tbuckley/cabot-search huggingface dataset:
Adenovirus-Mediated Retinoblastoma 94 Gene Transfer Induces Human Pancreatic Tumor Regression in a Mouse Xenograft Model
Authors: Josep Maria Roig, Miguel Angel Molina, Anna Cascante, Joaquim Calbó, Neus Carbó, Uwe Wirtz, Sunil Sreedharan, Cristina Fillat, Adela Mazo
Journal: Clinical Cancer Research (2004)

Abstract Purpose: Gene transfer of a truncated variant of the retinoblastoma (RB) gene encoding a Mr 94,000 protein that lacks the NH2-terminal 112 amino acid residues, termed RB94, has been shown to inhibit proliferation of several human tumor cell types. We have assessed its therapeutic effectiveness on pancreatic cancer, one of the most aggressive and therapy-resistant types of cancer. For this purpose, preclinical studies aimed to evaluate the therapeutic potential of RB94 gene transfer in pancreatic cancer were carried out. Experimental Design: We have compared the antiproliferative effects of adenovirus-mediated gene transfer of RBwt and RB94 at the in vitro and in vivo levels in three RB-positive human pancreatic tumor cell lines: (a) NP-9; (b) NP-18; and (c) NP-31. We have also examined their effects on cell cycle and their capacity to induce apoptosis. Results: In vitro results indicate that RB94 gene transfer has stronger antiproliferative effects compared with RBwt. RB94 transduction correlated with accumulation at the S-G2 phase of the cell cycle in the three cell lines tested and induction of apoptosis in two of them. In vivo studies show significant decreases in the growth rate of tumors treated with Ad-RB94 when compared with those treated with Ad-RBwt. Moreover, terminal deoxynucleotidyl transferase-mediated nick end labeling analyses of Ad-RB94-treated tumor sections revealed that only RB94 is able to significantly induce apoptosis. Conclusions: RB94 gene expression has antiproliferative effects also in human pancreatic tumor cells, being more effective than wild-type RB in preventing tumor growth.
Cancer and Leukemia Group B 90206
Authors: Brian I. Rini, Susan Halabi, John Taylor, Eric J. Small, Richard L. Schilsky
Journal: Clinical Cancer Research (2004)

Abstract The majority of sporadic clear cell renal cell carcinoma (RCC) is characterized by loss of heterozygosity of the von Hippel-Lindau (VHL) tumor suppressor gene and somatic inactivation of the remaining VHL allele. The resulting VHL gene silencing leads to induction of hypoxia-regulated genes including vascular endothelial growth factor (VEGF). Thus, therapeutic inhibition of VEGF holds promise for treatment of this historically refractory malignancy. An antibody to VEGF (bevacizumab, Avastin) has demonstrated a significant prolongation of time to disease progression compared with placebo in patients with metastatic RCC. Interferon-α (IFN-α) is a standard initial cytokine therapy in RCC with a modest response rate and a survival advantage demonstrated in randomized trials. We hypothesized that the addition of anti-VEGF therapy to IFN-α would prolong survival in untreated metastatic RCC patients. A Phase III trial is now being conducted randomizing untreated, metastatic clear cell RCC patients to IFN-α alone or IFN-α plus Avastin.
Age-related macular degeneration: what do patients find on the internet?
Authors: C. A Rennie, S. Hannan, N. Maycock, C. Kang
Journal: Journal of the Royal Society of Medicine (2007)

ObjectiveTo assess the quality of information and readability of the top internet sites for age-related macular degeneration (AMD). DesignAn examination of the technical information provision, quality and readability of websites found during an internet search for ‘age-related macular degeneration’. Main outcome measuresTechnical information and quality were assessed using a simple grading system. Readability was assessed using a Simple Measure Of Gobbledygook (SMOG) rating. ResultsTwelve organizational, seven academic and seven commercial sites were identified. The average technical scores were 82.3%, 67.9% and 65.2% for each type of site, respectively (P=0.097, one way ANOVA). The average quality scores were 62.2%, 62.6%, and 49.5% for each type of site, respectively (P=0.356, one-way ANOVA). The average SMOG ratings were 16.3, 16.1, and 16.2 for each type of site, respectively (P=0.983, one-way ANOVA). Fifteen of the sites provided details of new and emerging treatments, with seven providing a detailed discussion. ConclusionsMany websites are now meeting the challenge of providing comprehensive information about AMD and its new treatments. Quality scores were disappointing, with sites needing to provide more evidence of authorship and attribution of information. The majority of sites had SMOG scores above 10, making them difficult for the average person to understand. As physicians we need to help design and direct patients to sites that provide high quality, current information.
Prostate Stem Cell Antigen Vaccination Induces a Long-term Protective Immune Response against Prostate Cancer in the Absence of Autoimmunity
Authors: Maria de la Luz Garcia-Hernandez, Andrew Gray, Bolyn Hubby, Otto J. Klinger, W. Martin Kast
Journal: Cancer Research (2008)

