tbuckley/cabot-search huggingface dataset:
Regression of Tumor Growth and Induction of Long-Term Antitumor Memory by Interleukin 12 Electro-Gene Therapy
Authors: Shulin Li, Xinjian Zhang, Xueqing Xia
Journal: JNCI Journal of the National Cancer Institute (2002)

Background: Interleukin 12 (IL-12) is a proinflammatory cytokine with antitumor activity. Plasmid-based intratumoral gene therapy for treating malignancy with IL-12 or other genes is safe, inexpensive, and simple to carry out. However, effective delivery methods for injecting DNA plasmid into a tumor to generate therapeutic levels of gene product are lacking. To overcome this obstacle, we used electroporation to deliver the IL-12 gene intratumorally in a murine squamous cell carcinoma (SCC) model, SCCVII. Methods: Plasmids with or without mouse IL-12 gene were injected into SCCVII tumors of C3H/HeJ mice (n = 5 per group). Electric pulses were then applied to the tumors, a process termed electro-gene therapy. The first treatment was administered when the tumor reached 4–6 mm in diameter, and the second treatment followed a week later. The tumor size, survival, and ability to generate systemic antitumor memory were assessed at various time intervals. Changes in gene expression were measured using northern blot analysis, and vessel density and T-cell infiltration were examined by immunostaining. The results were analyzed by two-sided Student's t tests. Results: Electroporation of 20 μg or 40 μg of IL-12 DNA plasmid eradicated tumors in 40% of mice (P = .031 and .022, respectively). A total of six mice from two separate experiments with regressed tumors were challenged with homologous SCCVII tumor cells multiple times; three of six mice showed no tumor growth for more than 11 months and thus indicated the generation of antitumor memory in these mice. IL-12 electro-gene therapy was associated with increased expression of IL-12, interferon-γ, monokine induced by interferon-γ, and interferon-inducible protein 10. IL-12 electro-gene therapy was also associated with decreased vessel density and increased infiltration of CD8+ T cells after the second administration (P = .02 and .03, respectively). Conclusion: IL-12 electro-gene therapy appears to be effective in reducing tumor growth by triggering both antiangiogenic effects and an immune response. The antitumor memory was seen to last more than 11 months. Because IL-12 electro-gene therapy is easy to administer and is effective, it could potentially be applicable in the treatment of electrode-accessible malignancies, such as head and neck SCCs.
Implications of B7-H1 Expression in Clear Cell Carcinoma of the Kidney for Prognostication and Therapy
Authors: R. Houston Thompson, Haidong Dong, Eugene D. Kwon
Journal: Clinical Cancer Research (2007)

Abstract B7-H1 encompasses a recently discovered cell surface glycoprotein within the B7 family of T-cell coregulatory molecules. B7-H1 expression can be induced on activated T lymphocytes and is normally expressed by macrophage lineage cells. In addition, some human tumors acquire the ability to aberrantly express B7-H1. Tumor-associated B7-H1, as well as B7-H1 on activated lymphocytes, has been shown to impair antigen-specific T-cell function and survival in vitro. In contrast, in vivo monoclonal antibody–mediated blockade of B7-H1 has been shown to potentiate antitumoral responses in several murine cancer models. Consequently, tumor-associated B7-H1 has garnered much attention in the recent literature as a potential inhibitor of host antitumoral immunity. Our group has recently reported that B7-H1 is aberrantly expressed in both primary and metastatic renal cell carcinoma (RCC) as revealed via immunohistochemical staining of both fresh-frozen and paraffin-embedded nephrectomy specimens. In addition, we have shown that B7-H1 expression by clear cell RCC tumors (or infiltrating mononuclear cells) correlates with aggressive pathologic features, including advanced tumor-node-metastasis stage, tumor size, higher nuclear grade, and coagulative necrosis. In one study of 306 patients, with a median clinical follow-up of 11 years, we reported that RCC B7-H1 expression correlates with increased risk of disease progression, cancer-specific death, and overall mortality even after multivariate adjustment. Five-year cancer-specific survival rates in this study were 42% and 83% for patients harboring B7-H1+ versus B7-H1− RCC tumors, respectively. Such associations may relate to the recognized ability of B7-H1 to inhibit T-cell–mediated antitumoral immunity. In summary, B7-H1 encompasses a potent independent predictor of prognosis for patients with RCC and an extremely promising target to facilitate immunotherapeutic responses during the management of this treatment-refractory tumor.
Abstract 5051: Overexpression of talin 1 (<i>TLN1</i>) in invasive oral squamous cell carcinoma (OSCC)
Authors: Jim J. Sheu, Ming-Tsung Lai, Hsien-Chang Tseng, Ying-Ju Lin, Lei Wan, Chun-Hung Hua, Ming-Hsui Tsai, I-Wen Chiu, Nai-Wen Chang, Chin-Fen Lin, Chih-Mei Chen, Min-Min Lee, Fuu-Jen Tsai
Journal: Cancer Research (2010)

