tbuckley/cabot-search huggingface dataset:
Peptide‐based radiopharmaceuticals: Future tools for diagnostic imaging of cancers and other diseases
Authors: S.M. Okarvi
Journal: Medicinal Research Reviews (2004)

Abstract An Erratum has been published for this article in Medicinal Research Reviews 2004;24:685–686 . Small synthetic receptor‐binding peptides are the agents of choice for diagnostic imaging and radiotherapy of cancers due to their favorable pharmacokinetics. Molecular modification techniques permit the synthesis of a variety of bioactive peptides with chelating groups, without compromising biological properties. Various techniques have been developed that allow efficient and site‐specific labeling of peptides with clinically useful radionuclides such as 99m Tc, 123 I, 111 In, and 18 F. Among them, 99m Tc is the radionuclide of choice because of its excellent chemical and imaging characteristics. Recently, many 99m Tc‐labeled peptides have proven to be useful imaging agents. Beside 99m Tc‐labeled peptides, several peptides radiolabeled with 111 In and 123 I have been prepared and characterized. In addition, 18 F‐labeled peptides hold clinical potential due to their ability to quantitatively detect and characterize a variety of human diseases using positron‐emission tomography. The availability of this wide range of peptides labeled with different radionuclides offers multiple diagnostic and therapeutic applications. Various receptors are over‐expressed in particular tumor types and peptides binding to these receptors can be used to visualize tumor lesions scintigraphically. Thus, radiolabeled peptides have potential use as carriers for the delivery of radionuclides to tumors, infarcts, and infected tissues for diagnostic imaging and radiotherapy. Many radiolabeled peptides are currently under investigation to determine their potential as imaging agents. These peptides are designed mainly for thrombus, tumor, and infection/inflammation imaging. This article presents recent developments in small synthetic peptides for imaging of thrombosis, tumors, and infection/inflammation. © 2004 Wiley Periodicals, Inc. Med Res Rev, 24, No. 3, 357–397, 2004
Frozen shoulder: adhesive capsulitis
Authors: D J Maberly
Journal: BMJ (1982)

identified.This pathogenic organism was initially identified in the cyst form in the faeces of an 18-year-old woman; she had had on occasions diarrhoea, vomiting, and nausea, rarely lasting more than two to three days, during a five-month period of travel through numerous parts of India.On her travels she ate local food and drank a great deal of local water.She presented in the UK, 22 days after returning from India, with frequent bouts of diarrhoea and some rectal bleeding on defecation.Shigella flexneri was isolated from her faeces.If the bacterium had been accepted as the sole cause of her condition and microscopic examination of her faeces omitted, she may well have advanced to a serious pathological consequence, and spread the pathogen to others.This case demonstrates that, while the incidence of pathogenic Entamoeba histolytica in Britain is extremely low, importation of this dangerous pathogen does occur.For this reason it is important that patients presenting with dysenteric symptoms are carefully screened for parasitic as well as bacterial pathogens.
High incidence of B cell lymphomas derived from thymectomized AKR mice expressing TL.4 antigen.
Authors: A Peled, N Haran-Ghera
Journal: The Journal of Experimental Medicine (1985)

AKR mice, 6-12 mo after birth, display a high incidence of spontaneous T cell lymphomas that can be prevented by thymus removal at the age of 1-3 mo. We report here the presence of dormant preleukemic cells among bone marrow cells of 8-12-mo-old AKR mice that have been thymectomized when 40-60 d old. Transplantation of bone marrow cells from these thymectomized AKR donors into syngeneic or hybrid (AKR X DBA/2)F1 intact or thymectomized recipients resulted in lymphoma development of AKR origin in 80-100% of the recipients. Analysis, by flow microfluorometry, of the antigenic cell surface phenotypes of the developing lymphomas revealed that all tumors were B cell lymphomas, since the cells stained with class-specific anti-IgM reagents and other reagents specific for B cells (RA3-2C2, RA3-6B2, anti-I-A, and anti-Fc receptor), and were Thy-1-. All these B cell tumors also expressed two T cell differentiation antigens, TL.4, found exclusively on T cell lymphomas, and Lyt-1 antigen, previously shown (11) to be expressed on some B cell neoplasms. The surface markers mu, I-A, RA3-2C2, and TL.4 identified by immunofluorescence, were shown to be integral membrane components synthesized by the tumor cells, rather than passively acquired proteins.
A survey of affective brain computer interfaces: principles, state-of-the-art, and challenges
Authors: Christian Mühl, Brendan Allison, Anton Nijholt, Guillaume Chanel
Journal: Brain-Computer Interfaces (2014)

