tbuckley/cabot-search huggingface dataset:
Beyond liver fibrosis: Hepatic stellate cell senescence links obesity to liver cancer by way of the microbiome
Authors: Nicholas A. Shackel, Mathew A. Vadas, Jennifer R. Gamble, Geoffrey W. McCaughan
Journal: Hepatology (2013)

Abstract Obesity has become more prevalent in most developed countries over the past few decades, and is increasingly recognized as a major risk factor for several common types of cancer. As the worldwide obesity epidemic has shown no signs of abating, better understanding of the mechanisms underlying obesity-associated cancer is urgently needed. Although several events were proposed to be involved in obesity-associated cancer, the exact molecular mechanisms that integrate these events have remained largely unclear. Here we show that senescence-associated secretory phenotype (SASP) has crucial roles in promoting obesity-associated hepatocellular carcinoma (HCC) development in mice. Dietary or genetic obesity induces alterations of gut microbiota, thereby increasing the levels of deoxycholic acid (DCA), a gut bacterial metabolite known to cause DNA damage. The enterohepatic circulation of DCA provokes SASP phenotype in hepatic stellate cells (HSCs), which in turn secretes various inflammatory and tumour-promoting factors in the liver, thus facilitating HCC development in mice after exposure to chemical carcinogen. Notably, blocking DCA production or reducing gut bacteria efficiently prevents HCC development in obese mice. Similar results were also observed in mice lacking an SASP inducer or depleted of senescent HSCs, indicating that the DCA-SASP axis in HSCs has key roles in obesity-associated HCC development. Moreover, signs of SASP were also observed in the HSCs in the area of HCC arising in patients with non-alcoholic steatohepatitis, indicating that a similar pathway may contribute to at least certain aspects of obesity-associated HCC development in humans as well. These findings provide valuable new insights into the development of obesity-associated cancer and open up new possibilities for its control.
Optimal Selection of Individuals for <i>BRCA</i> Mutation Testing
Authors: D. Gareth R. Evans, Fiona Lalloo, Diana Eccles
Journal: Journal of Clinical Oncology (2006)

status, the disease-free interval, and the focality and extent of recurrent disease.3][4][5] In addition, the utility of combined positron emission tomography/computed tomography for detecting recurrent ovarian cancer when conventional imaging studies are negative or equivocal is now readily apparent. 6 We certainly acknowledge that many clinicians treating women with ovarian cancer do not subscribe to this approach, and we appreciate Dr Markman's willingness to offer an alternative treatment paradigm.
Left Ventricular Remodeling in Transgenic Mice With Cardiac Restricted Overexpression of Tumor Necrosis Factor
Authors: Natarajan Sivasubramanian, Mytsi L. Coker, Karla M. Kurrelmeyer, William R. MacLellan, Francesco J. DeMayo, Francis G. Spinale, Douglas L. Mann
Journal: Circulation (2001)

Background The mechanisms responsible for tumor necrosis factor (TNF)–induced LV structural remodeling in the adult heart are not known. Methods and Results We generated a line of transgenic mice (MHCsTNF) with cardiac restricted overexpression of TNF that develop progressive LV dilation/remodeling from 4 to 12 weeks of age. During the early phases of LV structural remodeling, there was a significant increase in total matrix metalloproteinase (MMP) activity that corresponded to a decrease in total myocardial fibrillar collagen content. As the MHCsTNF mice aged, there was a significant decrease in total MMP zymographic activity that was accompanied by an increase in total fibrillar collagen content. The changes in total MMP activity and myocardial fibrillar collagen content were related to a time- dependent increase in myocardial tissue inhibitor of metalloproteinases (TIMP)-1 levels, resulting in a significant time-dependent decrease in the MMP activity/TIMP level ratio in the MHCsTNF mice. To determine a possible mechanism for the increase in myocardial fibrosis, we also measured levels of TGF-β 1 and TGF-β 2 protein levels, which were shown to be significantly elevated in the hearts of the MHCsTNF mice. Conclusions Our results suggest that progressive time-dependent changes in the balance between MMP activity and TIMP activity are responsible, at least in part, for the spectrum of TNF-induced changes in the myofibrillar collagen content that occur during LV structural remodeling in the MHCsTNF mice.
Immunochemical studies on blood groups LXVI. Competitive binding assays of A1 and A2 blood group substances with insolubilized anti-A serum and insolubilized A agglutinin from Dolichos biflorus.
Authors: E C Kisailus, E A Kabat
Journal: The Journal of Experimental Medicine (1978)

