tbuckley/cabot-search huggingface dataset:
Impact of Androgen-Deprivation Therapy on Physical Function and Quality of Life in Men With Nonmetastatic Prostate Cancer
Authors: Shabbir M.H. Alibhai, Henriette Breunis, Narhari Timilshina, Calvin Johnston, George Tomlinson, Ian Tannock, Murray Krahn, Neil E. Fleshner, Padraig Warde, Sarah Duff Canning, Lawrence Klotz, Gary Naglie
Journal: Journal of Clinical Oncology (2010)

Purpose This prospective longitudinal study evaluated the effect of androgen deprivation therapy (ADT) on objective and self-reported physical function. Patients and Methods Men with nonmetastatic prostate cancer (PC) starting continuous ADT were enrolled in this matched cohort study. Physical function was assessed with the 6-minute walk test (6MWT), grip strength, and the timed-up-and-go (TUG) test, representing endurance and upper and lower extremity strength, respectively. Quality of life (QOL) was measured with the Medical Outcomes Study Short-Form 36 (SF-36) questionnaire. Subjects were assessed at baseline, 3, 6, and 12 months. Two control groups (PC without ADT; no PC), matched on age, education, and baseline function were enrolled. Mixed effects regression models were fitted, adjusting for baseline covariates. Results We enrolled 87 patients on ADT, 86 PC controls, and 86 healthy controls; groups were similar in age (mean, 69.1 years; range, 50 to 87) and physical function. The 6MWT distance remained stable in the ADT group (P = .96) but improved in both control groups (P &lt; .05). Grip strength declined in the ADT group (P = .04), remained stable in PC controls (P = .31), and improved in healthy controls (P = .008). TUG scores remained stable over time and across groups (P &gt; .10). The SF-36 physical function summary score declined in the ADT group (P &lt; .001), but increased in both control groups (P &lt; .001). Negative effects on outcomes were observed within 3 months of starting ADT and were generally independent of age. Conclusion Endurance, upper extremity strength, and physical components of QOL are affected within 3 months of starting ADT. Up-front exercise interventions to counteract these losses are warranted.
Realignment treatment for medial tibiofemoral osteoarthritis: randomised trial
Authors: David Hunter, K D Gross, Paula McCree, Ling Li, Kelly Hirko, William F Harvey
Journal: Annals of the Rheumatic Diseases (2012)

The objective of this 30-week randomised crossover trial was to determine whether a multi-modal realignment treatmentwould be successful in relieving pain and improving function among persons with medial tibiofemoral osteoarthritis (OA).The authors conducted a double-blind randomised crossover trial of a multi-modal realignment treatment for medial tibiofemoral OA. Trial participants met American College of Rheumatology criteria for OA, with knee pain, aching or stiffness on most days of the past month and radiographic evidence of a definite osteophyte with predominant medial tibiofemoral OA. The authors tested two different treatments: (A) control treatment consisting of a neutral knee brace (no valgus angulation), flat unsupportive foot orthoses and shoes with a flexible mid-sole; and (B) active treatment consisting of a valgus knee brace, customised neutral foot orthoses and shoes designed for motion control. For each subject, the trial lasted 30 weeks, including 12 weeks each of active treatment and control treatment separated by a 6-week washout period. The primary outcome of the linear regression model was change in knee pain and function, as assessed by the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC).80 participants with medial tibiofemoral OA were randomised. Their mean age was 62 years, their mean body mass index was 34 kg/m(2) and their mean WOMAC Pain score was 9.2 (0-20 scale). There was no evidence of a carryover effect. The regression model demonstrated that the mean difference in pain between the active treatment and the control treatment was -1.82 units (95% CI -3.05 to -0.60; p=0.004) on the WOMAC Pain scale, indicating a small but statistically significant decrease in pain with the multi-modal active treatment. For WOMAC Function, the realignment intervention had a non-significant effect on function, with a -2.90 unit decrease (95% CI -6.60 to 0.79) compared with the control condition (p=0.12).Multi-modal realignment treatment decreases pain in persons with medial tibiofemoral OA.
Vaccination of Dendritic Cells Loaded with Interleukin-12-Secreting Cancer Cells Augments <i>In vivo</i> Antitumor Immunity: Characteristics of Syngeneic and Allogeneic Antigen-Presenting Cell Cancer Hybrid Cells
Authors: Takuji Suzuki, Tatsuro Fukuhara, Masashi Tanaka, Akira Nakamura, Kenichi Akiyama, Tomohiro Sakakibara, Daizo Koinuma, Toshiaki Kikuchi, Ryushi Tazawa, Makoto Maemondo, Koichi Hagiwara, Yasuo Saijo, Toshihiro Nukiwa
Journal: Clinical Cancer Research (2005)

