tbuckley/cabot-search huggingface dataset:
Visualization of Protease Activity In Vivo Using an Activatable Photo-Acoustic Imaging Probe Based on CuS Nanoparticles
Authors: Kai Yang, Lei Zhu, Liming Nie, Xiaolian Sun, Liang Cheng, Chenxi Wu, Gang Niu, Xiaoyuan Chen, Zhuang Liu
Journal: Theranostics (2014)

Herein, we for the first time report a novel activatable photoacoustic (PA) imaging nano-probe for in vivo detection of cancer-related matrix metalloproteinases (MMPs). A black hole quencher 3 (BHQ3) which absorbs red light is conjugated to near-infrared (NIR)-absorbing copper sulfide (CuS) nanoparticles via a MMP-cleavable peptide linker. The obtained CuS-peptide-BHQ3 (CPQ) nano-probe exhibits two distinctive absorption peaks at 630 nm and 930 nm. Inside the tumor microenvironment where MMPs present, the MMP-sensitive peptide would be cleaved, releasing BHQ3 from the CuS nanoparticles, the former of which as a small molecule is then rapidly cleared out from the tumor, whereas the latter of which as large nanoparticles would retain inside the tumor for a much longer period of time. As the result, the PA signal at 680 nm which is contributed by BHQ3 would be quickly diminished while that at 930 nm would be largely retained. The PA signal ratio of 680 nm / 930 nm could thus serve as an in vivo indicator of MMPs activity inside the tumor. Our work presents a novel strategy of in vivo sensing of MMPs based on PA imaging, which should offer remarkably improved detection depth compared with traditional optical imaging techniques.
Mechanism of cocaine-induced myocardial depression in dogs.
Authors: T D Fraker, P N Temesy-Armos, P S Brewster, R D Wilkerson
Journal: Circulation (1990)

Cocaine causes pronounced depression of left ventricular function in conscious dogs immediately after intravenous administration. To examine this effect, 14 mongrel dogs were anesthetized with pentobarbital sodium (32 mg/kg) and instrumented with arterial and venous catheters and a Doppler blood flow transducer on the left circumflex coronary artery. Two weeks later, heart rate, blood pressure, coronary blood flow, and regional left ventricular ejection fraction (by two-dimensional echocardiography) were measured before and 1, 2, 5, and 10 minutes after cocaine (4 mg/kg i.v.), while the animals were fully conscious. Heart rate, blood pressure, and coronary blood flow were increased significantly at each time after cocaine. Regional ejection fraction, however, was depressed by 50 +/- 7%, 35 +/- 4%, and 21 +/- 4% at 1, 2, and 5 minutes after cocaine treatment, respectively. Ten minutes after cocaine treatment, regional ejection fraction had recovered to a level not significantly different from baseline. Because the observed myocardial depression after cocaine was accompanied by a large increase in the rate-pressure product, and presumably, myocardial oxygen consumption, this depression could have been secondary to increased myocardial oxygen demand not appropriately matched by an increase in coronary blood flow. To minimize the effects of cocaine on myocardial oxygen demand, a subset of six dogs received cocaine (4 mg/kg i.v.) while sedated with pentobarbital (25 mg/kg). In these dogs, cocaine did not significantly alter heart rate or blood pressure; however, regional ejection fraction was significantly depressed by 44 +/- 5% and 36 +/- 6% at 1 and 2 minutes after cocaine treatment, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
Clinical Evaluation of the Delivery and Safety of Aerosolized Liposomal 9-Nitro-20(S)-Camptothecin in Patients with Advanced Pulmonary Malignancies
Authors: Claire F. Verschraegen, Brian E. Gilbert, Evelyne Loyer, Armando Huaringa, Garrett Walsh, Robert A. Newman, Vernon Knight
Journal: Clinical Cancer Research (2004)