Affective states, moods and emotions, are an integral part of human nature: they shape our thoughts, govern the behavior of the individual, and influence our interpersonal relationships. The last decades have seen a growing interest in the automatic detection of such states from voice, facial expression, and physiological signals, primarily with the goal of enhancing human-computer interaction with an affective component. With the advent of brain-computer interface research, the idea of affective brain-computer interfaces (aBCI), enabling affect detection from brain signals, arose. In this article, we set out to survey the field of neurophysiology-based affect detection. We outline possible applications of aBCI in a general taxonomy of brain-computer interface approaches and introduce the core concepts of affect and their neurophysiological fundamentals. We show that there is a growing body of literature that evidences the capabilities, but also the limitations and challenges of affect detection from neurophysiological activity.
Combination Phase I Trial of a Novel Oral Fluorouracil Derivative S-1 with Low-Dose Cisplatin for Unresectable and Recurrent Gastric Cancer (JFMC27–9902)
Authors: Bunzo Nakata, Yasushi Mitachi, Akihito Tsuji, Susumu Yamamitsu, Koichi Hirata, Tetsuhiko Shirasaka, Kosei Hirakawa
Journal: Clinical Cancer Research (2004)

The Japanese Foundation for Multidisciplinary Treatment of Cancer conducted a Phase I study of a novel oral fluorouracil derivative, S-1, combined with a low dose of cisplatin in unresectable and recurrent gastric cancer.S-1 was administered orally at 80-120 mg/body/day, depending on body surface area. One course consisted of consecutive administration for 28 days followed by a rest of 14 days. Low-dose cisplatin was given i.v. on days 1-5, 8-12, 15-19, and 22-26 of each course. The dose escalation of cisplatin began with an initial dose of 1 mg/m(2)/day as level 1 and was stepped up to 2, 3, 4, and 6 mg/m(2)/day as level 2, 3, 4, and 5, respectively. The regimen was repeated for at least two courses.A total of 24 patients was entered in the study. There was no treatment-related death. At level 5, consisting of 5 evaluable patients, dose-limiting toxicity was experienced as grade 3 appetite loss in 2 patients and grade 4 neutropenia in 1 patient. The maximum-tolerated dose of cisplatin was estimated to be 6 mg/m(2)/day. We decided on a recommended dose of cisplatin of 4 mg/m(2)/day because the dosage was one level under the maximum-tolerated dose. All 3 patients at level 4 showed partial response, suggesting promising clinical efficacy with this dosage. The serum concentration of cisplatin at level 4 was 918 +/- 92 ng/ml on day 26 of the first course.S-1 with low-dose cisplatin may become an effective regimen with acceptable toxicity for gastric cancer.
Runx Regulation of Sphingolipid Metabolism and Survival Signaling
Authors: Anna Kilbey, Anne Terry, Alma Jenkins, Gillian Borland, Qifeng Zhang, Michael J.O. Wakelam, Ewan R. Cameron, James C. Neil
Journal: Cancer Research (2010)

The Runx genes (Runx1, 2, and 3) regulate cell fate in development and can operate as either oncogenes or tumor suppressors in cancer. The oncogenic potential of ectopic Runx expression has been shown in transgenic mice that develop lymphoma in potent synergy with overexpressed Myc, and in established fibroblasts that display altered morphology and increased tumorigenicity. Candidate oncogenic functions of overexpressed Runx genes include resistance to apoptosis in response to intrinsic and extrinsic stresses. In a search for gene targets responsible for this aspect of Runx phenotype, we have identified three key enzymes in sphingolipid metabolism (Sgpp1, Ugcg, and St3gal5/Siat9) as direct targets for Runx transcriptional regulation in a manner consistent with survival and apoptosis resistance. Consistent with these changes in gene expression, mass spectrometric analysis showed that ectopic Runx reduces intracellular long-chain ceramides in NIH3T3 fibroblasts and elevated extracellular sphingosine 1 phosphate. Runx expression also opposed the activation of c-Jun-NH(2)-kinase and p38(MAPK), key mediators of ceramide-induced death, and suppressed the onset of apoptosis in response to exogenous tumor necrosis factor alpha. The survival advantage conferred by ectopic Runx could be partially recapitulated by exogenous sphingosine 1 phosphate and was accompanied by reduced phosphorylation of p38(MAPK). These results reveal a novel link between transcription factor oncogenes and lipid signaling pathways involved in cancer cell survival and chemoresistance.
Dietary Fiber and Colorectal Cancer Risk: A Nested Case-Control Study Using Food Diaries
Authors: C. C. Dahm, R. H. Keogh, E. A. Spencer, D. C. Greenwood, T. J. Key, I. S. Fentiman, M. J. Shipley, E. J. Brunner, J. E. Cade, V. J. Burley, G. Mishra, A. M. Stephen, D. Kuh, I. R. White, R. Luben, M. A. H. Lentjes, K. T. Khaw, S. A. Rodwell (Bingham)
Journal: JNCI Journal of the National Cancer Institute (2010)