Cancer immunotherapy by fusion of antigen-presenting cells and tumor cells has been shown to induce potent antitumor immunity. In this study, we characterized syngeneic and allogeneic, murine macrophage/dendritic cell (DC)-cancer fusion cells for the antitumor effects. The results showed the superiority of allogeneic cells as fusion partners in both types of antigen-presenting cells in an in vivo immunotherapy model. A potent induction of tumor-specific CTLs was observed in these immunized conditions. In addition, the immunization with DC-cancer fusion cells was better than that with macrophage-cancer fusion cells. Both syngeneic and allogeneic DC-cancer fusion cells induced higher levels of IFN-gamma production than macrophage-cancer fusion cells. Interestingly, allogeneic DC-cancer fusion cells were superior in that they efficiently induced Th1-type cytokines but not the Th2-type cytokines interleukin (IL)-10 and IL-4, whereas syngeneic DC-cancer fusion cells were powerful inducers of both Th1 and Th2 cytokines. These results suggest that allogeneic DCs are suitable as fusion cells in cancer immunotherapy. To further enhance the antitumor immunity in the clinical setting, we prepared DCs fused with IL-12 gene-transferred cancer cells and thus generated IL-12-secreting DC-cancer fusion cells. Immunization with these gene-modified DC-cancer fusion cells was able to elicit a markedly enhanced antitumor effect in the in vivo therapeutic model. This novel IL-12-producing fusion cell vaccine might be one promising intervention for future cancer immunotherapy.
PTU-026 Safety And Efficacy Of Transnasal Percutaneous Endoscopic Gastrostomy Placement-experience In A District General Hospital: Abstract PTU-026 Table 1
Authors: D Majumdar, C Wells, AD Dwarakanath
Journal: Gut (2014)

<h3>Introduction</h3> Percutaneous endoscopic gastrostomy (PEG) is an alternative and important way to maintain nutrition. Trans-nasal PEG insertion (t-PEG) using small-calibre endoscope has been reported to be safe and effective than the conventional trans-oral PEG (o-PEG) in malnourished patients with head and neck cancer.<sup>1</sup> The current study aims to evaluate the safety and efficacy of trans-nasal PEG in patients with benign condition. <h3>Methods</h3> In this prospective study twelve consecutive patients who were referred for PEG insertion for benign conditions were allocated for conventional and t-PEG into 1:1 ratio over the study period of five months. All the cases were discussed in PEG multidisciplinary team meeting and procedures were performed by a single experienced endoscopist. Data were collected for sedation and comfort score and complications. A visual analogue scale was used for objective assessment of comfort. 14 French CORFLO gastrostomy tubes were used in all the cases. <h3>Results</h3> Seven of them were male and the mean age was 64.2 year (range: 21–81 year). The median follow up period was 27 weeks. More patients needed sedation and analgesia in conventional PEG group and mean sedation dose and comfort score were lower in t-PEG group. Nutritional goals were achieved in all the cases. There was no immediate complication in both group but, one patient in each group had their PEG tube dislodged after four weeks of insertion. <h3>Conclusion</h3> The findings from this study reaffirm that t-PEG placement using a small calibre endoscope through nasal route is safe, well tolerated and effective to maintain nutrition in patients with benign conditions. A multicenter randomised controlled trial is necessary to validate our findings and to evaluate the cost effectiveness. <h3>Reference</h3> Vitale MA, Villotti G, D’Alba L, De Cesare MA, Frontespezi S, Iacopini G, Unsedated transnasal percutaneous endoscopic gastrostomy placement in selected patients. <i>Endoscopy</i> January 2005;37/1(48–51):0013–726X <h3>Disclosure of Interest</h3> None Declared.
Invasion of ovarian cancer cells is induced byPITX2-mediated activation of TGF-β and Activin-A
Authors: Moitri Basu, Rahul Bhattacharya, Upasana Ray, Satinath Mukhopadhyay, Uttara Chatterjee, Sib Sankar Roy
Journal: Molecular Cancer (2015)