Prostate stem cell antigen (PSCA) is an attractive antigen to target using therapeutic vaccines because of its overexpression in prostate cancer, especially in metastatic tissues, and its limited expression in other organs. Our studies offer the first evidence that a PSCA-based vaccine can induce long-term protection against prostate cancer development in prostate cancer-prone transgenic adenocarcinoma mouse prostate (TRAMP) mice. Eight-week-old TRAMP mice displaying prostate intraepithelial neoplasia were vaccinated with a heterologous prime/boost strategy consisting of gene gun-delivered PSCA-cDNA followed by Venezuelan equine encephalitis virus replicons encoding PSCA. Our results show the induction of an immune response against a newly defined PSCA epitope that is mediated primarily by CD8 T cells. The prostates of PSCA-vaccinated mice were infiltrated by CD4-positive, CD8-positive, CD11b-positive, and CD11c-positive cells. Vaccination induced MHC class I expression and cytokine production [IFN-gamma, tumor necrosis factor-alpha, interleukin 2 (IL-2), IL-4, and IL-5] within prostate tumors. This tumor microenvironment correlated with low Gleason scores and weak PSCA staining on tumor cells present in hyperplastic zones and in areas that contained focal and well-differentiated adenocarcinomas. PSCA-vaccinated TRAMP mice had a 90% survival rate at 12 months of age. In contrast, all control mice had succumbed to prostate cancer or had heavy tumor loads. Crucially, this long-term protective immune response was not associated with any measurable induction of autoimmunity. The possibility of inducing long-term protection against prostate cancer by vaccination at the earliest signs of its development has the potential to cause a dramatic paradigm shift in the treatment of this disease.
Nfil3/E4bp4 is required for the development and maturation of NK cells in vivo
Authors: Shintaro Kamizono, Gordon S. Duncan, Markus G. Seidel, Akira Morimoto, Koichi Hamada, Gerard Grosveld, Koichi Akashi, Evan F. Lind, Jillian P. Haight, Pamela S. Ohashi, A. Thomas Look, Tak W. Mak
Journal: The Journal of Experimental Medicine (2009)

Nuclear factor interleukin-3 (Nfil3; also known as E4-binding protein 4) is a basic region leucine zipper transcription factor that has antiapoptotic activity in vitro under conditions of growth factor withdrawal. To study the role of Nfil3 in vivo, we generated gene-targeted Nfil3-deficient (Nfil3−/−) mice. Nfil3−/− mice were born at normal Mendelian frequency and were grossly normal and fertile. Although numbers of T cells, B cells, and natural killer (NK) T cells were normal in Nfil3−/− mice, a specific disruption in NK cell development resulted in severely reduced numbers of mature NK cells in the periphery. This defect was NK cell intrinsic in nature, leading to a failure to reject MHC class I–deficient cells in vivo and reductions in both interferon γ production and cytolytic activity in vitro. Our results confirm the specific and essential requirement of Nfil3 for the development of cells of the NK lineage.
MECHANISM OF UREA EXCRETION
Authors: Jean Oliver
Journal: The Journal of Experimental Medicine (1921)

1. Urea is present in the cells of the proximal convoluted tubule in a concentration higher than that of the blood or than that of the cells of any of the other kidney tubules. 2. Such a condition can only be reconciled to an assumption of an active secretion (excretion) on the part of these cells. 3. Urea also passes through the glomerular filter with the other crystalloids of the blood plasma. 4. The final concentration of urea is due to the above mentioned secretion by the proximal convoluted tubule, and to the absorption of water in other parts of the tubule.
Postmenopausal Hormone Therapy Is Associated with a Reduced Risk of Colorectal Cancer Lacking CDKN1A Expression
Authors: Jennifer H. Lin, Teppei Morikawa, Andrew T. Chan, Aya Kuchiba, Kaori Shima, Katsuhiko Nosho, Gregory Kirkner, Shumin M. Zhang, JoAnn E. Manson, Edward Giovannucci, Charles S. Fuchs, Shuji Ogino
Journal: Cancer Research (2012)

