tbuckley/cabot-search huggingface dataset:
Abstract 3659: Next generation sulindac.
Authors: Nan Li, Yaguang Xi, Heather N. Tinsley, Evrim Gurpinar, Bernard D. Gary, Bing Zhu, Yonghe Li, Adam B. Keeton, William E. Grizzle, Gary A. Piazza
Journal: Cancer Research (2013)

Abstract Sulindac displays promising antineoplastic activity, but toxicity from cyclooxygenase (COX) inhibition limits its long-term use for chemoprevention. Previous studies have concluded that the tumor cell growth inhibitory activity of sulindac is COX-independent and suggest that safer and more efficacious drugs can be developed by targeting the underlying mechanism. Here we report that sulindac sulfide (SS) inhibits cyclic guanosine monophosphate phosphodiesterase (cGMP PDE) activity, increases intracellular cGMP levels and activates protein kinase G at concentrations that suppress proliferation and induce apoptosis of colon tumor cells. Normal colonocytes were refractory to the anti-proliferative and pro-apoptotic effects of SS as well as its ability to induce cGMP signaling. PDE5-specific inhibitors such as tadalafil also inhibited the growth of colon tumor cells that expressed high levels of the cGMP-specific PDE5 isozyme compared with colonocytes. RNAi knockdown of PDE5 selectively inhibited proliferation and induced apoptosis of colon tumor cells as did SS. SS, 8-bromo-cGMP, and PDE5 siRNA reduced β-catenin levels, as well as the expression of cyclin D and survivin that are regulated by β-catenin-dependent TCF transcriptional activity by a mechanism involving the transcriptional repression of β-catenin. The significance of these findings are highlighted by studies in the FCCC Min mouse model of intestinal tumorigenesis showing that a novel non-COX inhibitory derivative of SS can strongly inhibit colon tumor formation by a mechanism that appears to involve cGMP PDE inhibition. These observations suggest that safer and more efficacious drugs can be developed for colorectal cancer chemoprevention by targeting PDE5 and possibly other cGMP degrading isozymes. Citation Format: Nan Li, Yaguang Xi, Heather N. Tinsley, Evrim Gurpinar, Bernard D. Gary, Bing Zhu, Yonghe Li, Adam B. Keeton, William E. Grizzle, Gary A. Piazza. Next generation sulindac. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3659. doi:10.1158/1538-7445.AM2013-3659
Hb Q‐Thailand‐Hb H disease in a chinese living in Geneva, Switzerland: Characterization of the variant and identification of the two α‐thalassemic chromosomes
Authors: P. Beris, P. Huber, P. A. Miescher, J. B. Wilson, A. Kutlar, S. S. Chen, T. H. J. Huisman
Journal: American Journal of Hematology (1987)

Abstract Data on a 24‐year‐old Chinese male with Hb Q‐Thailand‐Hb H disease are presented. The hemoglobin variant was characterized by fast microprocedures, mainly by reverse‐phase high‐performance liquid chromatography. Gene mapping analyses identified the α‐thalassemia‐2, which is associated with the α‐Q chain, as caused by a 4.2‐kb deletion involving the α2 globin gene, while the α‐thalassemia‐1 anomaly was the common Southeast Asian type in which part of the Ψζ, the Ψα, and the α2 and α1 globin genes are deleted.
Directed Evolution of Adeno-associated Virus for Enhanced Gene Delivery and Gene Targeting in Human Pluripotent Stem Cells
Authors: Prashanth Asuri, Melissa A Bartel, Tandis Vazin, Jae-Hyung Jang, Tiffany B Wong, David V Schaffer
Journal: Molecular Therapy (2011)