Most ovarian cancers are highly invasive in nature and the high burden of metastatic disease make them a leading cause of mortality among all gynaecological malignancies. The homeodomain transcription factor, PITX2 is associated with cancer in different tissues. Our previous studies demonstrated increased PITX2 expression in human ovarian tumours. Growing evidence linking activation of TGF-β pathway by homeodomain proteins prompted us to look for the possible involvement of this signalling pathway in PITX2-mediated progression of ovarian cancer.The status of TGF-β signalling in human ovarian tissues was assessed by immunohistochemistry. The expression level of TGFB/INHBA and other invasion-associated genes was measured by quantitative-PCR (Q-PCR) and Western Blot after transfection/treatments with clones/reagents in normal/cancer cells. The physiological effect of PITX2 on invasion/motility was checked by matrigel invasion and wound healing assay. The PITX2- and activin-induced epithelial-mesenchymal transition (EMT) was evaluated by Q-PCR of respective markers and confocal/phase-contrast imaging of cells.Human ovarian tumours showed enhanced TGF-β signalling. Our study uncovers the PITX2-induced expression of TGFB1/2/3 as well as INHBA genes (p < 0.01) followed by SMAD2/3-dependent TGF-β signalling pathway. PITX2-induced TGF-β pathway regulated the expression of invasion-associated genes, SNAI1, CDH1 and MMP9 (p < 0.01) that accounted for enhanced motility/invasion of ovarian cancers. Snail and MMP9 acted as important mediators of PITX2-induced invasiveness of ovarian cancer cells. PITX2 over-expression resulted in loss of epithelial markers (p < 0.01) and gain of mesenchymal markers (p < 0.01) that contributed significantly to ovarian oncogenesis. PITX2-induced INHBA expression (p < 0.01) contributed to EMT in both normal and ovarian cancer cells.Overall, our findings suggest a significant contributory role of PITX2 in promoting invasive behaviour of ovarian cancer cells through up-regulation of TGFB/INHBA. We have also identified the previously unknown involvement of activin-A in promoting EMT. Our work provides novel mechanistic insights into the invasive behavior of ovarian cancer cells. The extension of this study have the potential for therapeutic applications in future.
Antitumor Activity of the Insulin-Like Growth Factor-I Receptor Kinase Inhibitor NVP-AEW541 in Musculoskeletal Tumors
Authors: Katia Scotlandi, Maria Cristina Manara, Giordano Nicoletti, Pier-Luigi Lollini, Stella Lukas, Stefania Benini, Stefania Croci, Stefania Perdichizzi, Diana Zambelli, Massimo Serra, Carlos García-Echeverría, Francesco Hofmann, Piero Picci
Journal: Cancer Research (2005)

Abstract Identification of new drugs is strongly needed for sarcomas. Insulin-like growth factor-I receptor (IGF-IR) was found to provide a major contribution to the malignant behavior of these tumors, therefore representing a very promising therapeutic target. In this study, we analyzed the therapeutic potential of a novel kinase inhibitor of IGF-IR, NVP-AEW541, in Ewing's sarcoma, osteosarcoma, and rhabdomyosarcoma, the three most frequent solid tumors in children and adolescents. NVP-AEW541 inhibits IGF-I-mediated receptor activation and downstream signaling. Ewing's sarcoma cells were generally found to be more sensitive to the effects of this drug compared with rhabdomyosarcoma and osteosarcoma, in agreement with the high dependency of this neoplasm to IGF-IR signaling. NVP-AEW541 induced a G1 cell cycle block in all cells tested, whereas apoptosis was observed only in those cells that show a high level of sensitivity. Concurrent exposure of cells to NVP-AEW541 and other chemotherapeutic agents resulted in positive interactions with vincristine, actinomycin D, and ifosfamide and subadditive effects with doxorubicin and cisplatin. Accordingly, combined treatment with NVP-AEW541 and vincristine significantly inhibited tumor growth of Ewing's sarcoma xenografts in nude mice. Therefore, results encourage inclusion of this drug especially in the treatment of patients with Ewing's sarcoma. For the broadest applicability and best efficacy in sarcomas, NVP-AEW541 may be combined with vincristine, actinomycin D, and ifosfamide, three major drugs in the treatment of sarcomas.
DOCK8 functions as an adaptor that links TLR-MyD88 signaling to B cell activation
Authors: Haifa H Jabara, Douglas R McDonald, Erin Janssen, Michel J Massaad, Narayanaswamy Ramesh, Arturo Borzutzky, Ingrid Rauter, Halli Benson, Lynda Schneider, Sachin Baxi, Mike Recher, Luigi D Notarangelo, Rima Wakim, Ghassan Dbaibo, Majed Dasouki, Waleed Al-Herz, Isil Barlan, Safa Baris, Necil Kutukculer, Hans D Ochs, Alessandro Plebani, Maria Kanariou, Gerard Lefranc, Ismail Reisli, Katherine A Fitzgerald, Douglas Golenbock, John Manis, Sevgi Keles, Reuben Ceja, Talal A Chatila, Raif S Geha
Journal: Nature Immunology (2012)
Endomysial antibody-negative coeliac disease: clinical characteristics and intestinal autoantibody deposits
Authors: T T Salmi, P Collin, I R Korponay-Szabo, K Laurila, J Partanen, H Huhtala, R Kiraly, L Lorand, T Reunala, M Maki, K Kaukinen
Journal: Gut (2006)