Abstract Experimental studies have shown that estrogen- or progesterone-activated signaling leads to growth inhibition effects on colon cancer cells through the upregulation of several cell-cycle regulators. However, epidemiologic studies evaluating hormone therapy use and colorectal cancer risk by the status of cell-cycle regulators are lacking. In this study, we used data from the prospective Nurses' Health Study to evaluate whether the association between hormone therapy use and colorectal cancer risk differs by the molecular pathologic status of microsatellite instability (MSI) and expression of cell-cycle–related tumor biomarkers, including CDKN1A (p21, CIP1), CDKN1B (p27, KIP1), and TP53 (p53) by immunohistochemistry. Duplication Cox regression analysis was used to determine an association between hormone therapy use, cancer risk, and specific tumor biomarkers in 581 incident colon and rectal cancer cases that occurred during 26 years of follow-up among 105,520 postmenopausal women. We found a difference between hormone therapy use and colorectal cancer risk according to CDKN1A expression (Pheterogeneity = 0.01). Current hormone therapy use was associated with a reduced risk for CDKN1A-nonexpressed [multivariate relative risk (RR), 0.61; 95% confidence interval (CI), 0.46–0.82] but not for CDKN1A-expressed (RR, 1.32; 95% CI, 0.76–2.31) tumors. The lower risk for CDKN1A-nonexpressed but not for CDKN1A-expressed cancers was also present among current users of estrogen-alone therapy. We found no significant difference in the relations between hormone therapy use and cancer risk according to MSI, CDKN1B, or TP53 status. Together, our molecular pathological epidemiology findings suggest a preventive effect of hormone therapy against colorectal carcinogenesis that depends, in part, on loss of cyclin-dependent kinase inhibitor CDKN1A. Cancer Res; 72(12); 3020–8. ©2012 AACR.
Timing of Antiretroviral Therapy after Diagnosis of Cryptococcal Meningitis
Authors: David R. Boulware, David B. Meya, Conrad Muzoora, Melissa A. Rolfes, Katherine Huppler Hullsiek, Abdu Musubire, Kabanda Taseera, Henry W. Nabeta, Charlotte Schutz, Darlisha A. Williams, Radha Rajasingham, Joshua Rhein, Friedrich Thienemann, Melanie W. Lo, Kirsten Nielsen, Tracy L. Bergemann, Andrew Kambugu, Yukari C. Manabe, Edward N. Janoff, Paul R. Bohjanen, Graeme Meintjes
Journal: New England Journal of Medicine (2014)

Cryptococcal meningitis accounts for 20 to 25% of acquired immunodeficiency syndrome-related deaths in Africa. Antiretroviral therapy (ART) is essential for survival; however, the question of when ART should be initiated after diagnosis of cryptococcal meningitis remains unanswered.We assessed survival at 26 weeks among 177 human immunodeficiency virus-infected adults in Uganda and South Africa who had cryptococcal meningitis and had not previously received ART. We randomly assigned study participants to undergo either earlier ART initiation (1 to 2 weeks after diagnosis) or deferred ART initiation (5 weeks after diagnosis). Participants received amphotericin B (0.7 to 1.0 mg per kilogram of body weight per day) and fluconazole (800 mg per day) for 14 days, followed by consolidation therapy with fluconazole.The 26-week mortality with earlier ART initiation was significantly higher than with deferred ART initiation (45% [40 of 88 patients] vs. 30% [27 of 89 patients]; hazard ratio for death, 1.73; 95% confidence interval [CI], 1.06 to 2.82; P=0.03). The excess deaths associated with earlier ART initiation occurred 2 to 5 weeks after diagnosis (P=0.007 for the comparison between groups); mortality was similar in the two groups thereafter. Among patients with few white cells in their cerebrospinal fluid (<5 per cubic millimeter) at randomization, mortality was particularly elevated with earlier ART as compared with deferred ART (hazard ratio, 3.87; 95% CI, 1.41 to 10.58; P=0.008). The incidence of recognized cryptococcal immune reconstitution inflammatory syndrome did not differ significantly between the earlier-ART group and the deferred-ART group (20% and 13%, respectively; P=0.32). All other clinical, immunologic, virologic, and microbiologic outcomes, as well as adverse events, were similar between the groups.Deferring ART for 5 weeks after the diagnosis of cryptococcal meningitis was associated with significantly improved survival, as compared with initiating ART at 1 to 2 weeks, especially among patients with a paucity of white cells in cerebrospinal fluid. (Funded by the National Institute of Allergy and Infectious Diseases and others; COAT ClinicalTrials.gov number, NCT01075152.).
Trauma, Resilience, and Recovery in a High-Risk African-American Population
Authors: Tanya N. Alim, Adriana Feder, Ruth Elaine Graves, Yanping Wang, James Weaver, Maren Westphal, Angelique Alonso, Notalelomwan U. Aigbogun, Bruce W. Smith, John T. Doucette, Thomas A. Mellman, William B. Lawson, Dennis S. Charney
Journal: American Journal of Psychiatry (2008)