Competitive binding assays using 3H-labeled blood group A substance and insolubilized Dolichos biflorus lectin or human anti-A were carried out, measuring competition by blood group A1 and A2 glycoproteins, and by unabsorbed anti-A sera, and with these sera absorbed with the A1 and A2 glycoproteins. With Dolichos lectin specific for (formula: see text) A1 substances had about 11 times as many determinants as did A2 substances, but the slopes of the lines in the competitive binding assays were the same. With insolubilized anti-A, A2 substances gave lines of lower slopes. Although individual A1 populations varied in the amounts giving 50% inhibition in the assays, as did A2 substances, the slopes of the lines for the A1 substances were the same and always higher than the slopes of the lines for the A2 substances. Competitive binding assays with unabsorbed anti-A sera and with these sera absorbed with insoluble polyleucyl A1 and A2 substances showed that partial absorption of polyleucyl A1 substances left antibodies of lower slope in the supernate, whereas absorption with polyleucyl A2 substance left antibodies (anti-A1) having the same or an even higher slope than the unabsorbed sera. The findings indicate that human A1 and A2 glycoproteins differ in their determinants, and that A2 specificity is determined by the type 2 chain in which the A trisaccharide (formula: see text) is linked beta 1 leads to 4 to DGlcNAc, whereas the A1 specificity is determined by the type 1 chain in which this trisaccharide is linked beta 1 leads to 3 to DGlcNAc; most of the determinants in the glycoproteins have a second LFuc linked alpha 1 leads to 3 and alpha 1 leads to 4 to the DGlcNAc of the type 2 and type 1 chains, respectively.
Physical activity in patients with cystic fibrosis: a new variable in the health-status equation unravelled?
Authors: M. Decramer
Journal: European Respiratory Journal (2006)

During the past few years, it has become clear that in chronic respiratory disease, health status is severely impaired and that this should be a prime target for treatment, both in patients with chronic obstructive pulmonary disease (COPD) and cystic fibrosis (CF) 1, 2. Lung function impairment is relatively poorly related to impaired health status in COPD patients 3. The same concepts appear to apply in CF patients 2. Indeed, evidence is available demonstrating that aerobic capacity in these patients is related to survival 4, quality of life 2 and professional achievements 5.

Exercise training programmes have been developed for chronic respiratory illness, and their popularity has increased tremendously since the late 1990s. In COPD, exercise training clearly enhances functional exercise capacity and health status and reduces the utilisation of healthcare resources 6, 7. Indirect indications suggest it may also improve survival in these patients, but, to date, no direct evidence to this effect has been provided 6. A clear demonstration of this effect would require a large study, which may no longer be ethically acceptable as the benefits of exercise training (in terms of functional exercise capacity and health status) have now been demonstrated beyond doubt. Similar effects were demonstrated in patients with CF, although on average the studies were understandably smaller 8. …
Paclitaxel Plus Carboplatin Versus Gemcitabine Plus Paclitaxel in Advanced Non–Small-Cell Lung Cancer: A Phase III Randomized Trial
Authors: Paris Kosmidis, Nick Mylonakis, Costas Nicolaides, Charalabos Kalophonos, Epaminontas Samantas, John Boukovinas, George Fountzilas, Dimosthenis Skarlos, Theophanis Economopoulos, Dimitrios Tsavdaridis, Pavlos Papakostas, Charalabos Bacoyiannis, Meletios Dimopoulos
Journal: Journal of Clinical Oncology (2002)

