tbuckley/cabot-search huggingface dataset:
Old Drug New Use—Amoxapine and Its Metabolites as Potent Bacterial β-Glucuronidase Inhibitors for Alleviating Cancer Drug Toxicity
Authors: Ren Kong, Timothy Liu, Xiaoping Zhu, Syed Ahmad, Alfred L. Williams, Alexandria T. Phan, Hong Zhao, John E. Scott, Li-An Yeh, Stephen T.C. Wong
Journal: Clinical Cancer Research (2014)

Abstract Purpose: Irinotecan (CPT-11) induced diarrhea occurs frequently in patients with cancer and limits its usage. Bacteria β-glucuronidase (GUS) enzymes in intestines convert the nontoxic metabolite of CPT-11, SN-38G, to toxic SN-38, and finally lead to damage of intestinal epithelial cells and diarrhea. We previously reported amoxapine as a potent GUS inhibitor in vitro. To further understand the molecular mechanism of amoxapine and its potential for treatment of CPT-11–induced diarrhea, we studied the binding modes of amoxapine and its metabolites by docking and molecular dynamics simulation, and tested the in vivo efficacy on mice in combination with CPT-11. Experimental Design: The binding of amoxapine, its metabolites, 7-hydroxyamoxapine and 8-hydroxyamoxapine, and a control drug loxapine with GUS was explored by computational protocols. The in vitro potencies of metabolites were measured by Escherichia coli GUS enzyme and cell-based assay. Low-dosage daily oral administration was designed to use along with CPT-11 to treat tumor-bearing mice. Results: Computational modeling results indicated that amoxapine and its metabolites bound in the active site of GUS and satisfied critical pharmacophore features: aromatic features near bacterial loop residue F365′ and hydrogen bond toward E413. Amoxapine and its metabolites were demonstrated as potent in vitro. Administration of low dosages of amoxapine with CPT-11 in mice achieved significant suppression of diarrhea and reduced tumor growth. Conclusions: Amoxapine has great clinical potential to be rapidly translated to human subjects for irinotecan-induced diarrhea. Clin Cancer Res; 20(13); 3521–30. ©2014 AACR.
Phenotype Switching: Tumor Cell Plasticity as a Resistance Mechanism and Target for Therapy
Authors: Kristel Kemper, Pauline L. de Goeje, Daniel S. Peeper, Renée van Amerongen
Journal: Cancer Research (2014)

Mutations in BRAF are present in the majority of patients with melanoma, rendering these tumors sensitive to targeted therapy with BRAF and MEK inhibitors. Unfortunately, resistance almost invariably develops. Recently, a phenomenon called "phenotype switching" has been identified as an escape route. By switching from a proliferative to an invasive state, melanoma cells can acquire resistance to these targeted therapeutics. Interestingly, phenotype switching bears a striking resemblance to the epithelial-to-mesenchymal-like transition that has been described to occur in cancer stem cells in other tumor types. We propose that these changes are manifestations of one and the same underlying feature, namely a dynamic and reversible phenotypic tumor cell plasticity that renders a proportion of cells both more invasive and resistant to therapy. At the same time, the specific characteristics of these tumor cell populations offer potential for being explored as target for therapeutic intervention.
Optimal inhalation technique with terbutaline Turbuhaler
Authors: OR Hansen, S Pedersen
Journal: European Respiratory Journal (1989)

The bronchodilator response after four different modes of inhalation of 0.25 mg terbutaline from a Turbuhaler was assessed, in a double-blind cross-over study, of 14 asthmatic children aged 8-14 yrs (mean 11.6 yrs). The children inhaled as fast as possible (mean peak inspiratory flow rate = 53 l.min-1), because fast inhalations have been found to be more efficient than slow inhalations when the Turbuhaler is used. Tilting the head back during inhalation and a breath-holding pause of 10 s after the inhalation had no significant effect upon bronchodilation. Furthermore, the response was the same whether the children inhaled from residual volume (RV) or functional residual capacity (FRC). These results suggest that this new inhaler can be used with a very simple inhalation technique without any loss of effect. A simple inhalation technique is likely to facilitate teaching and improve compliance.
Hip fracture and bone histomorphometry in a young adult with cystic fibrosis
Authors: C.S. Haworth, A.j Freemont, A.K. Webb, M.E. Dodd, P.l Selby, E.b Mawer, J.e Adams
Journal: European Respiratory Journal (1999)