Abstract Oral squamous cell carcinoma (OSCC) is a highly invasive disease displaying frequent tumor recurrence and lymph node metastasis. Genes involved in cytoskeleton remodeling, cell attachment, and cell mobility are suspicious candidates that promote invasiveness. A genomewide study based on Sty1 250K SNP array platform revealed the involvement of TLN1 gene in the 9p13.3 amplicon. Although large scale screening on 123 tumor tissues by dual color-fluorescence in situ hybridization (FISH) indicated low frequency (around 7.3%) of TLN1 amplification in OSCC, the overall gene expression levels were significantly higher in tumor tissues as compared to the adjacent normal oral epithelium (P &amp;lt; 0.01). As compared to other cytoskeleton crossing linkers that can trigger integrin activation, TLN1 stood out to be the most highly expressed one in OSCC. A mouse study revealed that TLN1 overexpression could be detected in invasive tumors but not in the lesions at early stages. Immunohistochemistry (IHC) data revealed stronger TLN1 immunereactivity in OSCC than in normal tissues. More intense staining pattern was detected at the leading edge of cancer cells under going angiogenesis or lymphogenesis. Patients with TLN1 overexpression had a significantly shorter overall survival and higher recurrence rate than those without. Collectively, our study suggested an important role of TLN1 in oral cancer progression. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5051.
A Better-Quality Alternative
Authors: Gordon D. Schiff
Journal: JAMA (1994)

MANY MISCONSTRUE US health system reform options by presuming that "trade-offs" are needed to counterbalance the competing goals of increasing access, containing costs, and preserving quality.<sup>1,2</sup>Standing as an apparent paradox to this zero-sum equation are countries such as Canada that ensure access to all at a cost 40% per capita less, with satisfaction and outcomes as good as or better than those in the United States.<sup>3,4</sup>While the efficiencies of a single-payer universal program are widely acknowledged to facilitate simultaneous cost control and universal access, lingering concerns about quality have blunted support for this approach. See also p 797. Quality is of paramount importance to Americans. Opponents of reform appeal to fears of diminished quality, warning of waiting lists, rationing, and "government control."<sup>5</sup>Missing from more narrow discussions of the accuracy of such charges is a broader exploration of the quality implications of a universal health
Oesophageal acidification does not increase lower oesophageal sphincter pressure.
Authors: J F Helm, B T Massey, C J Martin, W J Dodds, W J Hogan, R C Arndorfer
Journal: Gut (1990)