Efficient approaches for the precise genetic engineering of human pluripotent stem cells (hPSCs) can enhance both basic and applied stem cell research. Adeno- associated virus (AAV) vectors are of particular interest for their capacity to mediate efficient gene delivery to and gene targeting in various cells. However, natural AAV serotypes offer only modest transduction of human embryonic and induced pluripotent stem cells (hESCs and hiPSCs), which limits their utility for efficiently manipulating the hPSC genome. Directed evolution is a powerful means to generate viral vectors with novel capabilities, and we have applied this approach to create a novel AAV variant with high gene delivery efficiencies (~50%) to hPSCs, which are importantly accompanied by a considerable increase in gene-targeting frequencies, up to 0.12%. While this level is likely sufficient for numerous applications, we also show that the gene-targeting efficiency mediated by an evolved AAV variant can be further enhanced (>1%) in the presence of targeted double- stranded breaks (DSBs) generated by the co-delivery of artificial zinc finger nucleases (ZFNs). Thus, this study demonstrates that under appropriate selective pressures, AAV vectors can be created to mediate efficient gene targeting in hPSCs, alone or in the presence of ZFN- mediated double-stranded DNA breaks. Efficient approaches for the precise genetic engineering of human pluripotent stem cells (hPSCs) can enhance both basic and applied stem cell research. Adeno- associated virus (AAV) vectors are of particular interest for their capacity to mediate efficient gene delivery to and gene targeting in various cells. However, natural AAV serotypes offer only modest transduction of human embryonic and induced pluripotent stem cells (hESCs and hiPSCs), which limits their utility for efficiently manipulating the hPSC genome. Directed evolution is a powerful means to generate viral vectors with novel capabilities, and we have applied this approach to create a novel AAV variant with high gene delivery efficiencies (~50%) to hPSCs, which are importantly accompanied by a considerable increase in gene-targeting frequencies, up to 0.12%. While this level is likely sufficient for numerous applications, we also show that the gene-targeting efficiency mediated by an evolved AAV variant can be further enhanced (>1%) in the presence of targeted double- stranded breaks (DSBs) generated by the co-delivery of artificial zinc finger nucleases (ZFNs). Thus, this study demonstrates that under appropriate selective pressures, AAV vectors can be created to mediate efficient gene targeting in hPSCs, alone or in the presence of ZFN- mediated double-stranded DNA breaks.
Polyposis of Gastro-intestinal Tract: the Peutz Syndrome
Authors: D. Bailey
Journal: BMJ (1957)

JOUaRNALThe study of sudden amnesia indicates that it is not possible to draw any sharp dividing-line between organic and functional disabilities and that it is not always possible to distinguish clinically the causes of pathological forgetting. SummaryThe aetiology of sudden loss of memory has been investigated in two series of cases, totalling 74 patients who were submitted to a full neurological and psychiatric examination.In both series a large proportion suffered from un- detected gross organic nervous disease.In the majority, whether organic disease was present or not, a simple psychogenic cause was found and the amnesia could be demonstrated to be a psychological escape mechanism.There is evidence that organic nervous disease may pre- dispose to this type of psychological mechanism.Sudden amnesia is a temporary state that responds well to simple psychotherapy, which can be given, if necessary, in a casualty department.It is essential in such cases to seek the causes of the patient's underlying maladjustment not only in his life and circumstances but in his central nervous system as well.
Acute Varicella Infection Mimics Recurrent Hodgkin's Disease on F-18 FDG PET/CT
Authors: Niall Sheehy, David A. Israel
Journal: Clinical Nuclear Medicine (2007)

We report a case where acute varicella infection, chickenpox, mimics the findings of recurrent Hodgkin disease on F-18 FDG PET/CT. A 28-year-old man with a history of Hodgkin disease in remission had fatigue, pyrexia, and a raised ESR. His F-18 FDG PET/CT, performed to exclude lymphoma recurrence, demonstrated FDG-avid lymphadenopathy and increased FDG uptake in his spleen. A day later he developed the generalized rash of acute varicella infection. This was managed with valacyclovir. Repeat F-18 FDG PET/CT done 1 month later showed no evidence of FDG-avid disease. In this patient the stimulation of an immune response by the acute viral infection mimics recurrent lymphoma.
Abstract LB-387: Blockade of the CXCL12/CXCR4 axis with AMD3100 induces multimodal antitumor effects in murine ovarian cancer and prolongs survival
Authors: Satoshi Kashiwagi, Elda Righi, Jianping Yuan, Michael Santosuosso, Rachel Ingraham, Sandra Orsulic, Michael Birrer, Richard Penson, Glenn Dranoff, Mark C. Poznansky
Journal: Cancer Research (2011)