Abstract Purpose: The purpose is to evaluate the feasibility and safety of aerosol administration of the topoisomerase I inhibitor, 9-nitrocamptothecin, in a liposome formulation, and to recommend a dosage for a Phase II trial for an 8-week daily treatment schedule. Experimental Design: Patients with primary or metastatic lung cancer received aerosolized liposomal 9-nitrocamptothecin for 5 consecutive days/week for 1, 2, 4, or 6 weeks followed by 2 weeks of rest to determine feasibility. For the Phase I part, the dose was increased stepwise from 6.7 up to 26.6 μg/kg/day Monday to Friday for 8 weeks followed by 2 weeks of rest. Results: Twenty-five patients received treatment. The mean baseline forced expiratory volume in 1 second for all patients was 85% of predicted. A dose-limiting toxicity was chemical pharyngitis seen after 1 week in 2 of 2 patients at 26.6 μg/kg/day. At 20.0 μg/kg/day, grade 2 and 3 fatigue prompting a dose reduction was seen after 4 weeks in 2 of 4 patients. Grade 2 toxic effects included nausea/vomiting (9 patients), cough and bronchial irritation (6 patients), fatigue (5 patients), anemia (4 patients), neutropenia (2 patients), anorexia (1 patient), and skin rash around the face mask (1 patient). 9-Nitro-20(S)-camptothecin (9NC) was absorbed systemically. Partial remissions were observed in 2 patients with uterine cancer, and stabilization occurred in 3 patients with primary lung cancer. Conclusions: Aerosol administration of liposomal 9NC was found to be feasible and safe. 9NC delivered as an aerosol was detected in patient’s plasma shortly after the start of treatment. The recommended dose for Phase II studies is 13.3 μg/kg/day (equivalent to 0.5 mg/m2/day), which constitutes two consecutive 30-min nebulizations/day from a nebulizer reservoir with 4 mg of 9NC in 10 ml of sterile water, Monday to Friday for 8 weeks every 10 weeks.
Cytomegalovirus infection in Crohn's colitis
Authors: S Olsen, J Gilbert
Journal: Journal of the Royal Society of Medicine (2004)

Most of the malrotations that are recognized are causing no symptoms and are diagnosed incidentally on radiography. 7The risk of this malformation is that it predisposes to a midgut volvulus due to a narrow mesenteric fixation.Patients can present acutely, with intestinal obstruction and ischaemia, or may experience years of vague abdominal pain and recurrent attacks of retching or vomiting. 8ontrast studies may reveal duodenal obstruction, duodenojejunal flexure located to the right of the spine and small bowel confined to the right side of abdomen, 4 but a normal small-bowel study does not exclude the possibility of malrotation 7 and barium enema may be necessary.Computed tomography may detect a midgut malrotation, with or without volvulus, by demonstrating spiralling of the mesentery around the superior mesenteric artery and the superior mesenteric vein lying to the left of the artery. 9,10his vascular anatomy may also be evident on duplex ultrasound. 11Surgical treatment entails counter-clockwise untwisting of the volvulus and careful assessment of bowel viability.Any abnormal bands should be divided (Ladd's procedure).Normal anatomy of the intestinal tract can be restored by duodenopexy and suture fixation of the caecum and ascending colon to the right abdominal wall and retroperitoneum.
Results of Dasatinib Therapy in Patients With Early Chronic-Phase Chronic Myeloid Leukemia
Authors: Jorge E. Cortes, Dan Jones, Susan O'Brien, Elias Jabbour, Farhad Ravandi, Charles Koller, Gautam Borthakur, Brenda Walker, Weiqiang Zhao, Jianqin Shan, Hagop Kantarjian
Journal: Journal of Clinical Oncology (2009)

