tbuckley/cabot-search huggingface dataset:
Abstract 4444: Targeted delivery of siRNAs to tumor cells and the tumor microenvironment
Authors: Lígia Catarina Gomes da Silva, José Ramalho, Maria Conceição Pedroso Lima, Sérgio Simões, João Nuno Moreira
Journal: Cancer Research (2011)

Abstract The limited effectiveness of conventional treatment strategies has generated considerable interest on the development of new types of anticancer agents, with improved molecular target specificity. In this context, gene silencing technology constitutes such new class of anticancer agents. The identification of activated oncogenes, as fundamental genetic differences relative to normal cells has made it possible to consider such genes as targets for antitumor therapy. A tumor is an organ, not a single cell type, which encompasses multiple cell types, each one contributing to the overall tumor aggressiveness. It is now recognized that novel therapeutic strategies should envisage the simultaneous inhibition of multiple targets or pathways, at different cell levels within a tumor, that regulate processes promoting tumor development. The main goal of this work was to design a novel ligand-mediated targeted lipid-based nanocarrier, containing a nucleic acid (siRNA), aiming at targeting, simultaneously, human breast cancer and endothelial cells from angiogenic vessels. We have been able to develop a novel ligand-targeted sterically stabilized lipid-based nanoparticle with adequate features for systemic administration: it is characterized by high siRNA encapsulation efficiency, efficient protection of siRNA, average size around 200 nm, and charge close to neutrality. Our results have shown that the covalent attachment of a specific ligand at the extremity of poly(ethylene glycol) chains, brings a major advantage as it significantly improves the internalization of the lipid-based nanoparticle by both human cancer cells (MDA-MB-435 and MDA-MB-231) and endothelial cells from angiogenic blood vessels (HMEC-1). Moreover, it was not observed a significant internalization by the non-transformed cell line, BJ fibroblasts, indicating the cellular specificity of the developed targeted nanoparticle. In order to evaluate the potential of the developed targeted nanoparticle to silence a target gene, the green fluorescent protein (GFP)-overexpressing MDA-MB-435 cells were used. A specific downregulation of GFP, both at the protein and mRNA levels, was further observed with the targeted nanoparticle when compared with the non-targeted counterpart. As the developed nanoparticle is adequate for the encapsulation and delivery of any siRNA sequence, studies with a siRNA targeting a validated molecular target are now ongoing. 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 4444. doi:10.1158/1538-7445.AM2011-4444
"SPINAL ANESTHESIA EXCLUDING THE MOTOR NERVES"
Authors: Joseph Horgan
Journal: JAMA (1931)

To the Editor:  —I have noted inThe Journal, April 4, page 1168, the excellent suggestions of Dr. Edward G. Martin in reference to Spinal Anesthesia Excluding the Motor Nerves and I am happy to be able to confirm his observations for I have been using small doses (from 40 to 70 mg.) of procaine intraspinally since October, 1929.  There is another decided advantage, I believe, which the intradural administration of procaine makes available, when the procedure permits, and that is the use of the ventral posture. The lateral (Sims) and dorsal postures are not ideal for anorectal treatments. Surgical treatment of the anus and rectum can be executed with comfort to the patient and with greater ease to the surgeon when the patient is placed in a ventral, semiflexed posture. With the patient lying prone on the  this can be effected by breaking the table so as to
Detection and Quantitation of Serum Mesothelin, a Tumor Marker for Patients with Mesothelioma and Ovarian Cancer
Authors: Raffit Hassan, Alan T. Remaley, Maureen L. Sampson, Jingli Zhang, Derrick D. Cox, James Pingpank, Richard Alexander, Mark Willingham, Ira Pastan, Masanori Onda
Journal: Clinical Cancer Research (2006)