Abstract The chemokine, CXCL12, and its receptor, CXCR4, have been shown to be expressed by various tumors including ovarian cancer. CXCL12/CXCR4 expression by tumors has been associated with enhanced progression including tumor cell proliferation, invasion, and angiogenesis. We proposed that modulation of the CXCL12/CXCR4 axis in ovarian cancer would have multimodal effects on tumor pathogenesis. This was addressed using RNAi technology and a selective CXCR4 antagonist, AMD3100, in an immunocompetent mouse model of intraperitoneal papillary epithelial ovarian cancer derived from a syngeneic cell line (BR5–1) that constitutively expresses both CXCL12 and CXCR4. CXCL12 knockdown of BR5–1 cells using RNAi reduced cell proliferation in vitro (p&amp;lt;0.01) and tumor growth in vivo (p&amp;lt;0.05) compared to controls. AMD3100 treatment of BR5–1-derived tumors resulted in the increase of tumor apoptosis (p&amp;lt;0.05)and necrosis and in a significant reduction of intraperitoneal dissemination, angiogenesis, and intratumoral infiltration of FoxP3+ regulatory T cells compared to controls (T-regs)(p &amp;lt; 0.05). In addition, selective CXCR4 blockade with AMD3100 resulted in significantly increased anti-tumor T cell mediated immune responses compared to controls (p&amp;lt;0.05). These multimodal anti-tumor effects translated into a significant survival advantage in AMD3100-treated mice as compared to controls (p&amp;lt;0.05). Selective CXCR4 antagonism also significantly decreased intratumoral T-regs infiltration in a second model of aggressive melanoma (p&amp;lt;0.05). In summary, these data generated in an immunocompetent syngeneic and orthotopic murine model of ovarian cancer lend important support to the view that the CXCL12/CXCR4 axis plays multiple roles in the pathogenesis of this disease. Furthermore, the availability of a safe, effective and clinically applicable CXCR4 antagonist in AMD3100 adds both to the direct clinical translatability of this study and to the potential for the use of this agent as an adjunct to conventional chemotherapy or in combination with other immunotherapies aimed at enhancing CD8+ T cell responses in human ovarian cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-387. doi:10.1158/1538-7445.AM2011-LB-387
THE COST OF LIVING AND MEDICAL CARE PRICES
Authors: Frank G. Dickinson
Journal: JAMA (1952)

In the past year, the index of the prices of all items in the consumers' budget has risen almost twice as many points as the price of medical care. The Consumers' Price Index rose 13.7 points in 1951, and the index of medical care and drugs rose 7.1 points. In 1951, the Consumers' Price Index reached an all-time high of 185.6 while the index of the prices of medical care and drugs stood at 155.0. While the Consumers' Price Index has been considerably higher than the index of medical care prices in recent years, the spread between the two indexes became even more pronounced during 1951. The Consumers' Price Index had risen 86% since the base period, while the cost of medical care rose only 55%. In terms of purchasing power of the consumer dollar, medical care was 16% cheaper in 1951 than in 1935-1939, that is, 155.0 is 84%
Report on the annual statistical survey of the Japanese Society for Dialysis Therapy in 1996
Authors: Toru Shinzato, Shigeru Nakai, Takashi Akiba, Seiji Yamagami, Chikao Yamazaki, Tateki Kitaoka, Kazuo Kubo, Kenji Maeda, Hirotoshi Morii
Journal: Kidney International (1999)
Tracer kinetic model of blood-brain barrier transport of plasma protein-bound ligands. Empiric testing of the free hormone hypothesis.
Authors: W M Pardridge, E M Landaw
Journal: Journal of Clinical Investigation (1984)

Previous studies have shown that the fraction of hormone or drug that is plasma protein bound is readily available for transport through the brain endothelial wall, i.e., the blood-brain barrier (BBB). To test whether these observations are reconcilable with the free-hormone hypothesis, a tracer-kinetic model is used in the present investigations to analyze in vivo initial extraction data on BBB transport of protein-bound steroid hormones (dihydrotestosterone, testosterone, estradiol, and corticosterone), thyroid hormones (triiodothyronine), and lipophilic amine drugs (propranolol). The plasma proteins used are bovine albumin and human orosomucoid. Transport data was fit to a modification of the Kety-Renkin-Crone equation of capillary physiology; the modified equation incorporates the principles of both capillary physiology and plasma protein-ligand mass action binding relationships. In most cases, the experimental data is best fit to the model equation when the apparent in vivo dissociation constant, KDa, of the ligand protein binding reaction increases to values that are 5- to 50-fold greater than the in vitro dissociation constant, KD. This result indicates that the rate of ligand dissociation from the plasma protein is accelerated in the capillary bed relative to the in vitro situation. It is hypothesized that the major factor leading to the rapid transport in vivo of protein-bound ligands into tissues such as brain is an endothelial-induced decrease in the affinity of the plasma protein for the ligand. Under these conditions, the amount of plasma ligand available for tissue clearance in vivo parallels the protein-bound fraction, not the free hormone.
IN VITRO INDUCTION OF SPECIFIC UNRESPONSIVENESS OF IMMUNOLOGICALLY REACTIVE, NORMAL BONE MARROW CELLS
Authors: Sharwan K. Singhal, Hans Wigzell
Journal: The Journal of Experimental Medicine (1970)