We studied the effect of distal oesophageal acidification on lower oesophageal sphincter (LOS) pressure in normal human volunteers and in cats. The distal oesophagus was acidified by intraluminal injection of 0.1N HCl (pH 1.2). The LOS pressure was recorded by a sleeve device while pharyngeal and oesophageal pressures were monitored by nonperfused, water filled catheters. In normal human subjects, distal oesophageal acidification did not elicit a change in LOS pressure. In anaesthetised cats, injection of acid into the distal oesophagus elicited immediate LOS relaxation followed by a secondary peristaltic sequence. With propagation of the peristaltic sequence into the LOS, the LOS pressure abruptly increased 20-100 mmHg and gradually returned to the preinjection value over 15-180 s. In the one instance in which we were able to acidify the distal oesophagus without evoking secondary peristalsis, the LOS pressure did not change. Injection of saline into the distal oesophagus evoked a response in the LOS and oesophageal body that was indistinguishable from that seen with acid. We conclude that contrary to common belief, distal oesophageal acidification itself does not affect LOS pressure in man or the cat.
Concomitant Use of Antiplatelet Therapy with Dabigatran or Warfarin in the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) Trial
Authors: Antonio L. Dans, Stuart J. Connolly, Lars Wallentin, Sean Yang, Juliet Nakamya, Martina Brueckmann, Michael Ezekowitz, Jonas Oldgren, John W. Eikelboom, Paul A. Reilly, Salim Yusuf
Journal: Circulation (2012)

The Randomized Evaluation of Long-term Anticoagulation Therapy (RE-LY) trial showed that dabigatran etexilate 150 mg BID was superior and dabigatran etexilate 110 mg BID was noninferior to warfarin in preventing stroke and systemic embolism in patients with atrial fibrillation. In this subgroup analysis, we assess the efficacy and safety of dabigatran in patients who did and did not receive concomitant antiplatelets.All comparisons used a Cox proportional hazards model with adjustments made for risk factors for bleeding. A time-dependent analysis was performed when comparing patients with concomitant antiplatelets with those without. Of 18 113 patients, 6952 (38.4%) received concomitant aspirin or clopidogrel at some time during the study. Dabigatran etexilate 110 mg BID was noninferior to warfarin in reducing stroke and systemic embolism, whether patients received antiplatelets (hazard ratio [HR], 0.93; 95% confidence interval [95% CI], 0.70-1.25) or not (HR, 0.87; 95% CI, 0.66-1.15; interaction P=0.738). There were fewer major bleeds than warfarin in both subgroups (HR, 0.82; 95% CI, 0.67-1.00 for patients who used antiplatelets; HR, 0.79; 95% CI, 0.64-0.96 for patients who did not; interaction P=0.794). Dabigatran etexilate 150 mg BID reduced the primary outcome of stroke and systemic embolism in comparison with warfarin. This effect seemed attenuated among patients who used antiplatelets (HR, 0.80; 95% CI, 0.59-1.08) in comparison with those who did not (HR, 0.52; 95% CI, 0.38-0.72; P for interaction=0.058). Major bleeding was similar to warfarin regardless of antiplatelet use (HR, 0.93; 95% CI, 0.76-1.12 for patients who used antiplatelets; HR, 0.94; 95% CI, 0.78-1.15 for patients who did not; P for interaction=0.875). In the time-dependent analysis, concomitant use of a single antiplatelet seemed to increase the risk of major bleeding (HR, 1.60; 95% CI, 1.42-1.82). Dual antiplatelet seemed to increased this even more (HR, 2.31; 95% CI, 1.79-2.98). The absolute risks were lowest on dabigatran etexilate 110 mg BID in comparison with dabigatran etexilate 150 mg BID or warfarin.Concomitant antiplatelet drugs appeared to increase the risk for major bleeding in RE-LY without affecting the advantages of dabigatran over warfarin. Choosing between dabigatran etexilate 110 mg BID and dabigatran etexilate 150 mg BID requires a careful assessment of characteristics that influence the balance between benefit and harm.URL: http://clinicaltrials.gov. Unique identifier: NCT00262600.
Leukocyte-Reduced Red Blood Cell Transfusions in Patients With Anemia and Human Immunodeficiency Virus Infection&lt;SUBTITLE&gt;The Viral Activation Transfusion Study: A Randomized Controlled Trial&lt;/SUBTITLE&gt;
Authors: A C Collier, L A Kalish, M P Busch, T Gernsheimer, S F Assmann, T A Lane, D M Asmuth, M M Lederman, E L Murphy, P Kumar, M Kelley, T P Flanigan, D K McMahon, H S Sacks, M S Kennedy, P V Holland
Journal: JAMA (2001)