Purpose Dasatinib is effective therapy for chronic myeloid leukemia (CML) after imatinib failure. In this study, we investigate the efficacy of dasatinib as initial therapy for patients with CML in early chronic phase. Patients and Methods Patients with newly diagnosed CML in early chronic phase were randomly assigned to receive dasatinib 100 mg once daily or 50 mg twice daily as initial therapy. Results Among 50 patients observed for at least 3 months, 49 patients (98%) achieved a complete cytogenetic response (CCyR), and 41 patients (82%) achieved a major molecular response (MMR). Responses occurred rapidly, with 94% of patients achieving CCyR by 6 months. There was no difference in response rate by treatment arm. The projected event-free survival rate at 24 months is 88%, and all patients are alive after a median follow-up time of 24 months. Grade ≥ 3 neutropenia and thrombocytopenia occurred in 21% and 10% of patients, respectively. Nonhematologic toxicity was usually grade 1 to 2. There was no significant difference in toxicity between the two arms, and the actual median dose at 12 months was 100 mg (range, 20 to 100 mg). Conclusion Dasatinib is an effective agent for the initial management of CML in early chronic phase, producing high rates of CCyR and MMR.
Dietary calcium intake and rates of bone loss in women.
Authors: B L Riggs, H W Wahner, L J Melton, L S Richelson, H L Judd, W M O'Fallon
Journal: Journal of Clinical Investigation (1987)

We measured bone mineral density (BMD) at the midradius and lumbar spine in 106 normal women, ages 23-84 yr (61 were postmenopausal). Three to nine measurements (median, four) were made over 2.6 to 6.6 yr (mean, 4.1 yr). The correlation between calcium intake (range, 260-2,035 mg/d) and rate of change in BMD was not significant at the midradius (r = 0.06) or lumbar spine (r = 0.08), even after adjusting for age, menopausal status, and serum estrogen levels by multiple regression analysis. Women in the lower (mean, 501 mg/d) and in the upper (mean, 1,397 mg/d) quartiles of dietary intake had similar rates of change in BMD (%/yr [mean +/- SE], at midradius, -0.78 +/- 0.24 and -0.91 +/- 0.17 for lower and upper quartiles, respectively; at lumbar spine, -1.06 +/- 0.24 and 0.98 +/- 0.24). These data do not support the hypothesis that insufficient dietary calcium is a major cause of bone loss in women.
International Union of Basic and Clinical Pharmacology. LXXXI. Nomenclature and Classification of Adenosine Receptors—An Update
Authors: Bertil B. Fredholm, Adriaan P. IJzerman, Kenneth A. Jacobson, Joel Linden, Christa E. Müller
Journal: Pharmacological Reviews (2011)

In the 10 years since our previous International Union of Basic and Clinical Pharmacology report on the nomenclature and classification of adenosine receptors, no developments have led to major changes in the recommendations. However, there have been so many other developments that an update is needed. The fact that the structure of one of the adenosine receptors has recently been solved has already led to new ways of in silico screening of ligands. The evidence that adenosine receptors can form homo- and heteromultimers has accumulated, but the functional significance of such complexes remains unclear. The availability of mice with genetic modification of all the adenosine receptors has led to a clarification of the functional roles of adenosine, and to excellent means to study the specificity of drugs. There are also interesting associations between disease and structural variants in one or more of the adenosine receptors. Several new selective agonists and antagonists have become available. They provide improved possibilities for receptor classification. There are also developments hinting at the usefulness of allosteric modulators. Many drugs targeting adenosine receptors are in clinical trials, but the established therapeutic use is still very limited.
Loss of Collapsin Response Mediator Protein1, as Detected by iTRAQ Analysis, Promotes Invasion of Human Gliomas Expressing Mutant EGFRvIII
Authors: Joydeep Mukherjee, Leroi V. DeSouza, Johann Micallef, Zia Karim, Sid Croul, K.W. Michael Siu, Abhijit Guha
Journal: Cancer Research (2009)