Normal rabbit bone marrow cells have been studied according to their immunological reactivity in vitro. The test system involved stimulation by antigen after the subsequent stimulation into cellular proliferation by measuring the uptake of tritium-labeled thymidine. Specific separation of immunological reactivity was obtained by filtration of cells through antigen-coated bead columns. All experimental evidence supported the view that this separation was due to the existence of preformed antibody molecules on the outer cell surface of the antigen-recognizing cells. The response to antigenic stimulation was shown to be strictly dose related and, using supraoptimal concentrations of one antigen, no increased DNA synthesis was recorded. That this state of unresponsiveness represented a state of immunological paralysis was indicated by the normal response of these cells to stimulation by a second antigen in optimal concentration. Thus both methods, cell separation on antigen-coated columns or induction of specific unresponsiveness by antigen in vitro, can produce a cell population specifically devoid of cells reactive against a given antigen.
Abstract 4537: Tumoral expression on peroxisome proliferator-activated receptor ≤ is an independent prognostic marker in intestinal type of gastric cancer
Authors: Soo-Jeong Cho, Jun Ho Lee, Myoung-Cheorl Kook, Il Ju Choi, Keun Won Ryu, Young-Woo Kim
Journal: Cancer Research (2012)

Abstract Introduction: Peroxisome proliferator-activated receptor ≤ (PPARδ) is a member of the nuclear hormone receptor family that regulates the expression of mediators of the inflammatory response. Metaplastic change secondary to chronic inflammation of gastric mucosa is regarded as a premalignant condition of intestinal-type gastric cancer (IGC). We aimed to evaluate the prognostic significance of PPARδ in IGC patients. Methods: The clinical significance of PPARδ was explored using tissue microarray methods and immunohistochemical staining of specimens from 306 IGC patients. The Kaplan-Meier method was used to calculate survival curves, and differences between the survival curves were assessed using the log-rank test. Cox proportional hazards regression was used to assess the effect of PPARδ expression on survival while controlling for other confounding covariates. Results: Among 306 patients with IGC (stage I-IV), PPARδ expression was detected by immunohistochemistry in the tumors of 209 (68.3%). The patients with PPARδ-positive tumors had significantly lower overall and gastric cancer-specific mortalities (P = 0.0010 and 0.0016, respectively, by the log-rank test) than did those with PPARδ-negative tumors. A positive PPARδ expression was a significant independent prognostic factor for gastric cancer-specific mortality by the Cox regression analysis in patients with IGC (adjusted hazard ratio, 0.42; 95% confidence interval, 0.22-0.81). The relationship between PPARδ and lower mortality was not modified by other clinical variables including tumor stage (all Pinteraction &amp;gt; 0.05). Conclusions: tumor expression of PPARδ was independently associated with lower mortality of patients with IGC. Keywords: Gastric cancer, Intestinal-type gastric cancer, Peroxisome proliferator-activated receptor ≤ (PPARδ), Prognostic marker, Survival Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4537. doi:1538-7445.AM2012-4537
Priorities in Oregon
Authors: Philip Caper
Journal: JAMA (1992)

<h3>To the Editor.</h3> —The recent article about "the Oregon plan" by Fisher et al<sup>1</sup>presents an attractive alternative to rationing-defined classes of medical service based on cost/benefit ratios.<sup>2</sup>Effective constraint of the capacity of the health care system is our best hope for the control of overall health care costs, and will at the same time permit a reduction in the irksome, intrusive, and ineffective micromanagement of medical care that is becoming such a burden to physicians and patients alike. Because of rapid advances in microcomputer hardware and software technology,<sup>3</sup>we are now able routinely to monitor patterns of the use of medical care over large populations at a level of detail not heretofore possible. Such "epidemiologic surveillance of medical care"<sup>4</sup>has made it clear to us that not all equivalent per capita rates of hospital use are necessarily equal. For example, some years ago, we
Construction of tumor-specific toxins using ubiquitin fusion technique
Authors: Sergey O. Tcherniuk, Jadwiga Chroboczek, Maxim Y. Balakirev
Journal: Molecular Therapy (2004)