Three children who presented with steroid-resistant airflow obstruction are described. They all had bronchomalacia in the setting of a rare visceral arrangement, namely left bronchial isomerism with normal atrial arrangement. Imaging and, in two cases, a normal residual volume in the face of severe airflow obstruction were diagnostic pointers to a nonasthmatic cause of wheeze. Although the association of these abnormalities may be coincidental, together they may constitute a new clinical syndrome.
Increased bronchial responsiveness in primary and secondary Sjogren's syndrome
Authors: A Potena, R La Corte, LM Fabbri, A Papi, F Trotta, A Ciaccia
Journal: European Respiratory Journal (1990)

We examined one group of 33 patients with primary Sjögren's syndrome, one group of 17 patients with secondary Sjögren's syndrome, i.e. associated with other connective tissue diseases, and one group of 14 patients with connective tissue diseases but without Sjögren's syndrome. In each patient we obtained chest radiographs and measured lung volumes, carbon monoxide diffusing capacity and airway responsiveness to methacholine. We observed no difference in chest radiograph abnormalities, in lung volumes and in carbon monoxide diffusing capacity among the three groups. However, we found a slight but significant increase of bronchial responsiveness in patients with primary and secondary Sjögren's syndrome compared with patients with connective tissue disorders but without Sjögren's syndrome. Thus PD20FEV1 methacholine was 1.07 mg (1.2) (geometric mean and GSEM) in primary Sjögren's syndrome, 0.91 mg (1.4) in secondary Sjögren's syndrome (NS), and 2.24 mg (1.09) in patients with connective tissue diseases but without Sjögren's syndrome (t = 2.59 and t = 2.8, both p less than 0.05, vs primary and secondary Sjögren's syndrome, respectively). These results show that some patients with Sjögren's syndrome have mild bronchial hyperresponsiveness, which may be related to the specific airway abnormalities of this disease.
Eight-year experience with allogeneic stem cell transplantation for relapsed follicular lymphoma after nonmyeloablative conditioning with fludarabine, cyclophosphamide, and rituximab
Authors: Issa F. Khouri, Peter McLaughlin, Rima M. Saliba, Chitra Hosing, Martin Korbling, Ming S. Lee, L. Jeffrey Medeiros, Luis Fayad, Felipe Samaniego, Amin Alousi, Paolo Anderlini, Daniel Couriel, Marcos de Lima, Sergio Giralt, Sattva S. Neelapu, Naoto T. Ueno, Barry I. Samuels, Fredrick Hagemeister, Larry W. Kwak, Richard E. Champlin
Journal: Blood (2008)
Colony-Forming Ability of a Lymphoid and a Myeloid Murine Leukemia2
Authors: M. Boranić, M. Dominis, Z. Pavelić, M. Blaži-Polja
Journal: JNCI Journal of the National Cancer Institute (1973)

Journal Article Colony-Forming Ability of a Lymphoid and a Myeloid Murine Leukemia Get access M. Boranić, M. Boranić Laboratory for Experimental Therapy, Department of Experimental Biology and Meclicine, Rudjer Bosković Institute: and Department of Pathologic Anatomy, Medical Faculty, University of Zagreb, Zagreb, Yugoslavia Search for other works by this author on: Oxford Academic PubMed Google Scholar M. Dominis, M. Dominis Laboratory for Experimental Therapy, Department of Experimental Biology and Meclicine, Rudjer Bosković Institute: and Department of Pathologic Anatomy, Medical Faculty, University of Zagreb, Zagreb, Yugoslavia Search for other works by this author on: Oxford Academic PubMed Google Scholar Z. Pavelić, Z. Pavelić Laboratory for Experimental Therapy, Department of Experimental Biology and Meclicine, Rudjer Bosković Institute: and Department of Pathologic Anatomy, Medical Faculty, University of Zagreb, Zagreb, Yugoslavia Search for other works by this author on: Oxford Academic PubMed Google Scholar M. Blaži-Polja M. Blaži-Polja Laboratory for Experimental Therapy, Department of Experimental Biology and Meclicine, Rudjer Bosković Institute: and Department of Pathologic Anatomy, Medical Faculty, University of Zagreb, Zagreb, Yugoslavia Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 51, Issue 1, July 1973, Pages 275–282, https://doi.org/10.1093/jnci/51.1.275 Published: 01 July 1973 Article history Received: 05 March 1973 Accepted: 29 March 1973 Published: 01 July 1973
Time Course of Pathogenic and Adaptation Mechanisms in Cystinotic Mouse Kidneys
Authors: Héloïse P. Gaide Chevronnay, Virginie Janssens, Patrick Van Der Smissen, Francisca N’Kuli, Nathalie Nevo, Yves Guiot, Elena Levtchenko, Etienne Marbaix, Christophe E. Pierreux, Stéphanie Cherqui, Corinne Antignac, Pierre J. Courtoy
Journal: Journal of the American Society of Nephrology (2014)