Despite increased risk for psychiatric disorders after trauma exposure, many people are able to adapt with minimal life disruption, and others eventually recover after a symptomatic period. This study examined psychosocial factors associated with resilience and recovery from psychiatric disorders in a high-risk sample of African American adults exposed to a range of severe traumas, who participated in structured diagnostic interviews.The sample included 259 patients exposed to at least one severe traumatic event, recruited from primary care offices at Howard University and administered the Structured Clinical Interview for DSM-IV Axis I disorders. Multinomial logistic regression was used to identify potential psychosocial factors associated with resilience and recovery, including purpose in life, mastery, and coping strategies.Forty-seven patients had no lifetime psychiatric disorders (resilient), 85 met criteria for at least one past DSM-IV disorder but no current disorders (recovered), and 127 met criteria for at least one current DSM-IV disorder (currently ill). The resilient group was characterized by a significantly lower lifetime trauma load. Female gender was predictive of currently ill status. In the final model, purpose in life emerged as a key factor associated with both resilience and recovery, and mastery was also significantly associated with recovery.The identification of psychosocial factors associated with resistance to severe trauma can inform future studies of preventive and treatment interventions for high-risk populations. Further study is needed to determine which psychosocial factors are consistently associated with resilience and to what extent they can be modified through clinical intervention.
Insulin resistance affects the cytoprotective effect of insulin in cardiomyocytes through an impairment of MAPK phosphatase-1 expression
Authors: C MORISCO, C MARRONE, V TRIMARCO, S CRISPO, M MONTI, J SADOSHIMA, B TRIMARCO
Journal: Cardiovascular Research (2007)

Insulin protects cardiomyocytes from apoptosis. Insulin resistance usually refers to a defect in the ability of insulin to stimulate glucose uptake. It is unknown, however, whether or not insulin resistance compromises the cell-protective effect of the hormone. Caspases are a family of cysteine proteases that regulate apoptosis. We explored the effects of insulin resistance on hypoxia-induced caspase-3 activation in cardiomyocytes.Experiments were performed in cultured neonatal rat cardiomyocytes. Insulin resistance was induced by treating cardiac myocytes with isoproterenol, a beta-adrenergic receptor agonist.Twelve hours of hypoxia-induced caspase-3 cleavage, which was inhibited by treatment with insulin, while pre-treatment with isoproterenol abolished the insulin effect. Hypoxia-induced cleavage of caspase-3 was mediated by p38 mitogen-activated protein kinase (MAPK). Insulin inhibited hypoxia-induced phosphorylation of p38 through MAPK phosphatase-1 (MKP-1). Insulin-induced MKP-1 expression was mediated by extracellular signal-regulated protein kinases (ERK) 1/2, c-Jun NH2-terminal kinases (JNK) MAPK, and phosphatidylinositol 3-kinase (PI3K)/Akt pathways. Isoproterenol stimulation failed to induce expression of MKP-1; moreover, insulin resistance induced by long-term beta-adrenergic stimulation inhibited insulin-evoked expression of MKP-1 by impairing insulin-induced phosphorylation of both ERK1/2 and JNK without affecting Akt kinase activity. Furthermore, concomitant activation of Akt, ERK 1/2, and JNK was required for insulin to exert its protective effect against the hypoxia-induced cleavage of caspase-3.The results of this study lead to the conclusions that, in cardiac myocytes, antiapoptotic signals induced by insulin are mediated by more than one signaling pathway, and that long-term beta-adrenergic receptor stimulation impairing some of these pathways affects the cytoprotective action of insulin.
Risk of Esophageal Adenocarcinoma Decreases With Height, Based on Consortium Analysis and Confirmed by Mendelian Randomization
Authors: Aaron P. Thrift, Harvey A. Risch, Lynn Onstad, Nicholas J. Shaheen, Alan G. Casson, Leslie Bernstein, Douglas A. Corley, David M. Levine, Wong–Ho Chow, Brian J. Reid, Yvonne Romero, Laura J. Hardie, Geoffrey Liu, Anna H. Wu, Nigel C. Bird, Marilie D. Gammon, Weimin Ye, David C. Whiteman, Thomas L. Vaughan
Journal: Clinical Gastroenterology and Hepatology (2014)
Predicting Retroperitoneal Histology in Postchemotherapy Testicular Germ Cell Cancer: A Model Update and Multicentre Validation with More Than 1000 Patients
Authors: Yvonne Vergouwe, Ewout W. Steyerberg, Richard S. Foster, Dirk T. Sleijfer, Sophie D. Fosså, Arthur Gerl, Ronald de Wit, J. Trevor Roberts, J. Dik F. Habbema
Journal: European Urology (2006)
Acute Suppurative Middle-Ear Disease in Infancy
Authors: J. H. Marsh
Journal: BMJ (1897)