Abstract Glioblastoma multiforme (GBM) is the most common and lethal primary human brain tumor. GBMs are characterized by a variety of genetic alterations, among which oncogenic mutations of epidermal growth factor receptor (EGFRvIII) is most common. GBMs harboring EGFRvIII have increased proliferation and invasive characteristics versus those expressing wild-type (wt) EGFR. To identify the molecular basis of this increased tumorgenic phenotype, we used iTRAQ-labeling differential proteomic analysis. Among several differentially expressed proteins, we selected CRMP1, a protein implicated in cellular invasion that was markedly decreased in GBMs expressing EGFRvIII, for further study. The differential expression of CRMP1 was confirmed in a panel of human GBM cell lines and operative specimens that express wtEGFR or mutant EGFRvIII by quantitative real-time PCR, Western blot, and immunohistochemical analysis. In human GBM samples, decreased expression of CRMP1 correlated with EGFRvIII positivity. Knockdown of CRMP1 by siRNA resulted in increased invasion of wtEGFR expressing human GBM cells (U87 and U373) to those found in isogenic GBM cells. Exogenous expression of EGFRvIII in these wtEGFR-expressing GBM cells promoted their ability to invade and was accompanied by decreased expression of CRMP1. Rescuing CRMP1 expression decreased invasion of the EGFRvIII-expressing GBM cells by tilting the balance between Rac and Rho. Collectively, these results show that the loss of CRMP1 contribute to the increased invasive phenotype of human GBMs expressing mutant EGFRvIII. [Cancer Res 2009;69(22):8545–54]
Definition of treatment response in rheumatoid arthritis based on the simplified and the clinical disease activity index
Authors: Daniel Aletaha, Jose Martinez-Avila, Tore K Kvien, Josef S Smolen
Journal: Annals of the Rheumatic Diseases (2012)

<h3>Background</h3> The simplified disease activity index (SDAI) and the clinical disease activity index (CDAI) are established instruments to measure disease activity in rheumatoid arthritis (RA). To date, no validated response definitions for the SDAI and CDAI are available. <h3>Objective</h3> The authors aimed to define minor, moderate and major response criteria for the SDAI. <h3>Methods</h3> The authors used data from two clinical trials on infliximab versus methotrexate in early (ASPIRE) or established (ATTRACT) RA, and identified the three SDAI cutpoints based on the best agreement (by κ statistics) with the American College of Rheumatology (ACR)20/50/70 responses. Cutpoints were then tested for different aspects of validity in the trial datasets and in a Norwegian disease modifying antirheumatic drug prescription dataset (NOR-DMARD). <h3>Results</h3> Based on agreement with the ACR response, the minor, moderate and major responses were identified as SDAI 50%, 70% and 85% improvement. These cutpoints had good face validity concerning the disease activity states achieved by the different response definitions. Construct validity was shown by a clear association of increasing SDAI response categories with increasing levels of functional improvement, achievement of better functional states and lower annual radiographic progression. Across SDAI 50/70/85, the sensitivities regarding a patient-perceived improvement decreased (73%/39%/22%) and the specificities increased (61%/89%/96%) in a meaningful way. Further, the cutpoints discriminated the different treatment arms in ASPIRE and ATTRACT. The same cutpoints were used for the CDAI, with similar results in the validation analyses. <h3>Conclusion</h3> These new response criteria expand the usefulness of the SDAI and CDAI for their use as endpoints in clinical trials beyond the definition of disease activity categories.
Bradycardia-Induced Coronary Angiogenesis Is Dependent on Vascular Endothelial Growth Factor
Authors: Wei Zheng, Margaret D. Brown, Tommy A. Brock, Robert J. Bjercke, Robert J. Tomanek
Journal: Circulation Research (1999)