Results of epidemiological studies of dietary fiber and colorectal cancer risk have not been consistent, possibly because of attenuation of associations due to measurement error in dietary exposure ascertainment. To examine the association between dietary fiber intake and colorectal cancer risk, we conducted a prospective case–control study nested within seven UK cohort studies, which included 579 case patients who developed incident colorectal cancer and 1996 matched control subjects. We used standardized dietary data obtained from 4- to 7-day food diaries that were completed by all participants to calculate the odds ratios for colorectal, colon, and rectal cancers with the use of conditional logistic regression models that adjusted for relevant covariates. We also calculated odds ratios for colorectal cancer by using dietary data obtained from food-frequency questionnaires that were completed by most participants. All statistical tests were two-sided. Intakes of absolute fiber and of fiber intake density, ascertained by food diaries, were statistically significantly inversely associated with the risks of colorectal and colon cancers in both age-adjusted models and multivariable models that adjusted for age; anthropomorphic and socioeconomic factors; and dietary intakes of folate, alcohol, and energy. For example, the multivariable-adjusted odds ratio of colorectal cancer for highest vs the lowest quintile of fiber intake density was 0.66 (95% confidence interval = 0.45 to 0.96). However, no statistically significant association was observed when the same analysis was conducted using dietary data obtained by food-frequency questionnaire (multivariable odds ratio = 0.88, 95% confidence interval = 0.57 to 1.36). Intake of dietary fiber is inversely associated with colorectal cancer risk. Methodological differences (ie, study design, dietary assessment instruments, definition of fiber) may account for the lack of convincing evidence for the inverse association between fiber intake and colorectal cancer risk in some previous studies.
Lung Stress and Strain during Mechanical Ventilation for Acute Respiratory Distress Syndrome
Authors: Davide Chiumello, Eleonora Carlesso, Paolo Cadringher, Pietro Caironi, Franco Valenza, Federico Polli, Federica Tallarini, Paola Cozzi, Massimo Cressoni, Angelo Colombo, John J. Marini, Luciano Gattinoni
Journal: American Journal of Respiratory and Critical Care Medicine (2008)

Lung injury caused by a ventilator results from nonphysiologic lung stress (transpulmonary pressure) and strain (inflated volume to functional residual capacity ratio).To determine whether plateau pressure and tidal volume are adequate surrogates for stress and strain, and to quantify the stress to strain relationship in patients and control subjects.Nineteen postsurgical healthy patients (group 1), 11 patients with medical diseases (group 2), 26 patients with acute lung injury (group 3), and 24 patients with acute respiratory distress syndrome (group 4) underwent a positive end-expiratory pressure (PEEP) trial (5 and 15 cm H2O) with 6, 8, 10, and 12 ml/kg tidal volume.Plateau airway pressure, lung and chest wall elastances, and lung stress and strain significantly increased from groups 1 to 4 and with increasing PEEP and tidal volume. Within each group, a given applied airway pressure produced largely variable stress due to the variability of the lung elastance to respiratory system elastance ratio (range, 0.33-0.95). Analogously, for the same applied tidal volume, the strain variability within subgroups was remarkable, due to the functional residual capacity variability. Therefore, low or high tidal volume, such as 6 and 12 ml/kg, respectively, could produce similar stress and strain in a remarkable fraction of patients in each subgroup. In contrast, the stress to strain ratio-that is, specific lung elastance-was similar throughout the subgroups (13.4 +/- 3.4, 12.6 +/- 3.0, 14.4 +/- 3.6, and 13.5 +/- 4.1 cm H2O for groups 1 through 4, respectively; P = 0.58) and did not change with PEEP and tidal volume.Plateau pressure and tidal volume are inadequate surrogates for lung stress and strain. Clinical trial registered with www.clinicaltrials.gov (NCT 00143468).
p18<i>Ink4c</i> Collaborates with <i>Men1</i> to Constrain Lung Stem Cell Expansion and Suppress Non–Small-Cell Lung Cancers
Authors: Xin-Hai Pei, Feng Bai, Matthew D. Smith, Yue Xiong
Journal: Cancer Research (2007)