The use of cytotoxic agents to eliminate cancer cells is limited because of their nonselective toxicity and unwanted side effects. One of the strategies to overcome these limitations is to use latent prodrugs that become toxic in situ after being enzymatically activated in target cells. In this work we describe a method for producing tumor-specific toxins by using a ubiquitin fusion technique. The method is illustrated by the production of recombinant toxins by in-frame fusion of ubiquitin to saporin, a toxin from the plant Saponaria officinalis. Ubiquitin-fused toxins were rapidly degraded via the ubiquitin-proteasome system, significantly reducing their nonspecific toxicity. The insertion of the protease-cleavage sequence between ubiquitin and saporin led to the removal of ubiquitin by the protease and resulted in protease-dependent stabilization of the toxin. We engineered toxins that can be stabilized by specific proteases such as deubiquitinating enzymes and prostate-specific antigen (PSA). Both constructs were activated in vitro and in cultured cells by the appropriate enzyme. Processing by the protease resulted in a greater than 10-fold increase in the toxicity of these constructs. Importantly, the PSA-cleavable toxin was able to kill specifically the PSA-producing prostate cancer cells. The ubiquitin fusion technique is thus a versatile and reliable method for obtaining selective cytotoxic agents and can easily be adapted for different kinds of toxins and activating proteases.
Incidence of Lower-Extremity Amputation in American Indians
Authors: Helaine E. Resnick, Elizabeth A. Carter, Jay M. Sosenko, Susan J. Henly, Richard R. Fabsitz, Frederick K. Ness, Thomas K. Welty, Elisa T. Lee, Barbara V. Howard
Journal: Diabetes Care (2004)

OBJECTIVE—To define incidence and predictors of nontraumatic lower-extremity amputation (LEA) in a diverse cohort of American Indians with diabetes. RESEARCH DESIGN AND METHODS—The Strong Heart Study is a study of cardiovascular disease and its risk factors in 13 American-Indian communities. Data on the presence/absence of amputations were collected at each of three serial examinations (1989–1992, 1993–1995, and 1997–1999) by direct examination of the lower extremity. The logistic regression model was used to quantify the relationship between risk of LEA and potential risk factors, including diabetes duration, HbA1c, peripheral arterial disease, and renal function. RESULTS—Of the 1,974 individuals with diabetes and without prevalent LEA at baseline, 87 (4.4%) experienced an LEA during 8 years of follow-up, and a total of 157 anatomical sites were amputated among these individuals. Amputation of toes was most common, followed by below-the-knee and above-the-knee amputations. Age-adjusted odds of LEA were higher among individuals with unfavorable combinations of risk factors, such as albuminuria and elevated HbA1c. Multivariable modeling indicated that male sex, renal dysfunction, high ankle-brachial index, longer duration of diabetes, less than a high school education, increasing systolic blood pressure, and HbA1c predicted LEA risk. CONCLUSIONS—The 8-year cumulative incidence of LEA in American Indians with diabetes is 4.4%, with marked differences in risk by sex, educational attainment, renal function, and glycemic control.
Should healthy volunteers in clinical trials be paid according to risk? Yes
Authors: E. Jones, K. Liddell
Journal: BMJ (2009)

<b>Eleri Jones</b> and <b>Kathleen Liddell</b> argue that objections to paying according to risk are paternalistic, but <b>John Saunders</b> (doi:10.1136/bmj.b4145) thinks that it would lead to people being exposed to unacceptable danger
A Case of Double Hare-Lip in a Man Aged 32
Authors: W. Rose
Journal: BMJ (1883)

unlikely, to my mind, that two distinct diseases are at present gr4uped under the name of progressive muscular atrophy, the disease of the muscles being in the one primary, and in the other secondary an affection of the trophic centres in the spinal cord.With reference to the morbid changes in the muscles in the case of W. T., little need be said, inasmuch as they conform accurately to the descriptions of other observers.The annexed wood-cut, from a drawing by Mr. A. H. Young, of altered muscular fibres in Dr.Leech's case will illustrate the changes usually met with.In the least altered muscular fibres the transverse striation is often indis- tinct, and a considerable increase of the muscle corpuscles is
Incidence of Fall-Related Traumatic Brain Injuries Among Older Finnish Adults Between 1970 and 2011
Authors: Niina Korhonen, Seppo Niemi, Jari Parkkari, Harri Sievänen, Pekka Kannus
Journal: JAMA (2013)

To the Editor: Traumatic brain injury (TBI) is a major cause of hospitalization, disability, and death worldwide, and among older adults, falling is the most common cause of TBI.1 We reported that the number and incidence of adults aged 80 years or older admitted to the hospital due to fall-induced TBI in Finland increased from 1970 through 1999.2 We now report follow-up of this population through 2011.