Abstract —A marked coronary angiogenesis is known to occur with chronic bradycardia. We tested the hypothesis that vascular endothelial growth factor (VEGF), an endothelial cell mitogen and a major regulator of angiogenesis, is upregulated in response to low heart rate and consequential increased stroke volume. Bradycardia was induced in rats by administering the bradycardic drug alinidine (3 mg/kg body weight) twice daily. Heart rate decreased by 32% for 20 to 40 minutes after injection and was chronically reduced by 10%, 14%, and 18.5% after 1, 2, and 3 weeks of treatment, respectively. Arterial pressure and cardiac output were unchanged. Left ventricular capillary length density (mm/mm 3 ) increased gradually with alinidine administration; a 15% increase after 2 weeks and a 40% increase after 3 weeks of alinidine treatment were documented. Left ventricular weight, body weight, and their ratio were not significantly altered by alinidine treatment. After 1 week of treatment, before an increase in capillary length density, VEGF mRNA increased &gt;2-fold and then declined to control levels after 3 weeks of treatment. VEGF protein was higher in alinidine-treated rats than in controls after 2 weeks and increased further after 3 weeks of treatment. Injection of VEGF-neutralizing antibodies over a 2-week period completely blocked alinidine-stimulated angiogenesis. In contrast, bFGF mRNA was not altered by alinidine treatment. These data suggest that VEGF plays a key role in the angiogenic response that occurs with chronic bradycardia. The mechanism underlying this VEGF-associated angiogenesis may be an increase in stretch due to enhanced diastolic filling.
Induction of PD-L1 Expression by the EML4–ALK Oncoprotein and Downstream Signaling Pathways in Non–Small Cell Lung Cancer
Authors: Keiichi Ota, Koichi Azuma, Akihiko Kawahara, Satoshi Hattori, Eiji Iwama, Junko Tanizaki, Taishi Harada, Koichiro Matsumoto, Koichi Takayama, Shinzo Takamori, Masayoshi Kage, Tomoaki Hoshino, Yoichi Nakanishi, Isamu Okamoto
Journal: Clinical Cancer Research (2015)

Therapies targeted to the immune checkpoint mediated by PD-1 and PD-L1 show antitumor activity in a subset of patients with non-small cell lung cancer (NSCLC). We have now examined PD-L1 expression and its regulation in NSCLC positive for the EML4-ALK fusion gene.The expression of PD-L1 at the protein and mRNA levels in NSCLC cell lines was examined by flow cytometry and by reverse transcription and real-time PCR analysis, respectively. The expression of PD-L1 in 134 surgically resected NSCLC specimens was evaluated by immunohistochemical analysis.The PD-L1 expression level was higher in NSCLC cell lines positive for EML4-ALK than in those negative for the fusion gene. Forced expression of EML4-ALK in Ba/F3 cells markedly increased PD-L1 expression, whereas endogenous PD-L1 expression in EML4-ALK-positive NSCLC cells was attenuated by treatment with the specific ALK inhibitor alectinib or by RNAi with ALK siRNAs. Furthermore, expression of PD-L1 was downregulated by inhibitors of the MEK-ERK and PI3K-AKT signaling pathways in NSCLC cells positive for either EML4-ALK or activating mutations of the EGFR. Finally, the expression level of PD-L1 was positively associated with the presence of EML4-ALK in NSCLC specimens.Our findings that both EML4-ALK and mutant EGFR upregulate PD-L1 by activating PI3K-AKT and MEK-ERK signaling pathways in NSCLC reveal a direct link between oncogenic drivers and PD-L1 expression.
HLA HAPLOTYPE AND HIV INFECTION
Authors: Liliane Hallé, Françoise Castellano, Cécile Kaplan, Jean-Jacques Lefrère, Denise Salmon, Charles Salmon, I. Pabinger, K. Lechner, P.A. Kyrle, A.Hajek Rosenmayr, M. Kirnbauer
Journal: The Lancet (1988)
Evaluation of Midkine as a Diagnostic Serum Biomarker in Hepatocellular Carcinoma
Authors: Wen-Wei Zhu, Jia-Jian Guo, Lei Guo, Hu-Liang Jia, Ming Zhu, Ju-Bo Zhang, Christopher A. Loffredo, Marshonna Forgues, Hua Huang, Xu-Jian Xing, Ning Ren, Qiong-Zhu Dong, Hai-Jun Zhou, Zheng-Gang Ren, Nai-Qing Zhao, Xin Wei Wang, Zhao-You Tang, Lun-Xiu Qin, Qing-Hai Ye
Journal: Clinical Cancer Research (2013)