Mutant mice lacking both cyclin-dependent kinase (CDK) inhibitors p18(Ink4c) and p27(Kip1) develop a tumor spectrum reminiscent of human multiple endocrine neoplasia (MEN) syndromes. To determine how p18 and p27 genetically interact with Men1, the tumor suppressor gene mutated in familial MEN1, we characterized p18-Men1 and p27-Men1 double mutant mice and showed that p18, but not p27, functionally collaborates with Men1 in suppressing lung tumorigenesis. Lung tumors developed in both Men1(+/-) and p18(-/-);Men1(+/-) mice at a high penetrance and contain both neuroendocrine and nonneuroendocrine cells. The remaining wild-type Men1 allele was lost in most lung tumors from Men1(+/-) mice but was retained in most tumors from p18(-/-);Men1(+/-) mice, showing a functional collaboration between p18 and Men1 in lung tumor suppression. Phosphorylation of Rb protein at both CDK2 and CDK4/CDK6 sites were significantly increased in normal bronchial epithelia and tumor cells derived from p18(-/-);Men1(+/-) mice compared to those from single p18(-/-) or Men1(+/-) mice. Lung tumors developed in p18(-/-);Men1(+/-) mice were multifocal, more heterogeneous, and highly invasive compared to those developed in either p18(-/-) or Men1(+/-) mice. Bronchioalveolar stem cells are expanded in normal and tumorigenic lungs of p18(-/-) mice and are further expanded in p18(-/-);Men1(+/-) lung tumors. These results reveal a previously unrecognized function of p18 in lung tumor suppression through collaboration with Men1 to control lung stem cell proliferation.
Endocardial and epicardial infarct size after preconditioning by a partial coronary artery occlusion without intervening reperfusion. Importance of the degree and duration of flow reduction
Authors: M. M.G. Koning, B. C.G. Gho, E. van Klaarwater, D. J. Duncker, P. D. Verdouw
Journal: Cardiovascular Research (1995)

Objective: Recently, we reported that a partial coronary artery occlusion immediately preceding a sustained coronary artery occlusion limited infarct size. We now investigated whether the protection by partial coronary artery occlusions (i) depends on the severity and(or) duration of the flow reduction and (ii) varies in the different myocardial layers. Methods: In 71 open-chest pigs (eight groups) left ventricular area at risk (AR) and infarct area (IA) were determined for the endocardial (IAendo and ARendo) and epicardial halves (IAepi and ARepi). Results: In control animals (60 min total coronary artery occlusion (TCO) followed by 120 min reperfusion (Rep)) there were highly linear relations between LA and AR in the endocardium (r = 0.98, P < 0.01) and epicardium (r = 0.97, P < 0.01), which could be described by IAendo = 1.01ARendo − 4.5 and by IAepi = 0.88ARepi − 3.6, respectively. In animals that underwent a 10 min TCO + 15 min Rep prior to the 60 min TCO + 120 min Rep, IA in both myocardial layers were again highly linearly related with AR, with less steep slopes for both the endocardium (0.63) and epicardium (0.57) (both P < 0.01). Two groups of pigs were subjected to either a 30 or 90 min 70% reduction in coronary blood flow (FR) immediately preceding the 60 min TCO + 120 min Rep, without intervening reperfusion. A 30 min 70% FR decreased IA to the same degree in the endo- and epicardial half. A 90 min 70% FR resulted in protection in the epicardium (P < 0.01) but not in the endocardium, most likely because 90 min 70% FR without 60 min TCO already caused infarction which was more severe in the endo- than in the epicardium (P < 0.01). Endocardial and epicardial IA after either a 30 or 90 min 30% FR prior to the 60 min TCO was not different from that in the control group, indicating that this mild flow reduction failed to limit irreversible damage. Conclusions: Thirty or ninety min of severe (70%) but not mild (30%) coronary flow reductions protected against myocardial infarction. The protection by a 70% FR was influenced by the duration of FR as a 30 min 70% FR similarly decreased IA in the endocardial and epicardial halves, while 90 min 70% FR preferentially limited IA in the epicardial half. These findings suggest that perfusion abnormalities immediately preceding an infarction could be an important source of infarct size variability in patients.
Reduced Toxicity and Superior Therapeutic Activity of a Mitomycin C Lipid-Based Prodrug Incorporated in Pegylated Liposomes
Authors: Alberto A. Gabizon, Dinah Tzemach, Aviva T. Horowitz, Hilary Shmeeda, Jerry Yeh, Samuel Zalipsky
Journal: Clinical Cancer Research (2006)

