tbuckley/cabot-search huggingface dataset:
Synergistic Interaction Between Oncolytic Viruses Augments Tumor Killing
Authors: Fabrice Le Boeuf, Jean-Simon Diallo, J Andrea McCart, Steve Thorne, Theresa Falls, Marianne Stanford, Femina Kanji, Rebecca Auer, Christopher W Brown, Brian D Lichty, Kelley Parato, Harold Atkins, David Kirn, John C Bell
Journal: Molecular Therapy (2010)

A major barrier to all oncolytic viruses (OVs) in clinical development is cellular innate immunity, which is variably active in a spectrum of human malignancies. To overcome the heterogeneity of tumor response, we combined complementary OVs that attack cancers in distinct ways to improve therapeutic outcome. Two genetically distinct viruses, vesicular stomatitis virus (VSV) and vaccinia virus (VV), were used to eliminate the risk of recombination. The combination was tested in a variety of tumor types in vitro, in immunodeficient and immunocompetent mouse tumor models, and ex vivo, in a panel of primary human cancer samples. We found that VV synergistically enhanced VSV antitumor activity, dependent in large part on the activity of the VV B18R gene product. A recombinant version of VSV expressing the fusion-associated small-transmembrane (p14FAST) protein also further enhanced the ability of VV to spread through an infected monolayer, resulting in a "ping pong" oncolytic effect wherein each virus enhanced the ability of the other to replicate and/or spread in tumor cells. Our strategy is the first example where OVs are rationally combined to utilize attributes of different OVs to overcome the heterogeneity of malignancies and demonstrates the feasibility of combining complementary OVs to improve therapeutic outcome.
Clinical trial of allogeneic cultured dermal substitute for the treatment of intractable skin ulcers in 3 patients with recessive dystrophic epidermolysis bullosa*
Authors: Toshio Hasegawa, Yasushi Suga, Masayuki Mizoguchi, Shigaku Ikeda, Hideoki Ogawa, Kentaro Kubo, Hiromichi Matsui, Shizuko Kagawa, Yoshimitsu Kuroyanagi
Journal: Journal of the American Academy of Dermatology (2004)
Atrial and brain natriuretic peptides inhibit the endothelin-1 secretory response to angiotensin II in porcine aorta.
Authors: M Kohno, K Yokokawa, T Horio, K Yasunari, K Murakawa, T Takeda
Journal: Circulation Research (1992)

We have recently shown that the porcine aorta releases immunoreactive endothelin-1 in a time-dependent way. Here, we examined the inhibition by atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) of endothelin-1 secretion after stimulation with angiotensin II (Ang II) by using porcine aorta. Ang II dose-dependently stimulated immunoreactive endothelin-1 secretion. Porcine ANP-(1-28) and porcine BNP-26 both inhibited such secretion in a dose-dependent way. The addition of a cyclic guanosine 5'-monophosphate (cGMP) analogue, 8-bromo-cGMP, reduced the immunoreactive endothelin-1 secretion after stimulation with Ang II. In cultured porcine endothelial cells the inhibition by porcine ANP-(1-28) and porcine BNP-26 of immunoreactive endothelin-1 secretion after stimulation with Ang II was paralleled by an increase in the cellular cGMP level. Rat ANP-(5-25) was weaker than porcine ANP-(1-28) in inhibiting immunoreactive endothelin-1 secretion and increasing cGMP in cultured cells. There was negative correlation between the percent decrease in immunoreactive endothelin-1 and the percent increase in cGMP. Neither porcine ANP-(1-28) nor BNP-26 affected the number or sensitivity of Ang II binding sites in cultured porcine endothelial cells. These results suggest that ANP and BNP inhibit endothelin-1 secretion after stimulation with Ang II, probably through a cGMP-dependent process.
The Story of God
Authors: Trevor Jackson
Journal: BMJ (2005)

While the latest exhibition at the American Museum of Natural History in New York explores evolution ( BMJ 2005;331: 1379), several hundred miles away at the start of the US Bible belt some of those who reject Darwin's theory are building a museum of creation. So far creationists have raised $25m (£14m; €21m) towards the project, which is nearing completion in Petersburg, Kentucky, and which claims to show that the world came into being exactly as told in the book of Genesis. It would not be so worrying if the museum, which bizarrely displays mankind side by side with …
AMPK Promotes p53 Acetylation via Phosphorylation and Inactivation of SIRT1 in Liver Cancer Cells
Authors: Chi-Wai Lee, Leo Lap-Yan Wong, Edith Yuk-Ting Tse, Heong-Fai Liu, Veronica Yee-Law Leong, Joyce Man-Fong Lee, D. Grahame Hardie, Irene Oi-Lin Ng, Yick-Pang Ching
Journal: Cancer Research (2012)