Cystinosis, a main cause of Fanconi syndrome, is reproduced in congenic C57BL/6 cystinosin knockout (KO) mice. To identify the sequence of pathogenic and adaptation mechanisms of nephropathic cystinosis, we defined the onset of Fanconi syndrome in KO mice between 3 and 6 months of age and analyzed the correlation with structural and functional changes in proximal tubular cells (PTCs), with focus on endocytosis of ultrafiltrated disulfide-rich proteins as a key source of cystine. Despite considerable variation between mice at the same age, typical event sequences were delineated. At the cellular level, amorphous lysosomal inclusions preceded cystine crystals and eventual atrophy without crystals. At the nephron level, lesions started at the glomerulotubular junction and then extended distally. In situ hybridization and immunofluorescence revealed progressive loss of expression of megalin, cubilin, sodium-glucose cotransporter 2, and type IIa sodium-dependent phosphate cotransporter, suggesting apical dedifferentiation accounting for Fanconi syndrome before atrophy. Injection of labeled proteins revealed that defective endocytosis in S1 PTCs led to partial compensatory uptake by S3 PTCs, suggesting displacement of endocytic load and injury by disulfide-rich cargo. Increased PTC apoptosis allowed luminal shedding of cystine crystals and was partially compensated for by tubular proliferation. We conclude that lysosomal storage triggered by soluble cystine accumulation induces apical PTC dedifferentiation, which causes transfer of the harmful load of disulfide-rich proteins to more distal cells, possibly explaining longitudinal progression of swan-neck lesions. Furthermore, our results suggest that subsequent adaptation mechanisms include lysosomal clearance of free and crystalline cystine into urine and ongoing tissue repair.
Analgesic Effect of Auricular Acupuncture for Cancer Pain: A Randomized, Blinded, Controlled Trial
Authors: David Alimi, Carole Rubino, Evelyne Pichard-Léandri, Sabine Fermand-Brulé, Marie-Laure Dubreuil-Lemaire, Catherine Hill
Journal: Journal of Clinical Oncology (2003)

During the last 30 years, auricular acupuncture has been used as complementary treatment of cancer pain when analgesic drugs do not suffice. The purpose of this study is to examine the efficacy of auricular acupuncture in decreasing pain intensity in cancer patients.Ninety patients were randomly divided in three groups; one group received two courses of auricular acupuncture at points where an electrodermal signal had been detected, and two placebo groups received auricular acupuncture at points with no electrodermal signal (placebo points) and one with auricular seeds fixed at placebo points. Patients had to be in pain, attaining a visual analog score (VAS) of 30 mm or more after having received analgesic treatment adapted to both intensity and type of pain, for at least 1 month of therapy. Treatment efficacy was based on the absolute decrease in pain intensity measured 2 months after randomization using the VAS.The main outcome was pain assessed at 2 months, with the assessment at 1 month carried over to 2 months for the eight patients who interrupted treatment after 1 month. For three patients, no data were available because they withdrew from the study during the first month. Pain intensity decreased by 36% at 2 months from baseline in the group receiving acupuncture; there was little change for patients receiving placebo (2%). The difference between groups was statistically significant (P <.0001).The observed reduction in pain intensity measured on the VAS represents a clear benefit from auricular acupuncture for these cancer patients who are in pain, despite stable analgesic treatment.
Cancer-Associated Transforming Growth Factor β Type II Receptor Gene Mutant Causes Activation of Bone Morphogenic Protein-Smads and Invasive Phenotype
Authors: Savita Bharathy, Wen Xie, Jonathan M. Yingling, Michael Reiss
Journal: Cancer Research (2008)