Abstract Purpose: To determine whether mesothelin, a cell surface protein highly expressed in mesothelioma and ovarian cancer, is shed into serum and if so to accurately measure it. Experimental Design: We developed a sandwich ELISA using antibodies reacting with two different epitopes on human mesothelin. To quantitate serum mesothelin levels, a standard curve was generated using a mesothelin-Fc fusion protein. Sera from 24 healthy volunteers, 95 random hospital patients, 56 patients with mesothelioma, and 21 patients with ovarian cancer were analyzed. Serum mesothelin levels were also measured before and after surgical cytoreduction in six patients with peritoneal mesothelioma. Results: Elevated serum mesothelin levels were noted in 40 of 56 (71%) patients with mesothelioma and in 14 of 21 (67%) patients with ovarian cancer. Serum mesothelin levels were increased in 80% and 75% of the cases of mesothelioma and ovarian cancer, respectively, in which the tumors expressed mesothelin by immunohistochemistry. Out of the six patients with peritoneal mesothelioma who underwent surgery, four had elevated serum mesothelin levels before surgery. Out of these four patients, three had cytoreductive surgery and the serum mesothelin level decreased by 71% on postoperative day 1 and was undetectable by postoperative day 7. Conclusions: We developed a serum mesothelin assay that shows that mesothelin is elevated in patients with mesothelioma and ovarian cancer. The rapid decrease in mesothelin levels after surgery in patients with peritoneal mesothelioma suggests that serum mesothelin may be a useful test to monitor treatment response in mesothelin-expressing cancers.
Purely cutaneous Rosai-Dorfman disease
Authors: G. ANNESSI, A. GIANNETTI
Journal: British Journal of Dermatology (1996)

Summary Cutaneous lesions of Rosai-Dorfman disease (RDD) are usually associated with nodal or other extranodal localization. We describe a female patient with RDD clinically limited to the skin. The patient presented with asymptomatic red brown papules and nodules on the legs, arms, Back and nose. Histologically the lesions consisted of a proliferation of large histiocytes occasionally showing emperipolesis. Histiocytes were also observed within dilated lymphatic vessels. Immunohistochemical study showed that histiocytes expressed S-l protein and both macrophage and tonicity markers. All lesions resolved completely with Roentgen therapy. No recurrence has been observed over a 3-year follow-up period.
Smoking and doctors' mortality.
Authors: J M Davies, C Chilvers
Journal: BMJ (1980)

was particularly marked in one patient, who had been following an intensive endurance training programme for several years.On pindolol he was unable to complete his training programme and complained of an insatiable apetite, presumably owing to low blood glucose levels.On metoprolol these changes were not apparent.Similar differences in terms of working capacity have also been shown by Fellenius et al2 between the non-selective betablocker propranolol and metoprolol.Fatigue is a commonly encountered problem in patients treated with beta-blockers.On the basis of these findings it would appear that in these circumstances the predominantly cardioselective beta-blocker metoprolol may be preferable since it would appear to have less effect on energy metabolism during physical stress.
Aflatoxin and hepatocellular carcinoma: A useful paradigm for environmentally induced carcinogenesis
Authors: Joseph C. Kolars
Journal: Hepatology (1992)

Aflatoxin is believed to be a major causative agent in the high incidence of primary liver cancer seen in certain regions of the world. In Fujian Province, an aflatoxin–endemic region of China, we compared the cigarette smoking habits of 200 primary hepatoma patients with those of 200 matched nonhepatoma controls. We excluded from our study all individuals with evidence of hepatitis B virus serum antigen and/or alcoholic cirrhosis. Interestingly, two groups of hepatoma patients could be discerned. In patients more than 50 years of age, a significantly higher number of cases of primary hepatoma was found among nonsmokers than smokers (odds ratio = 2.06; 95% confidence interval = 1.32-3.20). In patients less than 50 years of age, this difference was not seen. Previous studies in the rat, mouse and duck had suggested that agents present in cigarette smoke might induce a cytochrome P450–mediated detoxication pathway, leading to protection against aflatoxin–induced primary liver cancer. Our clinical data in the present study are therefore consistent with the previous laboratory animal experiments. Mutations of the p53 gene are found in hepatocellular carcinoma (HCC), the most common form of primary liver cancer. Specific mutations might reflect exposure to specific carcinogens and we have screened HCC samples from patients in 14 different countries to determine the frequency of a hotspot mutation at codon 249 of the tumour suppressor p53 gene. We detected mutations in 17% of tumours (12/72) from four countries in south Africa and the southeast coast of Asia. There was no codon 249 mutation in 95 specimens of HCC from other geographical locations including North America, Europe, Middle East, and Japan. Worldwide, the presence of the codon 249 mutation in HCCs correlated with high risk of exposure to aflatoxins and the hepatitis B virus (HBV). Further studies were completed in two groups of HBV–infected patients at different risks of exposure to aflatoxins. 53% of patients (8/15) from Mozambique at high risk of aflatoxin exposure had a tumour with a codon 249 mutation, in contrast with 8% of patients from Transkei (1/12) who were at low risk. HCC is an endemic disease in Mozambique and accounts for up to two thirds of all tumours in men. A codon 249 mutation of the p53 gene identifies an endemic form of HCC strongly associated with dietary aflatoxin intake.
Marked Inflammatory Sequelae to Implantation of Biodegradable and Nonbiodegradable Polymers in Porcine Coronary Arteries
Authors: Willem J. van der Giessen, A. Michael Lincoff, Robert S. Schwartz, Heleen M.M. van Beusekom, Patrick W. Serruys, David R. Holmes, Stephen G. Ellis, Eric J. Topol
Journal: Circulation (1996)