Abstract AMP-activated protein kinase (AMPK), a biologic sensor for cellular energy status, has been shown to act upstream and downstream of known tumor suppressors. However, whether AMPK itself plays a tumor suppressor role in cancer remains unclear. Here, we found that the α2 catalytic subunit isoform of AMPK is significantly downregulated in hepatocellular carcinoma (HCC). Clinicopathologic analysis revealed that underexpression of AMPK-α2 was statistically associated with an undifferentiated cellular phenotype and poor patient prognosis. Loss of AMPK-α2 in HCC cells rendered them more tumorigenic than control cells both in vitro and in vivo. Mechanistically, ectopic expression of AMPK enhanced the acetylation and stability of p53 in HCC cells. The p53 deacetylase, SIRT1, was phosphorylated and inactivated by AMPK at Thr344, promoting p53 acetylation and apoptosis of HCC cells. Taken together, our findings suggest that underexpression of AMPK is frequently observed in HCC, and that inactivation of AMPK promotes hepatocarcinogenesis by destabilizing p53 in a SIRT1-dependent manner. Cancer Res; 72(17); 4394–404. ©2012 AACR.
TIME LOSS AND INJURY CHANGES WITH MULTIDISCIPLINARY PREVENTIVE APPROACH IN FEMALE VOLLEYBALL PLAYERS
Authors: M Mendes de Almeida Gomide Leite, C Bolling, D Reis, N Bittencourt, G Gonçalves
Journal: British Journal of Sports Medicine (2014)

Background Youth volleyball players have high injury rates in shoulder, knee and ankle. Specific preventive programs could reduce time loss and injury severity reflecting in athlete's performance. Objective To describe the difference in time loss and injuries occurrence after a multidisciplinary prevention approach in youth volleyball athletes. Design This is longitudinal and prospective study. Setting The data colection and interventions were conducted with volleyball players competing in a national level in a Brazilian sports club. Participants 42 female youth volleyball athletes with a mean age of 13.8 years (±1.4), body mass of 59.2 (±8.6) kg and height of 171.2 (±5.5 cm ). Intervention A multidisciplinary preventive approach (MPA) was characterized by CORE, knee and ankle stabilization exercises during warm up. Shoulder rotators, gluteus maximus and hamstrings muscles were trained in strengthening sessions. Main outcome measurements The MPA was conducted by team's physiotherapist and coach, performed twice a week, with 20 minutes duration. Injuries and time loss was reported by the team's physiotherapist. Results There was a 60% reduction of days out of training and 10% reduction in the number of injuries. Conclusions MPA reduces the time loss and injuries occurrence in youth volleyball athletes. It is important to design preventive interventions by the injury profile, focusing in most predisposed injured areas. Time loss and lower injury occurrence reflect in athletes' performance.
Sustained Remissions of High-Risk Acute Myeloid Leukemia and Myelodysplastic Syndrome After Reduced-Intensity Conditioning Allogeneic Hematopoietic Transplantation: Chronic Graft-Versus-Host Disease Is the Strongest Factor Improving Survival
Authors: David Valcárcel, Rodrigo Martino, Dolores Caballero, Jesus Martin, Christelle Ferra, Jose B. Nieto, Antonia Sampol, M. Teresa Bernal, Jose L. Piñana, Lourdes Vazquez, Jose M. Ribera, Joan Besalduch, Jose M. Moraleda, Dolores Carrera, M. Salut Brunet, Jose A. Perez-Simón, Jorge Sierra
Journal: Journal of Clinical Oncology (2007)