PURPOSE: We conducted this randomized study comparing the activity and toxicity of paclitaxel and gemcitabine (PG) and paclitaxel and carboplatin (PC) combinations for the treatment of advanced non–small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Chemotherapy-naive patients were randomized to paclitaxel 200 mg/m 2 on day 1 plus either carboplatin at an area under the concentration-time curve of 6 on day 1 (group A) or gemcitabine 1,000 mg/m 2 on days 1 and 8 (group B) every 3 weeks. A retrospective cost analysis was conducted using Student’s t test to compare independent samples between groups. RESULTS: A total of 509 patients (group A, 252 patients; group B, 257 patients) were enrolled; all characteristics were well balanced. The median survival time was 10.4 months (95% confidence interval [CI], 8.8 to 12 months) for group A and 9.8 months (95% CI, 8.0 to 11.7 months) for group B (P = .32). Respective 1-year survival rates were 41.7% and 41.4%. The response rate for group A was 28.0% (2% complete response [CR], 26% partial response [PR] [95% CI, 22% to 34%]), and the response rate for group B was 35.0% (5% CR, 30% PR) [95% CI, 29% to 41%]) (P = .12). Toxicity was mild. Grades 3/4 neutropenia, thrombocytopenia, and anemia for groups A and B were seen in 15% and 15%, 2% and 1%, and 5% and 2%, respectively. The mean total cost (outpatient clinic visits plus chemotherapy drug fee) for group A (€ 7,612.64) versus group B (€ 7,484.77) was not statistically significant (P &lt; .66). CONCLUSION: The PG combination is as equally active and well tolerated as the PC combination in patients with advanced NSCLC.
Pneumococcal polysaccharide vaccination in rheumatoid arthritis patients receiving tocilizumab therapy
Authors: Shunsuke Mori, Yukitaka Ueki, Yukihiro Akeda, Naoyuki Hirakata, Motohiro Oribe, Yoshiki Shiohira, Toshihiko Hidaka, Kazunori Oishi
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Objectives</h3> We assessed the impact of tocilizumab (TCZ), a humanised monoclonal anti-interleukin-6 receptor antibody, on antibody response following administration of the 23-valent pneumococcal polysaccharide vaccine (PPV23). <h3>Methods</h3> A total of 190 patients with rheumatoid arthritis (RA) received PPV23. Patients were classified into TCZ (n=50), TCZ + methotrexate (MTX) (n=54), MTX (n=62) and RA control (n=24) groups. We measured serotype-specific IgG concentrations of pneumococcal serotypes 6B and 23F using ELISA and functional antibody activity using a multiplexed opsonophagocytic killing assay, reported as the opsonisation indices (OIs), before and 4–6 weeks after vaccination. Positive antibody response was defined as a 2-fold or more increase in the IgG concentration or as a ≥10-fold or more increase in the OI. <h3>Results</h3> IgG concentrations and OIs were significantly increased in all treatment groups in response to vaccination. The TCZ group antibody response rates were comparable with those of the RA control group for each serotype. MTX had a negative impact on vaccine efficacy. Multivariate logistic analysis confirmed that TCZ is not associated with an inadequate antibody response to either serotype. No severe adverse effect was observed in any treatment group. <h3>Conclusions</h3> TCZ does not impair PPV23 immunogenicity in RA patients, whereas antibody responses may be reduced when TCZ is used as a combination therapy with MTX.
Gene structure of the Helicobacter pylori cytotoxin and evidence of its key role in gastric disease.
Authors: J L Telford, P Ghiara, M Dell'Orco, M Comanducci, D Burroni, M Bugnoli, M F Tecce, S Censini, A Covacci, Z Xiang
Journal: The Journal of Experimental Medicine (1994)