With the thrombogenic tendency and permanent implant nature of metallic stents, synthetic polymers have been proposed as candidate materials for stents and local drug delivery designs. We investigated the biocompatibility of several synthetic polymers after experimental placement in the coronary artery.Five different biodegradable polymers (polyglycolic acid/polylactic acid [PGLA], polycaprolactone [PCL], polyhydroxybutyrate valerate [PHBV], polyorthoester [POE], and polyethyleneoxide/polybutylene terephthalate [PEO/ PBTP]) and three nonbiodegradable polymers (polyurethane [PUR], silicone [SIL], and polyethylene terephthalate [PETP]) were tested as strips deployed longitudinally across 90 degrees of the circumferential surface of coil wire stents. Appropriately sized polymer-loaded stents were implanted in porcine coronary arteries of 2.5- to 3.0-mm diameter. Four weeks after implantation, stent patency was assessed by angiography followed by microscopic examination of the coronary arteries. The biodegradable PCL, PHBV, and POE and the nonbiodegradable PUR and SIL evoked extensive inflammatory responses and fibrocellular proliferation (thickness of tissue response: 0.79 +/- 0.22, 1.12 +/- 0.01, 2.36 +/- 0.60, 1.24 +/- 0.36, and 1.43 +/- 0.15 mm, respectively). Less but still severe responses were observed for the biodegradable PGLA and PEO/PBTP (0.46 +/- 0.18 and 0.61 +/- 0.23 mm, respectively) and for the nonbiodegradable PETP (0.46 +/- 0.11 mm).An array of both biodegradable and nonbiodegradable polymers has been demonstrated to induce a marked inflammatory reaction within the coronary artery with subsequent neointimal thickening, which was not expected on the basis of in vitro tests. The observed tissue response may be attributable to a combination of parent polymer compound, biodegradation products, and possibly implant geometry.
Abstract A21: microRNA-200 regulates tumor cell PD-L1 expression to control lung cancer metastasis.
Authors: Don L. Gibbons, Limo Chen, Sangeeta Goswami, Young-Ho Ahn, Lauren A. Byers, Lixia Diao, Jing Wang, Angelica Cortez, Jonathon Roybal, James Welsh, Xuejun Zhang, David Dwyer, Xiaohui Yi, Chen Lieping, Ignacio Wistuba, John V. Heymach, Jonathan M. Kurie, F. Xiao-Feng Qin
Journal: Clinical Cancer Research (2014)