<b>Background:</b> Some patients with untreated coeliac disease are negative for serum endomysial autoantibodies (EmA) targeted against transglutaminase 2 (TG2). <b>Aims:</b> To evaluate the clinical and histological features of EmA-negative coeliac disease, and to examine whether EmA-equivalent autoantibodies against TG2 can be seen in the small-bowel mucosa when absent in serum. <b>Patients:</b> Serum EmA was studied in 177 biopsy-proved specimens from adult patients with coeliac disease. 20 patients with intestinal diseases served as non-coeliac controls; three had autoimmune enteropathy with villous atrophy. <b>Methods:</b> Clinical manifestations, small-bowel mucosal morphology, intraepithelial inflammation and TG2-specific extracellular immunoglobulin A (IgA) deposits were investigated in both serum EmA-negative and EmA-positive patients. <b>Results:</b> 22 patients with IgA-competent coeliac disease were negative for serum EmA. Three of these had small-bowel lymphoma. Patients with EmA-negative coeliac disease were older, had abdominal symptoms more often, and the density of γδ+ intraepithelial lymphocytes in their intestinal mucosa was lower than in EmA-positive patients; otherwise the histology was similar. All serum EmA-negative patients with coeliac disease, but none of the disease controls, had gluten-dependent mucosal IgA deposits alongside TG2 in the small-bowel mucosal specimens. In vivo deposited IgA was shown to be TG2-specific by its ability to bind recombinant TG2. <b>Conclusions:</b> Negative serum EmA might be associated with advanced coeliac disease. TG2-targeted autoantibodies were deposited in the small-bowel mucosa even when absent in serum. This finding can be used in the diagnosis of seronegative coeliac disease when the histology is equivocal. It may also be helpful in the differential diagnosis between autoimmune enteropathy and coeliac disease.
Transient Depolarizations Induced by Acetylstrophanthidin in Specialized Tissue of Dog Atrium and Ventricle
Authors: KEITARO HASHIMOTO, GORDON K. MOE
Journal: Circulation Research (1973)

Isolated preparations of atrial specialized conduction fibers ("plateau" fibers) qualitatively resembled ventricular Purkinje fibers (false tendons) in their response to acetylstrophanthidin. Acetylstrophanthidin in concentrations of 1-3 x10 -7 g/ml caused coupled, frequency-dependent transient depolarizations (TDs) in both types of fiber. In free-running strands of plateau fibers the TDs could reach threshold and generate coupled action potentials, but TDs and automatic responses did not occur in ordinary atrial muscle fibers. TDs were suppressed by elevation of the external potassium concentration. Automatic activity and TDs in atrial plateau fibers were abolished by acetylcholine. Automatic activity was also sometimes suppressed in false tendons by acetylcholine, but TDs and related coupled responses were not influenced.
Human Herpesvirus 8 Infection and Transfusion History in Children With Sickle-Cell Disease in Uganda
Authors: Sam M. Mbulaiteye, Robert J. Biggar, Paul M. Bakaki, Ruth M. Pfeiffer, Denise Whitby, Anchilla M. Owor, Edward Katongole-Mbidde, James J. Goedert, Christopher M. Ndugwa, Eric A. Engels
Journal: JNCI Journal of the National Cancer Institute (2003)