ContextAllogeneic blood transfusions have immunomodulatory effects and have been associated with activation of human immunodeficiency virus (HIV) and cytomegalovirus (CMV) in vitro and of HIV in small pilot studies. Retrospective studies suggest that transfusions adversely affect the clinical course of HIV. Data in selected non–HIV-infected patients requiring blood transfusion have suggested clinical benefit with leukocyte-reduced red blood cells (RBCs).ObjectiveTo compare the effects of leukoreduced and unmodified RBC transfusions on survival, complications of acquired immunodeficiency syndrome, and relevant laboratory markers in HIV-infected patients.Design and SettingDouble-blind randomized controlled trial conducted in 11 US academic medical centers from July 1995 through June 1999, with a median follow-up of 12 months (24 months in survivors).PatientsA total of 531 persons infected with HIV and CMV, aged 14 years or older, who required transfusions for anemia; 259 received leukoreduced transfusions and 262 received unmodified transfusions (10 did not receive the planned transfusion).Main Outcome MeasuresSurvival and change in plasma HIV RNA level 7 days after transfusion, compared by type of transfusion.ResultsAt entry, the groups were similar in demographic, clinical, and relevant laboratory characteristics. A total of 3864 RBC units were transfused. Two hundred eighty-nine deaths occurred (151 with leukoreduced transfusion; 138 with unmodified transfusion); median survival was 13.0 and 20.5 months, respectively (relative hazard [RH], 1.20; 95% confidence interval [CI], 0.95-1.51; log-rank P = .12). Analyses adjusted for prognostic factors suggested possible worse survival with leukoreduction (RH, 1.35; 95% CI, 1.06-1.72). There was no difference in time to new opportunistic event/death or frequency of transfusion reactions. No changes in plasma HIV RNA level were seen in either group at days 7, 14, 21, or 28, even in patients not taking antiretroviral drugs. There were no differences in trends between groups in CMV DNA, CD4 cell counts, activated (CD38% or human leukocyte antigen-DR) CD8 cell counts, or plasma cytokine levels.ConclusionsWe found no evidence of HIV, CMV, or cytokine activation following blood transfusion in patients with advanced HIV infection. Leukoreduction provided no clinical benefit in these patients. These data demonstrate the importance of conducting controlled studies of effects of leukoreduction in different patient populations, since smaller studies in other patient populations have suggested leukoreduction may be beneficial.
Prefrontal Cortical Deficits and Impaired Cognition-Emotion Interactions in Schizophrenia
Authors: Stefan Ursu, Ann M. Kring, Marja Germans Gard, Michael J. Minzenberg, Jong H. Yoon, J. Daniel Ragland, Marjorie Solomon, Cameron S. Carter
Journal: American Journal of Psychiatry (2011)

Objective: Despite schizophrenia patients' reports of diminished experience of emotion in interviews and self-report measures, their emotional experience in the presence of emotional stimuli and in daily life ("in the moment") appears largely intact. To examine emotion-cognition interactions, the authors tested the hypothesis that schizophrenia patients have unimpaired in-the-moment emotional reactivity but have a deficit in prefrontal cortical mechanisms needed to maintain and report on experience following exposure to emotional stimuli. Method: Using a slow event-related functional MRI paradigm, the authors examined the brain activity of 23 schizophrenia patients and 24 healthy comparison subjects during trials in which they viewed an affective picture and, after a delay, reported their emotional experience while viewing it. Results: The patients' self-reports of emotional experience differed from those of the healthy subjects when they rated their experience on dimensions inconsistent with the stimulus valence but not when the dimension was consistent with it. In the presence of emotional stimuli, brain activity in the patients was similar to that of the comparison subjects. During the delay, however, patients showed decreased activation in a network of brain structures, including the dorsolateral prefrontal cortex and other prefrontal, limbic, and paralimbic areas. In patients, the delay-related response of the dorsolateral prefrontal cortex to pleasant stimuli correlated negatively with an anhedonia measure. Conclusions: These results suggest that schizophrenia is characterized by a failure of prefrontal circuitry supporting the link between emotion and goal-directed behavior and that the failure of this mechanism may contribute to deficits in processes related to emotion-cognition interaction.
Endothelin-1 enhances calcium entry through T-type calcium channels in cultured neonatal rat ventricular myocytes.
Authors: T Furukawa, H Ito, J Nitta, M Tsujino, S Adachi, M Hiroe, F Marumo, T Sawanobori, M Hiraoka
Journal: Circulation Research (1992)