Reduced-intensity conditioning (RIC) for allogeneic stem-cell transplantation (allo-SCT) reduces nonrelapse mortality (NRM). This reduction makes it possible for patients who are ineligible for high-dose myeloablative conditioning allo-SCT to benefit from graft-versus-leukemia reaction. In this multicenter, prospective study of patients with acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS), we investigated the efficacy of RIC allo-SCT from a human leukocyte antigen-identical sibling by using a regimen that uses fludarabine and busulfan.Ninety-three patients with AML (n = 59) and MDS (n = 34) were included, and the median age was of 53 years. Follow-up for survivors was 43 months (range, 3 to 89 months). The conditioning regimen consisted of fludarabine (150 mg/m(2)) and oral busulfan (8 to 10 mg/kg). All except one patient received mobilized peripheral blood stem cells. Graft-versus-host disease (GVHD) prophylaxis consisted of cyslosporine and methotrexate or mycophenolate mofetil.The 100-day, 1-year, and 4-year incidences of NRM were 8, 16%, and 21%, respectively. The 1- and 4-year relapse cumulative incidences were 23% and 37%, respectively, and leukemia recurrence was the main cause of death. The 4-year disease-free survival (DFS) and overall survival (OS) rates were 43% and 45%, respectively. The 4-year cumulative incidence of chronic GVHD was 53% (45% extensive), and its development was the major factor associated with lower relapse incidence and improved DFS and OS.Our results confirm the capacity of this RIC regimen to obtain long-term remissions in patients ineligible for a conventional allo-SCT. The results suggest an important role of the development of chronic GVHD in reducing relapse and improving DFS and OS.
RNA Silencing of Checkpoint Regulators Sensitizes<i>p53</i>-Defective Prostate Cancer Cells to Chemotherapy while Sparing Normal Cells
Authors: Utpal K. Mukhopadhyay, Adrian M. Senderowicz, Gerardo Ferbeyre
Journal: Cancer Research (2005)

Abstract p53 is frequently mutated in patients with prostate cancer, especially in those with advanced disease. Therefore, the selective elimination of p53 mutant cells will likely have an impact in the treatment of prostate cancer. Because p53 has important roles in cell cycle checkpoints, it has been anticipated that modulation of checkpoint pathways should sensitize p53-defective cells to chemotherapy while sparing normal cells. To test this idea, we knocked down ataxia telangiectasia mutated (ATM) gene by RNA interference in prostate cancer cell lines and in normal human diploid fibroblasts IMR90. ATM knockdown in p53-defective PC3 prostate cancer cells accelerated their cell cycle transition, increased both E2F activity and proliferating cell nuclear antigen expression, and compromised cell cycle checkpoints, which are normally induced by DNA damage. Consequently, PC3 cells were sensitized to the killing effects of the DNA-damaging drug doxorubicin. Combining ATM knockdown with the Chk1 inhibitor UCN-01 further increased doxorubicin sensitivity in these cells. In contrast, the same strategy did not sensitize either IMR90 or LNCaP prostate cancer cells, both of which have normal p53. However, IMR90 and LNCaP cells became more sensitive to doxorubicin or doxorubicin plus UCN-01 when both p53 and ATM functions were suppressed. In addition, knockdown of the G2 checkpoint regulators ATR and Chk1 also sensitized PC3 cells to doxorubicin and increased the expression of the E2F target gene PCNA. Together, our data support the concept of selective elimination of p53 mutant cells by combining DNA damage with checkpoint inhibitors and suggest a novel mechanistic insight into how such treatment may selectively kill tumor cells.
A Lecture ON PULMONARY TUBERCULOSIS IN CHILDREN: Delivered at the Medical Graduates' College and Polyclinic on April 3rd, 1906
Authors: J. E. Squire
Journal: BMJ (1906)

its functions are seriously impaired."After this examination he went home.Fig. 2.-Appearance of the stone.A letter dated May 11th, 1905, was received from the patient, and another from Dr. Owen, saying that his water was right enough and passed without pain, but that he often had pain in his back when walking, so that for days at a time he sometimes could not go out.He had not yet begun work again.One cannot help suspecting stone in the kidney, and hoping for an opportunity of submitting him to x-ray photography to try and settle the point; but
Lipid modification and cardiovascular risk assessment for the primary and secondary prevention of cardiovascular disease: summary of updated NICE guidance
Authors: S. Rabar, M. Harker, N. O'Flynn, A. S. Wierzbicki
Journal: BMJ (2014)