Abstract Background: Tumor cell regulation of the recruitment and activity of diverse inflammatory cells creates an immunosuppressive microenvironment that favors both tumor growth and metastasis. However, the mechanistic basis of how tumor cells trigger intra-tumoral immunosuppression have not been fully defined. Here we show that metastasis-prone lung adenocarcinoma cells suppress the proliferation and activity of intra-tumoral CD8+ T cells through a PD-L1 dependent mechanism and that PD-L1 expression is regulated by microRNA-200 (miR-200), a known mediator of tumor cell EMT. Results: Analysis of patient tumors from The Cancer Genome Atlas (TCGA) (230 adenocarcinomas) and a large MDACC cohort of resected tumors (N&amp;gt;150) demonstrated that tumors with a mesenchymal gene expression signature had repression of miR-200 family expression and higher levels of PD-L1 expression. These findings were confirmed experimentally in human and murine NSCLC cell lines. In vivo experiments with a Kras/p53 mutant mouse model of lung adenocarcinoma showed that decreased miR-200 led to increased expression of PD-L1 levels on tumor cells, causing profound CD8+ T cell suppression. Upon suppression of CD8+ T cell activity tumors acquired a growth advantage and metastatic capability. Confirmation of these results with the LLC model in PD-L1 knockout mice also demonstrated that PD-L1 expression on the tumor cells, rather than other cells in the tumor microenvironment, was critical to defining tumor immunity and metastastic ability. The metastases could be suppressed by genetic and pharmacologic blockade of PD-L1. Conclusion: Our findings demonstrate a novel biological role for miR-200 in cancer cells by simultaneous control of the cell-intrinsic EMT program and the cell-non-autonomous PD-L1-mediated immune evasion. These findings support further investigation into the mechanistic effects of miR-200 on metastasis and the use of specific EMT-related biomarkers to select immunomodulatory therapies. Citation Format: Don L. Gibbons, Limo Chen, Sangeeta Goswami, Young-Ho Ahn, Lauren A. Byers, Lixia Diao, Jing Wang, Angelica Cortez, Jonathon Roybal, James Welsh, Xuejun Zhang, David Dwyer, Xiaohui Yi, Chen Lieping, Ignacio Wistuba, John V. Heymach, Jonathan M. Kurie, F. Xiao-Feng Qin. microRNA-200 regulates tumor cell PD-L1 expression to control lung cancer metastasis. [abstract]. In: Proceedings of the AACR-IASLC Joint Conference on Molecular Origins of Lung Cancer; 2014 Jan 6-9; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2014;20(2Suppl):Abstract nr A21.
The Schreber Case: Psychoanalytic Profile of a Paranoid Personality
Authors: G. E. Gifford
Journal: JAMA (1975)

This is a history of the most famous paranoid delusional system in the psychiatric literature—that of Daniel Paul Schreber (1842 to 1911). Schreber, a distinguished jurist, became mentally ill after he was appointed Chief Justice of the Superior Court of Appeals in Dresden. His chief delusion rested in the idea that God would transform him (Schreber) into a woman, name him "Miss" Schreber, take the latter for His (God's) wife, and out of his physical intercourse with God, a better and healthier race of men would emerge after He had destroyed the world in a huge deluge. In 1903, after nine years of hospitalization in a mental hospital, Schreber published<i>Denkwürdigkteit eines Nervenkranken (Memoirs of a Mental Patient)</i>which was bought up by the Schreber family and taken out of circulation. Only a few copies remained and one of them came to the attention of Freud, who in 1911 published
Corticosteroid-Interferon Therapy for Hepatitis B Characterized as 'Potentially Exciting' so Far
Authors: Timothy F. Kirn
Journal: JAMA (1987)

IN THE late 1970s, Thomas Merigan, MD, and colleagues at Stanford (Calif) University School of Medicine noticed that patients with chronic active hepatitis B who had been receiving prednisone responded to interferon treatment better than patients who had not received steroids. At that time, corticosteroid treatment for chronic hepatitis B was losing favor, and a way to manufacture commercial amounts of interferon had just been discovered. Merigan, who now heads Stanford's Division of Infectious Diseases, and his group first described the steroid-antiviral connection in an article six years ago (<i>J Infect Dis</i>1981;143:772-783). But, enthusiasm for interferon, and later for the other new antiviral substances, was high. So, the investigators continued studying these as single-drug therapy. Today, the high hope many hepatitis researchers had for interferon and other antivirals is waning. These days, "everybody [in hepatitis B research] is doing combined-therapy trials," says Myron Tong, MD, PhD, professor of medicine,
Genes and physiology: molecular physiology in genetically engineered animals.
Authors: K R Chien
Journal: Journal of Clinical Investigation (1996)

‫ف‬ 20 genes involved in human lipid transport have been overexpressed or knocked out in transgenic mice.(Data from Breslow, 17; Ishibashi, 58; Lawn, 59).‡ For a more complete listing of mouse models with cardiovascular disease phenotypes, see 60.
Doctors on Strike — The Crisis in German Health Care Delivery
Authors: Dennis Nowak
Journal: New England Journal of Medicine (2006)