Endothelin-1 (ET-1), a 21-amino acid vasoconstrictive peptide, increases intracellular Ca2+ level and has hypertrophic action on ventricular myocytes. To elucidate a possible role of Ca2+ entry through sarcolemmal Ca2+ channels on this ET-1 action, we examined effects of ET-1 on L-type (ICa,L) and T-type (ICa,T) Ca2+ currents in cultured neonatal rat ventricular myocytes using the patch-clamp technique. ET-1 at a concentration of 10 nM increased the maximum current density of ICa,T from -3.0 +/- 1.4 microA/cm2 in the control condition to -4.4 +/- 1.6 microA/cm2 (p &lt; 0.01). Although the peak amplitude of ICa,L was decreased during ET-1 application (from -9.7 +/- 1.9 microA/cm2 in the control condition to -5.0 +/- 1.4 microA/cm2 [p &lt; 0.01]), this magnitude of decrease in ICa,T (52 +/- 19%) was comparable to that of spontaneous "run-down" of ICa,L (47 +/- 26%). The enhancement of ICa,T by ET-1 was dose dependent; it was initiated as low as 0.32 nM, and the maximal response was attained at approximately 10 nM, with a half-maximal dose of 1.26 nM. The enhancement of ICa,T by ET-1 was antagonized by protein kinase C inhibitors staurosporine (0.2 microM) and 1-(5-isoquinolinesulfonyl)-2-methylpiperazine (H-7, 20 microM) applied to the pipette solution. Extracellular application of tumor-promoting phorbol esters, phorbol 12,13-dibutyrate (PDBu) and 4 beta-phorbol 12-myristate 13-acetate, augmented ICa,T. PDBu (0.2 microM) increased the maximal current density of ICa,T from -4.2 +/- 0.5 microA/cm2 in the control condition to -5.5 +/- 1.0 microA/cm2 (p &lt; 0.01). In the presence of H-7 (20 microM) in the pipette solution, PDBu failed to enhance ICa,T, and an inactive isomer of PDBu (4 alpha-phorbol 12,13-dibutyrate, 0.2 microM) did not augment ICa,T. Thus, ET-1 enhances Ca2+ entry through the sarcolemmal T-type Ca2+ channel, possibly through a pathway involving activation of protein kinase C. This ET-1 action may be involved in the rise of the intracellular Ca2+ level and may contribute to the induction of cardiac hypertrophy by ET-1.
Hypervitaminosis D Mediates Compensatory Ca2+ Hyperabsorption in TRPV5 Knockout Mice
Authors: Kirsten Y. Renkema, Tom Nijenhuis, Bram C.J. van der Eerden, Annemiete W.C.M. van der Kemp, Harrie Weinans, Johannes P.T.M. van Leeuwen, René J.M. Bindels, Joost G.J. Hoenderop
Journal: Journal of the American Society of Nephrology (2005)

