Robert I. Haddad, Makoto Tahara, Yasuhisa Hasegawa, Chia-Jui Yen, Mark John Lynch, Manish Monga, William J. Geese, Everett E. Vokes
Journal: Journal of Clinical Oncology (2017)

5 Background: Nivolumab, an anti-programmed death-1 (PD-1) monoclonal antibody, demonstrated longer median overall survival (7.5 vs. 5.1 months) and improved response (13.3% vs. 5.8%) versus investigator choice chemotherapy (ICC) in patients with recurrent SCCHN after platinum failure in CheckMate 141 (NCT02105636), a randomized, open-label Phase 3 trial. We screened peripheral blood lymphocytes (PBL) to identify biomarkers which may predict response to nivolumab. Methods: Paired baseline (day 1) and on treatment (day 43) PBL samples (n=36; 24 nivolumab; 12 ICC) were analyzed using multicolor flow cytometry and a non-competing anti-PD-1 antibody. Results were correlated with clinical outcome: responders (complete/partial response) and non-responders (stable or progressive disease). Results: Levels of CD8+ T cells at baseline and on treatment were higher in nivolumab responders compared to non-responders (23% vs. 13%; p&lt;0.05). Interestingly, PD-1+ CD8+ and PD-1+ CTLA-4+ CD8+ effector T cells (likely exhausted T cells) decreased about 2-fold following nivolumab in both responders and non-responders (p&lt;0.05), whereas, the decrease in CTLA-4+ CD8+ effector T cells following nivolumab was significant in responders only (8% vs. 5%; p&lt;0.05). Levels of PD-1+ TIM-3+ CD8+ effector cells decreased following nivolumab in non-responders only (11% vs. 7%; p&lt;0.05), a similar non-significant reduction was observed in responders. Levels of PD-1+Tregs were lower in responders than non-responders at baseline (19% vs. 33%; p&lt;0.01), and following nivolumab (12% vs. 20%; p&lt;0.001). As in T effector cell populations, PD-1+ Tregs decreased about 1.6-fold after nivolumab in both responders and non-responders (p&lt;0.01). Interestingly, baseline Ki67+ Treg levels were lower in non-responders (28% vs. 17%; p&lt;0.05). Conclusions: Response to nivolumab may be associated with higher levels of CD8+ T cells and CTLA-4+ CD8+ effector T cells, and lower PD-1+ CD8+ effector T cells and PD-1+ Tregs at baseline. Targeting both PD-1 and CTLA-4 axes is warranted in SCCHN to overcome suppressive signals in CD8+ effector T cells and in Treg cells expressing both checkpoint receptors. Clinical trial information: NCT02105636.
Genetic evidence for interaction of the 5Q31 cytokine locus and the CARD15 gene in Crohn's disease
Authors: MM Mirza, SA Fisher, K King, AP Cuthbert, J Hampe, J Sanderson, J Mansfield, P Donaldson, A MacPherson, A Forbes, S Schreiber, CM Lewis, CG Mathew
Journal: Gut (2003)
Progression-specific markers in breast cancer obtained by microarray analysis are located to the malignant epithelial tumor cells
Authors: Joseph Riss, Chand Khanna, Seongjoon Koo, Gadisetti V R Chandramouli, Howard H. Yang, Ying Hu, David E. Kleiner, Andreas Rosenwald, Carl F. Schaefer, Shmuel A. Ben-Sasson, John Powell, David W. Kane, Robert A. Star, Olga Aprelikova, Kristin Bauer, James R. Vasselli, Jodi K. Maranchie, Kurt W. Kohn, Barry R. Zeeberg, Ken H. Buetow, W. Marston Linehan, John N. Weinstein, Maxwell P. Lee, Richard D. Klausner, J. Carl Barrett
Journal: Cancer Research (2006)