To evaluate the value of serum midkine (MDK) as a diagnostic biomarker in hepatocellular carcinoma, particularly for those with negative alpha-fetoprotein (AFP) and at an early stage.
Tetrandrine Induces Early G1 Arrest in Human Colon Carcinoma Cells by Down-Regulating the Activity and Inducing the Degradation of G1-S–Specific Cyclin-Dependent Kinases and by Inducing p53 and p21Cip1
Authors: Ling-hua Meng, Hongliang Zhang, Larry Hayward, Haruyuki Takemura, Rong-Guang Shao, Yves Pommier
Journal: Cancer Research (2004)

Abstract Tetrandrine is an antitumor alkaloid isolated from the root of Stephania tetrandra. We find that micromolar concentrations of tetrandrine irreversibly inhibit the proliferation of human colon carcinoma cells in MTT and clonogenic assays by arresting cells in G1. Tetrandrine induces G1 arrest before the restriction point in nocodazole- and serum-starved synchronized HT29 cells, without affecting the G1-S transition in aphidicolin-synchronized cells. Tetrandrine-induced G1 arrest is followed by apoptosis as shown by fluorescence-activated cell sorting, terminal deoxynucleotidyl transferase–mediated nick end labeling, and annexin V staining assays. Tetrandrine-induced early G1 arrest is mediated by at least three different mechanisms. First, tetrandrine inhibits purified cyclin-dependent kinase 2 (CDK2)/cyclin E and CDK4 without affecting significantly CDK2/cyclin A, CDK1/cyclin B, and CDK6. Second, tetrandrine induces the proteasome-dependent degradation of CDK4, CDK6, cyclin D1, and E2F1. Third, tetrandrine increases the expression of p53 and p21Cip1 in wild-type p53 HCT116 cells. Collectively, these results show that tetrandrine arrests cells in G1 by convergent mechanisms, including down-regulation of E2F1 and up-regulation of p53/p21Cip1.
Interleukin-10 inhibits tumor metastasis through an NK cell-dependent mechanism.
Authors: L M Zheng, D M Ojcius, F Garaud, C Roth, E Maxwell, Z Li, H Rong, J Chen, X Y Wang, J J Catino, I King
Journal: The Journal of Experimental Medicine (1996)

Interleukin-10 (IL-10) is a recently described pleiotropic cytokine secreted mainly by type 2 helper T cells. Previous studies have shown that IL-10 suppresses cytokine expression by natural killer (NK) and type 1 T cells, thus down-regulating cell-mediated immunity and stimulating humoral responses. We here report that injected IL-10 protein is an efficient inhibitor of tumor metastasis in experimental (B16-F10) and spontaneous (M27 and Lox human melanoma) metastasis models in vivo at doses that do not have toxic effects on normal or cancer cells. Histological characterization after IL-10 treatment confirmed the absence of CD8+ and CD4+ T cells and macrophages at the sites of tumor growth, but abundant NK cells were localized at these sites. This unexpected finding was confirmed by showing that IL-10 inhibits most B16-F10 and Lox metastases in mice deficient in T or B cells (SCID and nu/nu mice), but not in those deficient in NK cells (beige mice or NK cell-depleted mice). However, IL-10 downregulation of pro-inflammatory cytokine production and/or recruitment of additional effector cells may also be involved in the anti-tumor effect at higher local concentrations of IL-10, since transfected B16 tumor cells expressing high amounts of IL-10 were rejected by normal, nu/nu, or SCID mice at the primary tumor stage, and there was still a 33% inhibition of tumor metastasis in beige mice.
Pentothal Sodium in Mental Hospital Practice
Authors: J. S. Horsley
Journal: BMJ (1936)

I~~~~~~~~~~~~~~~~~~~MEDICAL JOURNAL absence of uraemia and tympanitis, and the rapid disappearance of existing tympanitis after administration of serum, are definite indications of its neutralizing action on the toxin.We have not yet been able to find a suitable method -for the titration of the serum.The method of titration on rabbits seems to be too expensive for adoption as a routine procedure.