Vitamin D plays an important role in Ca2+ homeostasis by controlling Ca2+ (re)absorption in intestine, kidney, and bone. The epithelial Ca2+ channel TRPV5 mediates the Ca2+ entry step in active Ca2+ reabsorption. TRPV5 knockout (TRPV5−/−) mice show impaired Ca2+ reabsorption, hypercalciuria, hypervitaminosis D, and intestinal hyperabsorption of Ca2+. Moreover, these mice demonstrate upregulation of intestinal TRPV6 and calbindin-D9K expression compared with wild-type mice. For addressing the role of the observed hypervitaminosis D in the maintenance of Ca2+ homeostasis and the regulation of expression levels of the Ca2+ transport proteins in kidney and intestine, TRPV5/25-hydroxyvitamin-D3-1α-hydroxylase double knockout (TRPV5−/−/1α-OHase−/−) mice, which show undetectable serum 1,25(OH)2D3 levels, were generated. TRPV5−/−/1α-OHase−/− mice displayed a significant hypocalcemia compared with wild-type mice (1.10 ± 0.02 and 2.54 ± 0.01 mM, respectively; P < 0.05). mRNA levels of renal calbindin-D28K (7 ± 2%), calbindin-D9K (32 ± 4%), Na+/Ca2+ exchanger (12 ± 2%), and intestinal TRPV6 (40 ± 8%) and calbindin-D9K (26 ± 4%) expression levels were decreased compared with wild-type mice. Hyperparathyroidism and rickets were present in TRPV5−/−/1α-OHase−/− mice, more pronounced than observed in single TRPV5 or 1α-OHase knockout mice. It is interesting that a renal Ca2+ leak, as demonstrated in TRPV5−/− mice, persisted in TRPV5−/−/1α-OHase−/− mice, but a compensatory upregulation of intestinal Ca2+ transporters was abolished. In conclusion, the elevation of serum 1,25(OH)2D3 levels in TRPV5−/− mice is responsible for the upregulation of intestinal Ca2+ transporters and Ca2+ hyperabsorption. Hypervitaminosis D, therefore, is of crucial importance to maintain normocalcemia in impaired Ca2+ reabsorption in TRPV5−/− mice.
High-Dose Recombinant Apolipoprotein A-I <sub>Milano</sub> Mobilizes Tissue Cholesterol and Rapidly Reduces Plaque Lipid and Macrophage Content in Apolipoprotein E–Deficient Mice
Authors: Prediman K. Shah, Juliana Yano, Odette Reyes, Kuang-Yuh Chyu, Sanjay Kaul, Charles L. Bisgaier, Sandra Drake, Bojan Cercek
Journal: Circulation (2001)

Background —Repeated doses of recombinant apolipoprotein A-I Milano phospholipid complex (apoA-I m ) reduce atherosclerosis and favorably change plaque composition in rabbits and mice. In this study, we tested whether a single high dose of recombinant apoA-I m could rapidly mobilize tissue cholesterol and reduce plaque lipid and macrophage content in apoE-deficient mice. Methods and Results —High cholesterol–fed, 26-week-old apoE-deficient mice received a single intravenous injection of saline (n=16), 1080 mg/kg dipalmitoylphosphatidylcholine (DPPC; n=14), or 400 mg/kg of recombinant apoA-I m complexed with DPPC (1:2.7 weight ratio; n=18). Blood was sampled before and 1 and 48 hours after injection, and aortic root plaques were evaluated for lipid content and macrophage content after oil-red O and immunostaining, respectively. One hour after injection, the plasma cholesterol efflux–promoting capacity was nearly 2-fold higher in recombinant apoA-I m –treated mice compared with saline and DPPC-treated mice ( P &lt;0.01). Compared with baseline values, serum free cholesterol, an index of tissue cholesterol mobilization, increased 1.6-fold by 1 hour after recombinant apoA-I m injection, and it remained significantly elevated at 48 hours ( P &lt;0.01). Mice receiving recombinant apoA-I m had 40% to 50% lower lipid content ( P &lt;0.01) and 29% to 36% lower macrophage content ( P &lt;0.05) in their plaques compared with the saline- and DPPC-treated mice, respectively. Conclusions —A single high dose of recombinant apoA-I m rapidly mobilizes tissue cholesterol and reduces plaque lipid and macrophage content in apoE-deficient mice. These findings suggest that this strategy could rapidly change plaque composition toward a more stable phenotype.