Although human herpesvirus 8 (HHV-8), the etiologic agent for Kaposi's sarcoma, can be detected in peripheral blood, blood-borne transmission of this virus has not been demonstrated. We studied the association between HHV-8 seropositivity and transfusion history among children with sickle-cell disease in Uganda, where HHV-8 infection is common in blood donors.We studied 600 children (aged 0-16 years) with sickle-cell disease at Mulago Hospital, Kampala, from November 2001 through April 2002. By design, about half had previously been transfused. HHV-8 serostatus was determined using enzyme-linked immunosorbent assays for antibodies against HHV-8 proteins K8.1 and orf 73. We used logistic regression to test for an association between HHV-8 serostatus and transfusion history and a Markov model to estimate the transmission risk per transfusion and the cumulative risk from community (i.e., nontransfusion) sources. Statistical tests were two-sided.HHV-8 antibodies were detected in 117 of 561 (21%) children with unambiguous K8.1 results. HHV-8 seroprevalence among the never-transfused children increased with age from 7% in children aged 0-2 years to 32% in those aged 13-16 years (P(trend)<.001). HHV-8 seropositivity was more frequent in transfused than never-transfused children (24% versus 17%, odds ratio = 1.48, 95% confidence interval [CI] = 0.97 to 2.26; P =.07). Seropositivity increased with number of reported transfusions, with age-adjusted odds ratios of 0.97 (95% CI = 0.54 to 1.75), 1.13 (95% CI = 0.59 to 2.17), 1.76 (95% CI = 0.81 to 3.83), and 2.17 (95% CI = 1.18 to 3.99) for children with one, two, three, or four or more transfusions, respectively (P(trend) =.007). Overall, the estimated HHV-8 transmission risk was 2.6% per transfusion (95% CI = 1.9% to 3.3%), whereas the annual risk of infection unrelated to transfusion was 2.7% (95% CI = 1.7% to 3.7%).Our study suggests that blood transfusion is associated with a small risk of HHV-8 transmission. In Uganda, this risk is approximately equivalent to the 1-year cumulative risk of infection from community sources.
Predicting the response to infliximab from trough serum levels
Authors: P. Rutgeerts, S. Vermeire, G. Van Assche
Journal: Gut (2009)

Optimal use of a drug implies the correct dosage, with the lowest level just before the periodically administered medicine is taken (trough level) being sufficiently high to exert the full effect of the drug. On the other hand, peak levels and average levels should not exceed concentrations which are associated with increased toxicity. Therapeutic monitoring with measurement of trough levels at regular intervals is routinely carried out in the treatment with small molecules which have a narrow therapeutic window, for example ciclosporin. Surprisingly this therapeutic monitoring is not used at all to optimise treatment with monoclonal antibodies against biological targets. It is generally accepted that the clearance of a monoclonal antibody is quite predictable. For infliximab the terminal half-life is 9.5 days with a slow clearance rate (9.8 ml/h). The prolonged bioavailability of infliximab together with its high affinity for tumour necrosis factor (TNF ( K a = 1010/M) should result in effective and prolonged blockade of TNF with administration of 5 mg/kg every 8 weeks. However, the pharmacokinetics may not always be predictable. Clearance of infliximab is greatly increased in the presence of antibodies to infliximab (ATI). Moreover rapid clearance is also observed in a minority of patients without the presence of antibodies. The problem of immunogenicity of anti-TNF agents and the importance of achieving good trough levels was not well recognised in the pivotal trials in inflammatory bowel disease (IBD), and it was investigator-initiated cohort studies that pinpointed the problem.

In this issue of Gut , Seow et …
A Two-Compartment Model Describing the Release and Negative Inotropic Action of Acetylcholine on the Heart
Authors: MAX E. VALENTINUZZI, HEBBEL E. HOFF, LESLIE A. GEDDES
Journal: Circulation Research (1973)

Single-pulse stimulation of the vagus nerve in turtles ( Pseudymys floridana ) produced the well-known negative inotropic effect on the atria. After stimulation, the peak amplitudes of the atrial contractions exhibited an envelope which appeared to be proportional to the concentration of acetylcholine at the receptor sites. Postulating a quantized release of acetylcholine with each stimulus, the envelope was modeled by a two-equal-compartment configuration. In about 63% of the cases this envelope behaved as if it described a critically damped system, in 18% of the cases it behaved as if the system were slightly overdamped, and in the remaining 19% it corresponded to a lightly underdamped system. The average washout time constant per compartment calculated from the single-pulse response was 4.7 ± 0.8 seconds ( SD ). Repetitive stimulation was provisionally equated with a constant release of acetylcholine; its mathematical description was derived from the time integral of the single-pulse case, i.e., from a direct application of indicator-dilution theory. However, the average time constant obtained from this second type of fit was only 0.84 ± 0.4 seconds. This lower value was interpreted as a dynamic modification (perhaps nonlinear) due to accumulation of acetylcholine and probably associated with an increase in acetylcholine esterase activity.
The "After-Drop" in Venous Occlusion Plethysmograms
Authors: M. J. ALLWOOD
Journal: Circulation Research (1956)

Venous occlusion plethysmograms from the dependent foot showed an "after-drop" in volume not seen with the foot at heart level. Factors affecting the development of this after-drop were studied. Blood flow was measured during the after-drop and corresponding changes in venous pressure recorded. The evidence obtained does not support the existing explanation that the after-drop is due to a reflex vasoconstriction. It is suggested that this phenomenon is due to a shifting of blood in the underlying vessels by the venous occlusion cuff.