The gram negative, microaerophilic bacterium Helicobacter pylori colonizes the human gastric mucosa and establishes a chronic infection that is tightly associated with atrophic gastritis, peptic ulcer, and gastric carcinoma. Cloning of the H. pylori cytotoxin gene shows that the protein is synthesized as a 140-kD precursor that is processed to a 94-kD fully active toxin. Oral administration to mice of the purified 94-kD protein caused ulceration and gastric lesions that bear some similarities to the pathology observed in humans. The cloning of the cytotoxin gene and the development of a mouse model of human gastric disease will provide the basis for the understanding of H. pylori pathogenesis and the development of therapeutics and vaccines.
Nonviral Oncogenic Antigens and the Inflammatory Signals Driving Early Cancer Development as Targets for Cancer Immunoprevention
Authors: Nina J. Chu, Todd D. Armstrong, Elizabeth M. Jaffee
Journal: Clinical Cancer Research (2015)

Cancer immunoprevention is an emerging field that holds much promise. Within the past 20 years, prophylactic vaccines have been implemented on the population level for the immunoprevention of carcinomas induced by viruses, specifically hepatitis B virus (HBV) and human papillomavirus (HPV) infection. Armed with the success of prophylactic vaccines that prevent viral-induced tumors, the field must overcome its next hurdle: to develop robust prophylactic vaccines that prevent the remaining >80% of human cancers not induced by viral infection. In this review, we discuss some of the most promising non-virus-associated prophylactic vaccines that target endogenous neoantigens, including the earliest oncogene products, altered mucin 1 (MUC1) and α-enolase (ENO1), all of which produce new targets in the earliest stages of nonviral-induced tumorigenesis. We also highlight a novel attenuated Listeria monocytogenes-based vaccine expressing mutant oncogene Kras(G12D) (LM-Kras) effective in a pancreatic cancer model. A novel chimeric human/rat HER-2 plasmid vaccine (HuRT-DNA vaccine) effective in a breast cancer model is also discussed. In addition to prophylactic vaccine developments, this review highlights the potential use of classic drugs, such as aspirin and metformin, as chemopreventive agents that can potentially be used as adjuvants to enhance the anticancer immunogenicity and efficacy of noninfectious prophylactic vaccines by modulating the inflammatory pathways within the early tumor microenvironment (TME) that propels tumorigenesis. Finally, timing of prophylactic vaccine administration is critical to its immunopreventive efficacy, providing a necessary role of current and emerging biomarkers for cancer screening and early cancer detection.
Onartuzumab (MetMAb): Using Nonclinical Pharmacokinetic and Concentration–Effect Data to Support Clinical Development
Authors: Hong Xiang, Brendan C. Bender, Arthur E. Reyes, Mark Merchant, Nelson L. ‘Shasha’ Jumbe, Mally Romero, Teresa Davancaze, Ihsan Nijem, Elaine Mai, Judy Young, Amy Peterson, Lisa A. Damico-Beyer
Journal: Clinical Cancer Research (2013)

We characterized the pharmacokinetics of onartuzumab (MetMAb) in animals and determined a concentration-effect relationship in tumor-bearing mice to enable estimation of clinical pharmacokinetics and target doses.A tumor growth inhibition model was used to estimate tumoristatic concentrations (TSC) in mice. Human pharmacokinetic parameters were projected from pharmacokinetics in cynomolgus monkeys by the species-invariant time method. Monte Carlo simulations predicted the percentage of patients achieving steady-state trough serum concentrations (Ctrough ss) ≥TSC for every 3-week (Q3W) dosing.Onartuzumab clearance (CL) in the linear dose range was 21.1 and 12.2 mL/d/kg in mice and cynomolgus monkeys with elimination half-life at 6.10 and 3.37 days, respectively. The estimated TSC in KP4 pancreatic xenograft tumor-bearing mice was 15 μg/mL. Projected CL for humans in the linear dose range was 5.74 to 9.36 mL/d/kg with scaling exponents of CL at 0.75 to 0.9. Monte Carlo simulations projected a Q3W dose of 10 to 30 mg/kg to achieve Ctrough ss of 15 μg/mL in 95% or more of patients.Onartuzumab pharmacokinetics differed from typical bivalent glycosylated monoclonal antibodies with approximately 2-times faster CL in the linear dose range. Despite this higher CL, xenograft efficacy data supported dose flexibility with Q1W to Q3W dose regimens in the clinical setting with a TSC of 15 μg/mL as the Ctrough ss target. The projected human efficacious dose of 10 to 30 mg/kg Q3W should achieve the target TSC of 15 μg/mL. These data show effective pharmacokinetic/pharmacodynamic modeling to project doses to be tested in the clinic.
A COMPARATIVE STUDY OF THE AMNESTIC SYNDROME IN VARIOUS ORGANIC CONDITIONS
Authors: V. A. KRAL, H. B. DUROST
Journal: American Journal of Psychiatry (1953)

