tbuckley/cabot-search huggingface dataset:
Phase I clinical and pharmacokinetic study of oral carboxyamidotriazole, a signal transduction inhibitor.
Authors: J Berlin, K D Tutsch, P Hutson, J Cleary, R P Rago, R Z Arzoomanian, D Alberti, C Feierabend, G Wilding
Journal: Journal of Clinical Oncology (1997)

PURPOSE We conducted a phase I trial of carboxyamidotriazole (CAI, NSC 609974), designed to determine the maximum-tolerated dose (MTD), toxicity profile, and pharmacokinetic characteristics of CAI gelatin capsule (gelcap) formulation administered daily as a single oral dose. PATIENTS AND METHODS Twenty-nine patients with advanced malignancy who met standard eligibility criteria were treated with once-daily CAI given in cycles of 28 days. Pharmacokinetic sampling was performed on days 1 and 29 and trough plasma CAI levels were assessed weekly. RESULTS Patients were entered at dose levels of 50, 75, and 100 mg/m2. All three patients at the 100-mg/m2 level experienced dose-limiting neurocerebellar toxicity. Other neurotoxicities were mild. Gastrointestinal side effects were common, but generally mild, with 23 patients experiencing nausea and/or vomiting of any grade. Fatigue was a frequent complaint, with 19 patients experiencing mild to moderate symptoms. Six patients with nausea and vomiting and five with fatigue experienced relief of symptoms with a change to nocturnal administration of CAI. Peak plasma concentrations (Cp) occurred at 2.4 +/- 1.5 hours after administration of the oral gelcap dose. Patients approached steady-state trough plasma concentrations (Css) by days 8 to 15 and maintained a relatively constant Css throughout the course of treatment. For all patients, the mean variation in weekly CAI Cp was 12.4% +/- 5.3%. CONCLUSION The MTD for the gelcap formulation was 75 mg/m2 with dose-limiting neurocerebellar toxicity (ataxia) seen at 100 mg/m2. Other prominent side effects, including nausea, vomiting, and fatigue, were partially alleviated through altering the administration schedule to nighttime dosing.
Mas and Its Related G Protein–Coupled Receptors, Mrgprs
Authors: Michael Bader, Natalia Alenina, Miguel A. Andrade-Navarro, Robson A. Santos
Journal: Pharmacological Reviews (2014)

The Mas-related G protein–coupled receptors (Mrgprs or Mas-related genes) comprise a subfamily of receptors named after the first discovered member, Mas. For most Mrgprs, pruriception seems to be the major function based on the following observations: 1) they are relatively promiscuous in their ligand specificity with best affinities for itch-inducing substances; 2) they are expressed in sensory neurons and mast cells in the skin, the main cellular components of pruriception; and 3) they appear in evolution first in tetrapods, which have arms and legs necessary for scratching to remove parasites or other noxious substances from the skin before they create harm. Because parasites coevolved with hosts, each species faced different parasitic challenges, which may explain another striking observation, the multiple independent duplication and expansion events of Mrgpr genes in different species as a consequence of parallel adaptive evolution. Their predominant expression in dorsal root ganglia anticipates additional functions of Mrgprs in nociception. Some Mrgprs have endogenous ligands, such as <i>β</i>-alanine, alamandine, adenine, RF-amide peptides, or salusin-<i>β</i>. However, because the functions of these agonists are still elusive, the physiologic role of the respective Mrgprs needs to be clarified. The best studied Mrgpr is Mas itself. It was shown to be a receptor for angiotensin-1–7 and to exert mainly protective actions in cardiovascular and metabolic diseases. This review summarizes the current knowledge about Mrgprs, their evolution, their ligands, their possible physiologic functions, and their therapeutic potential.
Male-specific hepatitis B virus large surface protein variant W4P potentiates tumorigenicity and induces gender disparity
Authors: Seoung-Ae Lee, Hong Kim, You-Sub Won, Seung-Hyeok Seok, YiRang Na, Han-Bo Shin, Kyung-Soo Inn, Bum-Joon Kim
Journal: Molecular Cancer (2015)