Cardiovascular disease (CVD) is the leading cause of death in England and Wales, accounting for almost a third of deaths. An update of existing National Institute for Health and Care Excellence (NICE) guidance (published in 2008)1 was necessary in light of new evidence on the efficacy and safety of statin therapy,2 on the effects of combining statins with non-statin drugs,3 4 5 and on novel risk assessment tools for predicting risk of CVD.6 Since the previous guideline, more statins have become available as generic drugs, and this has changed the cost effectiveness of statin treatment. The scope of the update included risk assessment for CVD and the use of lipid modification in people with type 1 diabetes, type 2 diabetes, and chronic kidney disease. This article summarises the most recent recommendations from NICE on lipid modification: cardiovascular risk assessment and the modification of blood lipids for the primary and secondary prevention of cardiovascular disease.7 NICE recommendations are based on systematic reviews of best available evidence and explicit consideration of cost effectiveness. When minimal evidence is available, recommendations are based on the guideline development group's experience and opinion of what constitutes good practice. Evidence levels for the recommendations are given in italic in square brackets. ### Assessing the risk of CVD #### Full formal risk assessment
Late skin‐prick‐test reactions to malted wheat. Clinical observations and immunohistochemical characterization
Authors: B. Meding, K. Ahonen, J. Brisman, M.‐A. Hedblad, A. Ståhl, B. Järvholm, A. Scheynius
Journal: Allergy (1998)

This study reports late skin‐prick‐test (SPT) reactions in seven bakers and seven control subjects to malted wheat appearing after 6–10 h. and not preceded by an immediate‐phase reaction. Two subjects in each group had a history of atopic symptoms and were Phadiatope™ positive. Serologic IgE analysis (RAST) of normal wheat flour and of mahed wheat grain was negative in all subjects. Skin biopsy specimens were obtained 16–18 h after SPT to malted wheat grain and to histamine and from untested skin. The late SPT reactions in all participants had an urticarial appearance, clinically and in routine histology. Immunohistologically mild to moderate perivascular dermal cell infiltrates were observed in both groups, consisting mainly of CD4* and HLA‐DR* cells. The number of CDla* epidermal cells was statistically significantly higher (P&lt;0.01) in the bakers” prick‐tested skin compared to tliat of the controls, a fact which might reflect preparedness to react upon challenge. There were no statistical differences between the two groups in IgE* epidermal cells or epidermal cells expressing the high‐affinity IgE receptor (Fc ɛ RI). However, there was a correlation between serum‐IgE levels and the number of IgE* epidermal cells. The late skin reactions observed in both bakers and controls were probably more of an irritant or toxic than immune‐mediated nature, but they raise the question of whether skin contact with malted flour contributes to an unfavorable prognosis of hand eczema in bakers.
Drug-resistant tuberculosis: time for visionary political leadership
Authors: Ibrahim Abubakar, Matteo Zignol, Dennis Falzon, Mario Raviglione, Lucica Ditiu, Susan Masham, Ifedayo Adetifa, Nathan Ford, Helen Cox, Stephen D Lawn, Ben J Marais, Timothy D McHugh, Peter Mwaba, Matthew Bates, Marc Lipman, Lynn Zijenah, Simon Logan, Ruth McNerney, Adam Zumla, Krishna Sarda, Payam Nahid, Michael Hoelscher, Michel Pletschette, Ziad A Memish, Peter Kim, Richard Hafner, Stewart Cole, Giovanni Battista Migliori, Markus Maeurer, Marco Schito, Alimuddin Zumla
Journal: The Lancet Infectious Diseases (2013)

<h2>Summary</h2> Two decades ago, WHO declared tuberculosis a global emergency, and invested in the highly cost-effective directly observed treatment short-course programme to control the epidemic. At that time, most strains of <i>Mycobacterium tuberculosis</i> were susceptible to first-line tuberculosis drugs, and drug resistance was not a major issue. However, in 2013, tuberculosis remains a major public health concern worldwide, with prevalence of multidrug-resistant (MDR) tuberculosis rising. WHO estimates roughly 630 000 cases of MDR tuberculosis worldwide, with great variation in the frequency of MDR tuberculosis between countries. In the past 8 years, extensively drug-resistant (XDR) tuberculosis has emerged, and has been reported in 84 countries, heralding the possibility of virtually untreatable tuberculosis. Increased population movement, the continuing HIV pandemic, and the rise in MDR tuberculosis pose formidable challenges to the global control of tuberculosis. We provide an overview of the global burden of drug-resistant disease; discuss the social, health service, management, and control issues that fuel and sustain the epidemic; and suggest specific recommendations for important next steps. Visionary political leadership is needed to curb the rise of MDR and XDR tuberculosis worldwide, through sustained funding and the implementation of global and regional action plans.
Incidence and risk of treatment-related mortality in cancer patients treated with the mammalian target of rapamycin inhibitors
Authors: T.K. Choueiri, Y. Je, G. Sonpavde, C.J. Richards, M.D. Galsky, P.L. Nguyen, F. Schutz, D.Y. Heng, M.D. Kaymakcalan
Journal: Annals of Oncology (2013)
Free fatty acids and the metabolic syndrome in patients with obstructive sleep apnoea
Authors: A. Barcelo, J. Pierola, M. de la Pena, C. Esquinas, A. Fuster, M. Sanchez-de-la-Torre, M. Carrera, A. Alonso-Fernandez, A. Ladaria, M. Bosch, F. Barbe
Journal: European Respiratory Journal (2010)