1. The amnestic syndromes as occurring in senile psychosis, alcoholic Korsakow, after electroshock treatment, and after bilateral prefrontal lobotomy are compared both clinically and by means of psychological tests. 2. Impairment of recent memory and immediate recall has been found as the type of memory impairment common to the 4 amnestic syndromes investigated. 3. The theoretical implications of these findings are discussed. 4. Impairment of partial memories as tested with Meyrat's method has been found only in senile psychosis.
Phase I and Pharmacokinetic Study of Irofulven Administered Weekly or Biweekly in Advanced Solid Tumor Patients
Authors: Jérôme Alexandre, Eric Raymond, Mahmoud Ould Kaci, Etienne C. Brain, François Lokiec, Carmen Kahatt, Sandrine Faivre, Alejandro Yovine, François Goldwasser, Sheri L. Smith, John R. MacDonald, Jean-Louis Misset, Esteban Cvitkovic
Journal: Clinical Cancer Research (2004)

We performed a Phase I and pharmacokinetic study to determine the maximum tolerated dose of irofulven (6-hydroxymethylacylfulvene; MGI-114, MGI PHARMA, Inc.), administered in intermittent weekly schedules in patients with advanced solid tumors.Three schedules were tested: A, days 1, 8, and 15 every 4 weeks; B, days 1 and 8 every 3 weeks; C, days 1 and 15 every 4 weeks. Drugs were administered as 5- and 30-min (schedules B and C) infusions. Dose levels of 10, 12, and 14 mg/m(2)/week were explored.Ninety-nine patients received 256 cycles. Fifteen of 74 patients evaluable for maximum tolerated dose experienced 16 dose-limiting toxicities (5 of 17 patients on schedule A, 2 of 25 on schedule B, and 8 of 32 on schedule C), principally treatment delay for thrombocytopenia. Schedule A was considered unsuitable because of frequent thrombocytopenia and treatment discontinuations. Twenty-three percent of the overall population (22 patients with grade 1-2, and 1 patient with grade 3), including 37% of patients on dose level 3, experienced unexpected dose-limiting visual toxicity, which included color perception and visual field alterations linked to retinal cone cell toxicity; the visual toxicity had an early onset, was mostly reversible, and was related to higher dose per infusion. Safety profiles were similar for 5- and 30-min infusions. The relationships between dose and area under the plasma concentration-time curve and maximum plasma concentration were linear for both 5- and 30-min infusions in the 78 patients evaluated for pharmacokinetics. The area under the plasma concentration-time curve and clearance were comparable between infusion durations. Responses included one complete (ovarian), one partial (renal), and seven disease stabilizations lasting >4 months.We recommend doses of 18 mg/m(2)/infusion for schedule B and 24 mg/m(2)/infusion for schedule C, limited to 0.55 mg/kg and a total dose of 50 mg/infusion, administered over 30-min.
Significance of antinuclear factor in the connective tissue diseases.
Authors: N R Rowell, J S Beck
Journal: Annals of the Rheumatic Diseases (1970)