834   Hematogenic metastasis is the major cause of mortality from malignant tumors. The potential of human breast tumor cells to metastasize is enabled after DCIS (ductal carcinoma in situ) to IDC (invasive ductal carcinoma) transition, when the cells become invasive and break through the basement membrane. It is imperative to gain more information about the molecular events accompanying this crucial step to improve the classification in risk groups for DCIS patients according to risk of relapse or progression and to advance in individualizing the therapy for DCIS and IDC patients. Our group combined Affymetrix microarray analysis with laser capture microdissection (LCM) to analyze matched DCIS and IDC tissue from nine patients. Subsequent to extensive statistical analysis (rank product, paired t-test, paired Mann-Whitney test), 446 up-regulated and 102 down-regulated Affymetrix probe sets were identified to be expressed differentially in either stage of the nine tumours (p-value: 0.01), characterizing the transition from DCIS to IDC. This gene list contains genes, already associated with breast cancer invasion (PLAU/uPa and MMP11) confirming the accuracy of the accomplished methods. Differential gene expression of 18 candidate genes (15 up-regulated, 3 down-regulated) was confirmed, analyzing triplicate real-time PCR experiments. Four PCR-validated candidates were selected for in situ hybridization experiments and the proteins of five PCR-validated candidates were detected using immunohistochemistry. These experiments confirm the localization of the transcripts or proteins for all tested candidates to the cytoplasm of the epithelial tumor cells. Regarding the immunohistochemical evaluation, differential gene expression corresponding to the microarray data could be visualized. In conclusion, we identified progression-specific candidate genes using an accurate stringent approach combining LCM and high-density oligonucleotide microarray analysis. New candidates, not yet correlated with breast cancer progression, could be validated using real-time PCR. Expression of candidate transcripts and proteins was localized to the epithelial tumor cells, respectively. Among these candidates are transmembrane receptors, transcription factors and tumour antigens, thus gene products with potential clinical importance.
Abstract 33: Endoplasmic Reticulum Stress and Vascular Dysfunction in Hypertension
Authors: Modar Kassan, Maria Galan, Megan Partyka, Daniel Henrion, Mohamed Trebak, Khalid Matrougui
Journal: Circulation Research (2012)

Objective: Cardiac damage and vascular dysfunction are major causes of morbidity and mortality in hypertension. In this study, we explored the beneficial therapeutic effect of endoplasmic reticulum (ER) stress inhibition on cardiac damage and vascular dysfunction in hypertension. Methods &amp; results: Mice were infused with angiotensin II (Ang-II, 400 ng/kg/min) with or without ER stress inhibitors (Tudca and PBA) for two weeks. Mice infused with Ang-II displayed an increase in blood pressure, cardiac hypertrophy and fibrosis associated with enhanced collagen-I content, TGFβ1 activity, and ER stress markers, which were blunted after ER stress inhibition. Hypertension induced ER stress in aorta and mesenteric resistance arteries (MRA), enhanced TGFβ1 activity in aorta but not in MRA, and reduced eNOS phosphorylation and endothelium-dependent relaxation (EDR) in aorta and MRA. The inhibition of ER stress significantly reduced TGFβ1 activity, enhanced eNOS phosphorylation and improved EDR. The inhibition of TGFβ1 pathway improved EDR in aorta but not in MRA, while the reduction in ROS levels ameliorated EDR in MRA only. Infusion of tunicamycin in control mice induced ER stress in aorta and MRA, and reduced EDR by a TGFβ1-dependent mechanism in aorta and ROS-dependent mechanism in MRA. Conclusion: ER stress inhibition reduces cardiac damage and improves vascular function in hypertension. Therefore ER stress could be a potential target for cardiovascular diseases.
Chronic inflammation‐elicited liver progenitor cell conversion to liver cancer stem cell with clinical significance
Authors: Xiao‐Feng Li, Cheng Chen, Dai‐Min Xiang, Le Qu, Wen Sun, Xin‐Yuan Lu, Teng‐Fei Zhou, Shu‐Zhen Chen, Bei‐Fang Ning, Zhuo Cheng, Ming‐Yang Xia, Wei‐Feng Shen, Wen Yang, Wen Wen, Terence Kin Wah Lee, Wen‐Ming Cong, Hong‐Yang Wang, Jin Ding
Journal: Hepatology (2017)

The substantial heterogeneity and hierarchical organization in liver cancer support the theory of liver cancer stem cells (LCSCs). However, the relationship between chronic hepatic inflammation and LCSC generation remains obscure. Here, we observed a close correlation between aggravated inflammation and liver progenitor cell (LPC) propagation in the cirrhotic liver of rats exposed to diethylnitrosamine. LPCs isolated from the rat cirrhotic liver initiated subcutaneous liver cancers in nonobese diabetic/severe combined immunodeficient mice, suggesting the malignant transformation of LPCs toward LCSCs. Interestingly, depletion of Kupffer cells in vivo attenuated the LCSC properties of transformed LPCs and suppressed cytokeratin 19/Oval cell 6–positive tumor occurrence. Conversely, LPCs cocultured with macrophages exhibited enhanced LCSC properties. We further demonstrated that macrophage‐secreted tumor necrosis factor‐α triggered chromosomal instability in LPCs through the deregulation of ubiquitin D and checkpoint kinase 2 and enhanced the self‐renewal of LPCs through the tumor necrosis factor receptor 1/Src/signal transducer and activator of transcription 3 pathway, which synergistically contributed to the conversion of LPCs to LCSCs. Clinical investigation revealed that cytokeratin 19/Oval cell 6–positive liver cancer patients displayed a worse prognosis and exhibited superior response to sorafenib treatment. Conclusion: Our results not only clarify the cellular and molecular mechanisms underlying the inflammation‐mediated LCSC generation but also provide a molecular classification for the individualized treatment of liver cancer. (H epatology 2017;66:1934–1951)
Update of a phase III trial of adjuvant vinorelbine plus cisplatin (NP) versus NP plus endostar (NPE) in patients with completely resected stage IB-IIIA non-small cell lung cancer (NSCLC).
Authors: He Jie, Baohui Han, Yongyu Liu, Shi Xiu Wu, Yukang Kuang, Yi Shen, Chun Chen, Qun Wang, Qiang Li, Ma Haitao, Shaofa Xu, Shidong Xu, Ping Wang, Weimin Mao, Zuoliang Pang, Shengcai Hou, Yue Yang
Journal: Journal of Clinical Oncology (2012)