In mid-March 2006, physicians at Germany's university clinics went on strike, protesting an increase in the hours of the official workweek that came without a corresponding increase in pay. The physicians' union, the Marburger Bund, argued that neither the old official workweek of 38.5 hours, nor the new one of 40 or 42 hours, reflected the reality known by most doctors in Germany, where 80-hour weeks are common and physicians often put in many additional, uncompensated hours. About 15,000 of the 20,000 physicians based at university hospitals joined in this unprecedented strike.After 3 months of collective action and negotiation, . . .
The Biochemistry and Physiology of Bone, vol 2: Physiology and Pathology
Authors: Reginald R. Cooper
Journal: JAMA (1972)

In this three-part series, the authors of volume 2 expertly and lucidly delineate their subject. The initial chapter on bone circulation offers an appropriate transition from the review of bone structure in volume 1 to bone metabolism discussed in this volume. After a synopsis of bone blood supply, the author reviews his extensive microradiographic studies which have increased our understanding of the relative contribution of each source of blood supply to bone healing under various experimental circumstances. A section on phosphatase superbly summarizes the experiments that try to unravel the elusive relation of phosphatase and mineralizable matrices in mature, developing, and repairing bone, in various animals. The multiple hypotheses now current indicate that we may have to wait for yet another edition before this mystery reaches its conclusion. A timely chapter on enamel and dentin matrix glycoproteins, elaborated by ameloblasts and odontoblasts, serves to remind us that bone and cartilage
Abstract OT1-1-07: Human epidermal growth factor receptor 2 (HER2) suppression with the addition of lapatinib to trastuzumab in HER2-positive metastatic breast cancer (LTP112515)
Authors: N Lin, MA Danso, AK David, J Muscato, D Rayson, WA Houck, C Ellis, M DeSilvio, A Garofalo, Y Nagarwala, E Winer
Journal: Cancer Research (2012)

Abstract Background: The combination of lapatinib (L) with trastuzumab (T) results in enhanced antitumor activity in preclinical models of HER2-positive breast cancer (BC), due to the complementary mechanisms of action of the two agents. In patients with prior T-treated HER2-positive metastatic BC (MBC), treatment with T plus L was associated with longer progression-free survival (PFS) and overall survival (OS) compared with L alone. The combination also had an acceptable safety and tolerability profile. In patients with stage II/III BC, preoperative treatment with the combination plus paclitaxel (P) resulted in significantly higher pathologic complete response rates compared with P combined with either agent alone. This evidence supports the concept of dual HER2 blockade as a treatment strategy for HER2-positive MBC. Current common clinical practice for most patients experiencing clinical benefit from first-line treatment with T plus chemotherapy is to continue T as maintenance therapy after completion of the recommended number of chemotherapy cycles. The present study is designed to evaluate whether the addition of L improves PFS among women with HER2-positive MBC receiving T as maintenance therapy. Methods: In this open-label, Phase III study, 280 patients will be stratified by line of treatment (first/second) and hormone receptor status (positive/negative), then randomized 1:1 to receive maintenance treatment with either L (1000 mg qd, continuously) in combination with T (6 mg/kg once every 3 weeks [q3w]), or T (6 mg/kg q3w) alone. Patients will receive study treatment until disease progression, death, discontinuation due to adverse events, or patient withdrawal. The primary endpoint is PFS; secondary endpoints are; OS, clinical benefit rate, and safety. Key eligibility criteria include females, age ≥18 years with HER2-positive MBC who have completed 12 to 24 weeks of first- or second-line treatment with T plus chemotherapy with an objective response or stable disease at time of chemotherapy discontinuation. Patients with stable brain metastases are eligible if entering the study on second-line treatment. Efficacy endpoints will be analyzed in the intent-to-treat population. A total of 193 PFS events is required to detect a 50% increase in median PFS (hazard ratio=0.667) from 18 weeks (T alone) to 27 weeks (L plus T). The hypothesis will be tested using a 1-sided test with 80% power and a type I error of 0.025. One interim analysis is planned for futility when approximately 97 PFS events (50% of the required events) have been observed. Safety endpoints will be analyzed in all randomized patients who receive ≥1 dose of study medication. The trial is currently open for accrual in the United States and Canada. ClinicalTrials.gov - NCT00968968 Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr OT1-1-07.