no further indication is required.In passing, it may be said that when this sodden appearance is present, and the knife cuts not crisply but as if passing through soaked blotting-paper, the opening thus made is frequently permanent, or at any rate remains for long periods; for the membrane has become so disorganised as to impair its tendency to repair.
Hamstring muscle strain injuries: what can we learn from history?
Authors: Bruce Hamilton
Journal: British Journal of Sports Medicine (2012)

Hamstring muscle strain injuries remain one of the most challenging issues facing sports medicine.1 Over the past 100 years, there has been a gradual evolution in our understanding and management of hamstring injuries, but the challenge of optimising the management of the acutely injured hamstring remains. In recent years, increasingly high-quality studies have addressed the aetiology, risk factors and management of hamstring strains.2,–,6 Paradoxically, many popular treatment options have little evidence and remain controversial.7,–,10 The history of hamstring injury management is characterised as a longstanding dissociation between popular clinical techniques and a limited evidence base. Taking a historical perspective on the management of hamstring muscle strains, this study aims to place the current management strategies in a temporal perspective.

> “Those who cannot remember the past are condemned to repeat it”. George Santayana, Philosopher, 1863 to 1952 

By the mid-18th century, the importance of exercise for health was established, and the physical demands of different forms of exercise were recognised, in a manner not dissimilar to descriptions 200 years later.11 ,12 By the start of the 20th century, the Olympics had been re-invented, sport and exercise were recognised as a means of developing character13 and maintaining health in a world experiencing an explosion in leisure time.14,–,16 Given the limitations of the training methodology of the time,17 it is possible that muscle strains were a common finding, but there is limited epidemiological literature available from the time.

> “ In football we find injuries occur in a poorly conditioned, a fatigued or dazed man, or in a team that is demoralised and receiving a severe beating. These individuals are slowing up, not coordinating, and are apt to be injured .”18

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Ranolazine for Congenital and Acquired Late I <sub>Na</sub> -Linked Arrhythmias
Authors: Jonathan D. Moreno, Pei-Chi Yang, John R. Bankston, Eleonora Grandi, Donald M. Bers, Robert S. Kass, Colleen E. Clancy
Journal: Circulation Research (2013)

The antianginal ranolazine blocks the human ether-a-go-go-related gene-based current IKr at therapeutic concentrations and causes QT interval prolongation. Thus, ranolazine is contraindicated for patients with preexisting long-QT and those with repolarization abnormalities. However, with its preferential targeting of late INa (INaL), patients with disease resulting from increased INaL from inherited defects (eg, long-QT syndrome type 3 or disease-induced electric remodeling (eg, ischemic heart failure) might be exactly the ones to benefit most from the presumed antiarrhythmic properties of ranolazine.We developed a computational model to predict if therapeutic effects of pharmacological targeting of INaL by ranolazine prevailed over the off-target block of IKr in the setting of inherited long-QT syndrome type 3 and heart failure.We developed computational models describing the kinetics and the interaction of ranolazine with cardiac Na(+) channels in the setting of normal physiology, long-QT syndrome type 3-linked ΔKPQ mutation, and heart failure. We then simulated clinically relevant concentrations of ranolazine and predicted the combined effects of Na(+) channel and IKr blockade by both the parent compound ranolazine and its active metabolites, which have shown potent blocking effects in the therapeutically relevant range. Our simulations suggest that ranolazine is effective at normalizing arrhythmia triggers in bradycardia-dependent arrhythmias in long-QT syndrome type 3 as well tachyarrhythmogenic triggers arising from heart failure-induced remodeling.Our model predictions suggest that acute targeting of INaL with ranolazine may be an effective therapeutic strategy in diverse arrhythmia-provoking situations that arise from a common pathway of increased pathological INaL.