Abstract Purpose: A lipid-based prodrug of mitomycin C [MMC; 2,3-(distearoyloxy)propane-1-dithio-4′-benzyloxycarbonyl-MMC] was designed for liposome formulation. The purpose of this study was to examine the in vitro cytotoxicity, pharmacokinetics, in vivo toxicity, and in vivo antitumor activity of this new lipid-based prodrug formulated in polyethylene glycol–coated (pegylated) liposomes. Experimental Design: MMC was released from the MMC lipid–based prodrug (MLP) by thiolytic-induced cleavage with a variety of thiol-containing reducing agents. MLP was incorporated with nearly 100% efficiency in cholesterol-free pegylated liposomes with hydrogenated phosphatidylcholine as the main component and a mean vesicle size of ∼90 nm. This formulation was used for in vitro and in vivo tests in rodents. Results: In vitro, the cytotoxic activity of pegylated liposomal MLP (PL-MLP) was drastically reduced compared with free MMC. However, in the presence of reducing agents, such as cysteine or N-acetyl-cysteine, its activity increased to nearly comparable levels to those of free MMC. Intravenous administration of PL-MLP in rats resulted in a slow clearance indicating stable prodrug retention in liposomes and long circulation time kinetics, with a pharmacokinetic profile substantially different from that of free MMC. In vivo, PL-MLP was ∼3-fold less toxic than free MMC. The therapeutic index and absolute antitumor efficacy of PL-MLP were superior to that of free MMC in the three tumor models tested. In addition, PL-MLP was significantly more active than a formulation of doxorubicin in pegylated liposomes (DOXIL) in the M109R tumor model, a mouse tumor cell line with a multidrug-resistant phenotype. Conclusions: Delivery of MLP in pegylated liposomes is a potential approach for effective treatment of multidrug-resistant tumors while significantly buffering the toxicity of MMC.
γ-Secretase Inhibitors Abrogate Oxaliplatin-Induced Activation of the Notch-1 Signaling Pathway in Colon Cancer Cells Resulting in Enhanced Chemosensitivity
Authors: Raymond D. Meng, Christopher C. Shelton, Yue-Ming Li, Li-Xuan Qin, Daniel Notterman, Philip B. Paty, Gary K. Schwartz
Journal: Cancer Research (2009)

Abstract Because Notch signaling is implicated in colon cancer tumorigenesis and protects cells from apoptosis by inducing prosurvival targets, it was hypothesized that inhibition of Notch signaling with γ-secretase inhibitors (GSI) may enhance the chemosensitivity of colon cancer cells. We first show that the Notch-1 receptor, as well as its downstream target Hes-1, is up-regulated with colon cancer progression, similar to other genes involved in chemoresistance. We then report that chemotherapy induces Notch-1, as oxaliplatin, 5-fluorouracil (5-FU), or SN-38 (the active metabolite of irinotecan) induced Notch-1 intracellular domain (NICD) protein and activated Hes-1. Induction of NICD by oxaliplatin was caused by an increase in the activity and expression of γ-secretase complex, as suppression of the protein subunit nicastrin with small interfering RNA (siRNA) prevented NICD induction after oxaliplatin. Subsequent inhibition of Notch-1 signaling with a sulfonamide GSI (GSI34) prevented the induction of NICD by chemotherapy and blunted Hes-1 activation. Blocking the activation of Notch signaling with GSI34 sensitized cells to chemotherapy and was synergistic with oxaliplatin, 5-FU, and SN-38. This chemosensitization was mediated by Notch-1, as inhibition of Notch-1 with siRNA enhanced chemosensitivity whereas overexpression of NICD increased chemoresistance. Down-regulation of Notch signaling also prevented the induction of prosurvival pathways, most notably phosphoinositide kinase-3/Akt, after oxaliplatin. In summary, colon cancer cells may up-regulate Notch-1 as a protective mechanism in response to chemotherapy. Therefore, combining GSIs with chemotherapy may represent a novel approach for treating metastatic colon cancers by mitigating the development of chemoresistance. [Cancer Res 2009;69(2):573–82]