Abstract Transforming growth factor β (TGFβ) plays a key role in maintaining tissue homeostasis by inducing cell cycle arrest, differentiation and apoptosis, and ensuring genomic integrity. Furthermore, TGFβ orchestrates the response to tissue injury and mediates repair by inducing epithelial to mesenchymal transition and by stimulating cell motility and invasiveness. Although loss of the homeostatic activity of TGFβ occurs early on in tumor development, many advanced cancers have coopted the tissue repair function to enhance their metastatic phenotype. How these two functions of TGFβ become uncoupled during cancer development remains poorly understood. Here, we show that, in human keratinocytes, TGFβ induces phosphorylation of Smad2 and Smad3 as well as Smad1 and Smad5 and that both pathways are dependent on the kinase activities of the type I and II TGFβ receptors (TβR). Moreover, cancer-associated missense mutations of the TβRII gene (TGFBR2) are associated with at least two different phenotypes. One type of mutant (TGFBR2E526Q) is associated with loss of kinase activity and all signaling functions. In contrast, a second mutant (TGFBR2R537P) is associated with high intrinsic kinase activity, loss of Smad2/3 activation, and constitutive activation of Smad1/5. Furthermore, this TGFBR2 mutant endows the carcinoma cells with a highly motile and invasive fibroblastoid phenotype. This activated phenotype is TβRI (Alk-5) independent and can be reversed by the action of a dual TβRI and TβRII kinase inhibitor. Thus, identification of such activated TβRII receptor mutations in tumors may have direct implications for appropriately targeting these cancers with selective therapeutic agents. [Cancer Res 2008;68(6):1656–66]
Mindfulness-Based Cognitive Therapy for Patients with Medically Unexplained Symptoms: A Randomized Controlled Trial
Authors: Hiske van Ravesteijn, Peter Lucassen, Hans Bor, Chris van Weel, Anne Speckens
Journal: Psychotherapy and Psychosomatics (2013)

&lt;b&gt;&lt;i&gt;Background:&lt;/i&gt;&lt;/b&gt; Patients with medically unexplained symptoms make heavy demands on the health care system. An offer for psychological treatment is often declined. There is a need for acceptable and effective treatments. We assessed the acceptability and effectiveness of mindfulness-based cognitive therapy (MBCT) for patients with persistent medically unexplained symptoms. &lt;b&gt;&lt;i&gt;Method:&lt;/i&gt;&lt;/b&gt; A randomized controlled trial comparing MBCT (n = 64) to enhanced usual care (EUC; n = 61). Participants were the 10% most frequently attending patients in primary care. The primary outcome measure was general health status at the end of treatment. Secondary outcome measures were mental and physical functioning. Assessments took place at the end of treatment and at the 9-month follow-up. &lt;b&gt;&lt;i&gt;Results:&lt;/i&gt;&lt;/b&gt; Health status and physical functioning did not significantly differ between groups. However, participants in the MBCT group reported a significantly greater improvement in mental functioning at the end of treatment (adjusted mean difference, 3.9; 95% CI, 0.24-7.6), in particular with regard to vitality and social functioning. In addition, at 9 months of follow-up, the mindfulness skills ‘observing' and ‘describing' were significantly higher in the MBCT group. Within the MBCT group, almost half of the outcome measures had significantly improved at the end of treatment, whereas in the EUC group none had. &lt;b&gt;&lt;i&gt;Conclusions:&lt;/i&gt;&lt;/b&gt; MBCT was feasible for frequently attending patients with persistent medically unexplained symptoms in primary care. Although MBCT did not lead to a significant difference in general health status between the two groups, it did result in a significant improvement in mental functioning.
Whole-Genome Sequencing of Tibetan Macaque (Macaca thibetana) Provides New Insight into the Macaque Evolutionary History
Authors: Zhenxin Fan, Guang Zhao, Peng Li, Naoki Osada, Jinchuan Xing, Yong Yi, Lianming Du, Pedro Silva, Hongxing Wang, Ryuichi Sakate, Xiuyue Zhang, Huailiang Xu, Bisong Yue, Jing Li
Journal: Molecular Biology and Evolution (2014)

Macaques are the most widely distributed nonhuman primates and used as animal models in biomedical research. The availability of full-genome sequences from them would be essential to both biomedical and primate evolutionary studies. Previous studies have reported whole-genome sequences from rhesus macaque (Macaca mulatta) and cynomolgus macaque (M. fascicularis, CE), both of which belong to the fascicularis group. Here, we present a 37-fold coverage genome sequence of the Tibetan macaque (M. thibetana; TM). TM is an endemic species to China belonging to the sinica group. On the basis of mapping to the rhesus macaque genome, we identified approximately 11.9 million single-nucleotide variants), of which 3.9 million were TM specific, as assessed by comparison two Chinese rhesus macaques (CR) and two CE genomes. Some genes carried TM-specific homozygous nonsynonymous variants (TSHNVs), which were scored as deleterious in human by both PolyPhen-2 and SIFT (Sorting Tolerant From Intolerant) and were enriched in the eye disease genes. In total, 273 immune response and disease-related genes carried at least one TSHNV. The heterozygosity rates of two CRs (0.002617 and 0.002612) and two CEs (0.003004 and 0.003179) were approximately three times higher than that of TM (0.000898). Polymerase chain reaction resequencing of 18 TM individuals showed that 29 TSHNVs exhibited high allele frequencies, thus confirming their low heterozygosity. Genome-wide genetic divergence analysis demonstrated that TM was more closely related to CR than to CE. We further detected unusual low divergence regions between TM and CR. In addition, after applying statistical criteria to detect putative introgression regions (PIRs) in the TM genome, up to 239,620 kb PIRs (8.84% of the genome) were identified. Given that TM and CR have overlapping geographical distributions, had the same refuge during the Middle Pleistocene, and show similar mating behaviors, it is highly likely that there was an ancient introgression event between them. Moreover, demographic inferences revealed that TM exhibited a similar demographic history as other macaques until 0.5 Ma, but then it maintained a lower effective population size until present time. Our study has provided new insight into the macaque evolutionary history, confirming hybridization events between macaque species groups based on genome-wide data.
An overview of melasma therapies
Authors: Aditya K Gupta
Journal: Journal of the American Academy of Dermatology (2004)