confirm it in 5 years' time.Is this correct ?Have you any plans for extending this investigation?DR.WOOD Not at the moment.Our initial object has been to find quick answers to guide future work, but wehave not yet finished digesting even these preliminary analyses.DR. HILL (Stoke Mandeville) The old criteria of definite and probable comes out if you take out the serology as we did in our follow-up studies of sheep cell tests.DR.WOOD We are hoping to validate this by further analysis of our data.PROF.BYWATERS (Taplow) I would support strongly the thesis that the follow-up is the ultimate validation of any particular theory.In a sense you have taken this into account.The final diagnosis is in fact a follow-up from when you first saw the patient.PROF .KELLG REN (Manchester) I should like to enlarge on this.For example, with gout, which is very much easier than all the other diagnoses, nearly all the patients in this study have had subsequent elaborate work-outs.
ACQUIRED HYPOMELANOSIS: HYPERPIGMENTATION FOLLOWING REACTIONS TO HYDROQUINONES
Authors: B. Bentley-Phillips, MargaretA. H. Bayles
Journal: British Journal of Dermatology (1974)

Journal Article ACQUIRED HYPOMELANOSIS: HYPERPIGMENTATION FOLLOWING REACTIONS TO HYDROQUINONES Get access B. Bentley‐Phillips, B. Bentley‐Phillips Department of Dermatology, University of Natal, and King Edward VIII Hospital, Durban, South Africa Search for other works by this author on: Oxford Academic Google Scholar MargaretA. H. Bayles MargaretA. H. Bayles Department of Dermatology, University of Natal, and King Edward VIII Hospital, Durban, South Africa Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 90, Issue 2, 1 February 1974, Pages 232–233, https://doi.org/10.1111/j.1365-2133.1974.tb06392.x Published: 01 February 1974
Randomized Phase II-III Trial of Combination Beta and Gamma Interferons and Etoposide and Cisplatin in Inoperable Non-Small Cell Cancer of the Lung
Authors: J. H. Schiller, B. Storer, R. Dreicer, D. Rosenquist, M. Frontiera, P. P. Carbone
Journal: JNCI Journal of the National Cancer Institute (1989)

We observed major responses in two patients with adenocarcinoma of the lung who had received a combination of interferon (IFN)-β and IFN-γ, immediately followed by chemotherapy. To verify these observations, we initiated a prospective randomized phase II–III trial of etoposide and cisplatin, with or without IFN-β and IFN-γ, in patients with inoperable non-small cell lung cancer. Thirty-seven patients were randomized to receive either two cycles of chemotherapy or 6 weeks of IFN-β plus IFN-γ followed by two cycles of chemotherapy. Chemotherapy consisted of 60 mg of cisplation/m2 on day 1 and 120 mg of etoposide/m2 on days 4, 6, and 8, repeated every 21 days. Patients who were randomized to the IFN plus chemotherapy arm received 200 μg of IFN-γ and 30 × 106 U of IFN-β three times per week for 6 weeks, followed by two cycles of chemotherapy. Three of 18 (17%) eligible patients in the chemotherapy arm and two of 18 (11%) patients in the combination arm had partial responses. All responses occurred while patients were receiving chemotherapy. Median survival was 190 days for the chemotherapy arm and 246 days in the combined modality arm, as estimated from Kaplan-Meier curves (P = .35). We observed no significant difference in subjective toxic effects between the two arms. We observed more hematologic toxicity during chemotherapy on the combined modality arm (P = .02). We conclude that pretreatment with IFN-β and IFN-γ does not enhance the efficacy of etoposide and cisplatin in this disease. Although the combined modality arm is relatively well tolerated, it does result in more chemotherapy-associated toxic effects. This study also exemplifies a hybrid phase II–III trial design, which is useful in allowing phase II results to be quickly incorporated into a phase III trial. [J Natl Cancer Inst 81:1739–1743, 1989]