e18013 Background: Adjuvant chemotherapy demonstrated a 5-15% benefit in 5-year survival in early-stage NSCLC. Endostar,a recombinant human Endostatin, could inhibit tumor angiogenesis. In a phase III trial, the addition of Endostar to NP regimen resulted in higher response rate, clinical benefit rate and longer median time to progression compared with NP alone in advanced NSCLC patients. Methods: Completely resected patients (stage IB-IIIA) were randomized to receive adjuvant NP plus Endostar (arm A, Vinorelbine 25mg/m 2 on d1 and d8 plus Cisplatin 80 mg/m 2 intravenously plus Endostar 7.5mg/m 2 per day, iv, for 14 consecutive days. 21 days as one cycle(arm A) or NP regimen alone (arm B) for four cycles. The randomization was stratified by gender, stage and histology. The primary endpoint was OS and the secondary endpoints were RFS and safety. Results: 1037 patients (arm A: 520; arm B: 517) from 43 centers in China were enrolled between 9/2007 and 12/2010. Two arms were well-balanced with regard to age, gender, histology, stage, and resection type. 184 patients in arm A and 202 patients in arm B had relapsed disease or died. The median RFS was 34.1 months in arm A and 30.3 months in arm B (p=0.1573). 79.0% of patients in arm A and 76.0% of patients in arm B received 4 cycles of chemotherapy. Median survival time was not available at this time. Grade 3/4 toxicities in arm A included leukopenia (57.4%), neutropenia (75.0%), anemia (12.9%), nausea (11.3%). Grade 3/4 toxicities in arm B included leukopenia (35.0%) neutropenia (60.5%), anemia (8.5%) and nausea (8.5%). It is worth noting that the incidence of cardiac toxicities in arm A (26.3%) was slightly higher than that in arm B (21.4%). Conclusions: The preliminary result showed that patients in arm A experienced a longer median relapse-free survival time than in arm B (34.1 months vs. 30.3 months), although the difference was not statistically significant by far. The toxicity profiles for both arms were tolerable in this study. The patient follow-up is still ongoing.
DNA methylation changes in leukemia patients treated with 5-aza-2′-deoxycytidine (decitabine)
Authors: Allen S. Yang, Ketan D. Doshi, Rajan K. Mannari, Guillermo Garcia-Manero, Hagop M. Kantarjian, Jean-Pierre Issa
Journal: Cancer Research (2004)

1599   5-aza-2′-deoxycytidine (decitabine) is a cytosine analog that has the unique ability to inhibit DNA methylation. Decitabine has been used in numerous clinical trials and has shown consistent activity in myeloid leukemias. We wished to investigate whether decitabine has activity in leukemia via its ability to inhibit DNA methylation. We therefore studied samples from leukemia patients who were treated in two clinical trials using decitabine. The first trial used a “high” dose of decitabine at 50-90mg/m 2  twice daily for 5 days. A second clinical trial used a “low” dose strategy of 5-20mg/m 2  once daily for 10 days in order to take advantage of the demethylating properties of decitabine. We analyzed DNA methylation of p15, H19, HoxA5 and Alu repetitive elements in peripheral blood samples of patients before, during and after treatment to examine methylation changes induced by decitabine. The p15 gene is a tumor suppressor gene that is normally unmethylated, but becomes aberrantly methylated in cancer. H19 is an imprinted locus that is only methylated on the paternal allele, and HoxA5 is a gene that is normally heavily methylated. Alu elements were studied as a surrogate marker for global genome methylation. We found that decitabine treatment could decrease DNA methylation in all the genes studied, but Alu methylation gave the most consistent results probably because Alu elements are more abundant and heavily methylated in the genome. Overall most patients (88%) showed a decrease in Alu methylation with decitabine treatment. However, the mean decrease in Alu methylation was only 7.7% with a range of –10.3 to 31.5% (SD=8.2%). We found a dose dependent decrease in methylation after decitabine treatment with a plateau at high doses. We examined patients treated at six doses (5, 10, 15, 20, 100 and 180mg/m 2 /day). Demethylation averaged 2.8%, 1.1%, 7.3%, 11.6%, 10.9%, and 8.5% at these six doses, respectively. Thus there did not appear to be a significant increase in demethylation beyond 20mg/m 2 /day. However, the number of patients studied at some doses was limited. There was a statistically significant correlation between inhibition of methylation and response to decitabine in the “low” dose strategy. Low dose study patients whose leukemia did not respond showed a mean decrease of only 3.3%, while those patients whose leukemia responded to decitabine showed a mean decrease of 11.5% (p=0.02). Remarkably, this dose-response relationship was not seen at high doses of decitabine, which in vitro induces primarily cytotoxic cell death. These data are consistent with previous in vitro studies that show that low doses of decitabine are optimal for inducing differentiation, and suggest that hypomethylation rather than cytotoxicity is critical for response to this agent.
C-X-C Motif Chemokine 10 Impairs Autophagy and Autolysosome Formation in Non-alcoholic Steatohepatitis
Authors: Xiang Zhang, William Kk Wu, Weiqi Xu, Kwan Man, Xiaojuan Wang, Juqiang Han, Wing Yan Leung, Ruonan Wu, Ken Liu, Jun Yu
Journal: Theranostics (2017)