Obesity and metabolic syndrome (MS) occur frequently in patients with obstructive sleep apnoea syndrome (OSAS). We hypothesised that circulating free fatty acids (FFAs) are elevated in OSAS patients independently of obesity. This elevation may contribute to the development of MS in these patients. We studied 119 OSAS patients and 119 controls. Participants were recruited and studied at sleep unit of our institution (Hospital Universitari Son Dureta, Palma de Mallorca, Spain) and were matched for sex, age and body mass index (BMI). The occurrence of MS was analysed by clinical criteria. Serum levels of FFAs, glucose, triglycerides, cholesterol, high-density lipoprotein–cholesterol, aspartate aminotransferase, alanine aminotransferase, γ-glutamyltransferase, C-reactive protein and 8-isoprostanes were determined. Prevalence of MS was higher in OSAS than in the control group (38 <i>versus</i> 21%; p = 0.006). OSAS patients had higher FFAs levels than controls (mean±sd 12.2±4.9 <i>versus</i> 10.5±5.0 mg·dL<sup>−1</sup>; p = 0.015). Among subjects without MS, OSAS patients (OSAS+ MS-) showed higher levels of FFAs than controls (OSAS- MS-) (11.6±4.7 <i>versus</i> 10.0±4.4 mg·dL<sup>−1</sup>; p = 0.04). In a multiple regression model, after adjustment for age, sex, BMI and the presence of MS, FFAs were significantly associated with apnoea/hypopnoea index (p = 0.04). This study shows that FFAs are elevated in OSAS and could be one of the mechanisms involved in the metabolic complications of OSAS.
Meaning and motor actions: Artificial life and behavioral evidence
Authors: Domenico Parisi, Anna M. Borghi, Andrea Di Ferdinando, Giorgio Tsiotas
Journal: Behavioral and Brain Sciences (2005)

Mirror neurons may play a role in representing not only signs but also their meaning. Because actions are the only aspect of behavior that are inter-individually accessible, interpreting meanings in terms of actions might explain how meanings can be shared. Behavioral evidence and artificial life simulations suggest that seeing objects or processing words referring to objects automatically activates motor actions.
The Continuing Increase in the Incidence of Hepatocellular Carcinoma in the United States: An Update
Authors: Hashem B. El-Serag, Jessica A. Davila, Nancy J. Petersen, Katherine A. McGlynn
Journal: Annals of Internal Medicine (2003)

Background: The incidence of hepatocellular carcinoma was reported to be increasing in the United States. However, alternate explanations were diagnostic or reclassification bias and changes in the demographic features of the general population. Objective: To examine the temporal trends in the incidence of hepatocellular carcinoma. Design: Retrospective cohort study. Setting: Information collected by population-based registries of the Surveillance, Epidemiology, and End Results (SEER) program. Patients: Persons given a diagnosis of hepatocellular carcinoma between 1975 and 1998. Measurements: Linear Poisson multivariate regression model, controlling for differences in age, sex, race or ethnicity, and geographic region among patients with hepatocellular carcinoma and in the underlying population. Results: The overall age-adjusted incidence rates of hepatocellular carcinoma increased from 1.4 per 100 000 in 1975 to 1977 to 3.0 per 100 000 in 1996 to 1998. There was a 25% increase during the last 3 years of the study compared with the preceding 3 years (1993 to 1995). The increase affected most age groups above 40 years, with the greatest increase in the 45- to 49-year-old age group. White men had the greatest increase (31%) in the last time period (1996 to 1998) compared with 1993 to 1995. The Poisson regression model confirmed an almost 2-fold increase in the incidence rate ratio for hepatocellular carcinoma between 1975 to 1978 and 1996 to 1998. Conclusions: The incidence of hepatocellular carcinoma continues to increase rapidly in the United States, with rates increasing the fastest in white men 45 to 54 years of age. These findings are consistent with a true increase and could be explained by consequences of hepatitis C virus acquired during the 1960s and 1970s.