Melasma is an acquired facial hypermelanosis, more often affecting women with Fitzpatrick skin types IV-VI, especially those living in areas of intense UV radiation. The precise cause of melasma is as yet unknown, but the contributing factors include: genetic predisposition, pregnancy, oral contraceptives, cosmetics, drugs containing phototoxic agents, endocrine dysfunction, and UV light exposure. Due to its refractory and recurrent nature, melasma is often difficult to treat. Discontinued use of birth control, scented cosmetics, and phototoxic drugs, as well as sunlight avoidance and use of broad-spectrum (UVA + UVB) sunscreens, are common strategies employed within the treatment regime. Hydroquinone, tretinoin, and azelaic acid are the more common topical depigmenting agents. Hydroquinone is the most popular treatment, but its adverse side-effects in some patients have lead to the investigation of other therapies. Other treatments include kojic acid, isopropylcatechol and N-acetyl-4-S-cysteaminylphenol. On-going research into agents that affect melanin has also yielded other products such as arbutin, licorice P-T, L-ascorbyl-2-phosphate, indomethacin, and Pyrogenol, a compound made from Pinus pinaster bark extracts. These products, however, require more study before they become a mainstay in melasma therapy. Chemical peels are another form of treatment. Superficial peels are usually well tolerated by lighter complexioned individuals. However, dermatologists have been reluctant to perform chemical peels on darker skin types because there is a tendency to develop dyschromia and postinflammatory hyperpigmentation. Trichloroacetic acid, Jessner's solution, salicylic acid, and glycolic acid are the peeling agents commonly used. While dermabrasion is a promising mechanical therapy, lasers are used more often in the melasma treatment process. The use of lasers in treatment of pigmentary disorders is based on the theory of selective photothermolysis and involves targeting melanocytes for specific destruction. Overall, many treatments have a high efficacy, but may also produce unwelcome side-effects. Others generate few adverse reactions, but have low efficacy. Combination therapies may also be effective and safe.
A Breaker of Advanced Glycation End Products Attenuates Diabetes-Induced Myocardial Structural Changes
Authors: Riccardo Candido, Josephine M. Forbes, Merlin C. Thomas, Vicki Thallas, Rachael G. Dean, Wendy C. Burns, Christos Tikellis, Rebecca H. Ritchie, Stephen M. Twigg, Mark E. Cooper, Louise M. Burrell
Journal: Circulation Research (2003)

The formation of advanced glycation end products (AGEs) on extracellular matrix components leads to accelerated increases in collagen cross linking that contributes to myocardial stiffness in diabetes. This study determined the effect of the crosslink breaker, ALT-711 on diabetes-induced cardiac disease. Streptozotocin diabetes was induced in Sprague-Dawley rats for 32 weeks. Treatment with ALT-711 (10 mg/kg) was initiated at week 16. Diabetic hearts were characterized by increased left ventricular (LV) mass and brain natriuretic peptide (BNP) expression, decreased LV collagen solubility, and increased collagen III gene and protein expression. Diabetic hearts had significant increases in AGEs and increased expression of the AGE receptors, RAGE and AGE-R3, in association with increases in gene and protein expression of connective tissue growth factor (CTGF). ALT-711 treatment restored LV collagen solubility and cardiac BNP in association with reduced cardiac AGE levels and abrogated the increase in RAGE, AGE-R3, CTGF, and collagen III expression. The present study suggests that AGEs play a central role in many of the alterations observed in the diabetic heart and that cleavage of preformed AGE crosslinks with ALT-711 leads to attenuation of diabetes-associated cardiac abnormalities in rats. This provides a potential new therapeutic approach for cardiovascular disease in human diabetes.