C-X-C motif chemokine 10 (CXCL10) is a crucial pro-inflammatory factor in chronic hepatitis. Autophagy dysregulation is known to contribute to hepatic inflammatory injury. Hence, we investigated the regulatory effect of CXCL10 on the autophagosome-lysosome system during non-alcoholic fatty liver disease (NAFLD) development. The effect of CXCL10 ablation by neutralizing monoclonal antibody (mAb) or genetic knockout on autophagic flux was evaluated in cultured hepatocytes and animal models of NAFLD. Results demonstrated that CXCL10 ablation protected against hepatocyte injury in vitro and steatohepatitis development in mice. Autophagic flux impairment was rectified by CXCL10 inhibition using anti-CXCL10 mAb in AML-12 and HepG2 liver cell lines and primary hepatocytes as evidenced by the attenuated accumulation of p62/SQSTM1 and LC3-II proteins and increased autophagic protein degradation. Impaired autophagic flux was significantly restored by CXCL10 knockout or anti-CXCL10 mAb in mice. Bafilomycin A1, an inhibitor of autolysosome formation, abolished the rectifying effect of anti-CXCL10 mAb or CXCL10 knockdown in AML-12 and primary hepatocytes, indicating CXCL10 impaired late-stage autophagy in NAFLD. Anti-CXCL10 mAb treatment also increased the fusion of LC3-positive autophagosomes with lysosomes in HepG2 cells challenged with palmitic acid, suggesting that CXCL10 ablation restored autolysosome formation. Consistently, the number of autolysosomes was significantly increased by CXCL10 knockout in mice as shown by electron microscopy. In conclusion, upregulated CXCL10 in steatohepatitis impairs autophagic flux by reducing autolysosome formation, thereby inhibiting autophagic protein degradation and the accumulation of ubiquitinated proteins, leading to the development of steatohepatitis.
Recovery of natural killer cell counts after one course of CHOP chemotherapy is diminished in patients older than 60 compared to patients younger than 60.
Authors: Amitabha Sarma, M. Alma Rodriguez, Fernando Cabanillas, Nam H. Dang, Peter McLaughlin, Fredrick B. Hagemeister, Barbara Pro, Jorge Romaguera, Anas Younes, Elizabeth A. Grimm
Journal: Cancer Research (2004)

2199   Melatonin (MEL) is a hormone made in the pineal gland that regulates sleep and influences a number of other hormonal body functions. Studies by Lissoni, et al. (Supportive Care in Cancer, 5: 126, 1997) also suggest a myeloprotective effect when administered with chemotherapy. T-lymphocytes have melatonin receptors and thus may be stimulated by melatonin. We conducted a randomized trial in adult patients with favorable prognosis aggressive B-cell lymphomas. Patients were treated with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) every three weeks and were randomized to take or not to take 20 mg of oral melatonin daily. Complete blood counts with differential and lymphocyte markers were assayed: in 79 patients prior to treatment; in 53 patients after the first cycle of chemotherapy; and in 41 patients both prior to treatment and after the first cycle. Analysis of lymphocyte counts was performed based on patient age and assigned treatment group. Shown below are the median CD4, CD8, and Natural Killer (NK) absolute cell counts before and after treatment along with the percentage change after one cycle of treatment.* P-values are for the Wilcoxon Rank Sum Test. In conclusion, there is no effect of melatonin on recovery of CD4, CD8, or NK cells. However, these data suggest that despite a similar baseline NK cell count, patients older than 60 years old have impaired recovery and reconstitution of NK cell counts after a single cycle of CHOP chemotherapy.