The underlying mechanisms of carcinogenesis and gender disparity in hepatitis B virus (HBV)-induced hepatocellular carcinoma (HCC) remain unclear. Recently, we reported a novel HCC-related W4P/R mutation in the large surface protein (LHB) of HBV genotype C, which was found exclusively in male HCC patients.LHB sequences from a carrier (wild type; WT) and W4P variant LHB sequence from an HCC patient were cloned and used to generate NIH3T3 and Huh7 cell lines. Cell proliferation and in vitro tumorigenicity were assessed by cell growth and transformation assays. Male and female nude mice were injected with the cells to determine in vivo tumorigenicity. To confirm the effect of estrogen in W4P-mediated tumorigenicity, male mice were injected with estrogen and challenged with W4P-expressing cells. The serum levels of different cytokines from the mouse model and patients were analyzed by ELISA. A critical role of interleukin (IL)-6 signaling in W4P-mediated tumorigenicity was tested by inhibition of Jak2.Although both WT and W4P variant LHBs enhanced cell proliferation by regulating the cell cycle and facilitated cell colony formation, the W4P variant demonstrated significantly higher activity. NIH3T3 cells expressing variant LHB, but not the WT, induced tumor in a nude mouse model. Tumor masses produced by variant LHB were significantly larger in male than female mice, and significantly reduced by estrogen. IL-6, but not tumor necrosis factor-α, was elevated in male mice harboring W4P-induced tumor, and was reduced by estrogen. IL-6 levels of HCC patients with the W4P variant were significantly higher than those of patients with WT LHB. W4P LHB induced higher production of IL-6 than WT LHB in cell lines, and the level was reduced by estrogen. The ability to reduce cell proliferation and colony formation of W4P LHB was hampered by inhibition of IL-6 signaling.This study suggests that the W4P mutation during the natural course of chronic hepatitis B infection may contribute to HCC development, particularly in male patients, in an IL-6-dependent manner.
Endocytosis of Peptide Hormones and Other Ligands
Authors: BARRY I. POSNER, MASOOD N. KHAN, JOHN J. M. BERGERON
Journal: Endocrine Reviews (1982)

ENDOCYTOSIS refers to the uptake of materials into cells from the external environment by means of vesicles derived from invaginations of the cell surface. Several types of endocytosis have been distinguished (1). Phagocytosis (cell eating) describes the uptake of large particulate matter; whereas pinocytosis (cell drinking) refers to the internalization of fluid and small particles. Although the term endocytosis in its general sense subsumes phagocytototic behavior, it has frequently been used interchangeably with pinocytosis, a universal activity of living cells. The terms adsorptive and fluid phase endocytosis (pinocytosis) distinguish between the uptake of macromolecules bound to the cell surface (and eventually the inner membrane of vesicles) and the uptake of solute in the extracellular fluid. The former is a device for both selecting and concentrating specific solutes for internalization by virtue of their binding to cell surface receptors. Receptor-mediated endocytosis has now been described for a diversity of substances including lipoproteins, glycoproteins, hydrolytic enzymes, toxins, hormones, and growth factors. In this review we focus on the receptor-mediated endocytosis of polypeptide hormones and growth factors but shall selectively refer to instructive observations on other substances as well.
Normalizing Tumor Microenvironment to Treat Cancer: Bench to Bedside to Biomarkers
Authors: Rakesh K. Jain
Journal: Journal of Clinical Oncology (2013)

For almost four decades, my work has focused on one challenge: improving the delivery and efficacy of anticancer therapeutics. Working on the hypothesis that the abnormal tumor microenvironment—characterized by hypoxia and high interstitial fluid pressure—fuels tumor progression and treatment resistance, we developed an array of sophisticated imaging technologies and animal models as well as mathematic models to unravel the complex biology of tumors. Using these tools, we demonstrated that the blood and lymphatic vasculature, fibroblasts, immune cells, and extracellular matrix associated with tumors are abnormal, which together create a hostile tumor microenvironment. We next hypothesized that agents that induce normalization of the microenvironment can improve treatment outcome. Indeed, we demonstrated that judicious use of antiangiogenic agents—originally designed to starve tumors—could transiently normalize tumor vasculature, alleviate hypoxia, increase delivery of drugs and antitumor immune cells, and improve the outcome of various therapies. Our trials of antiangiogenics in patients with newly diagnosed and recurrent glioblastoma supported this concept. They revealed that patients whose tumor blood perfusion increased in response to cediranib survived 6 to 9 months longer than those whose blood perfusion did not increase. The normalization hypothesis also opened doors to treating various nonmalignant diseases characterized by abnormal vasculature, such as neurofibromatosis type 2. More recently, we discovered that antifibrosis drugs capable of normalizing the tumor microenvironment can improve the delivery and efficacy of nano- and molecular medicines. Our current efforts are directed at identifying predictive biomarkers and more-effective strategies to normalize the tumor microenvironment for enhancing anticancer therapies.
Reactive arthritis or chronic infectious arthritis?
Authors: J Sibilia, F-X Limbach
Journal: Annals of the Rheumatic Diseases (2002)

Microbes reach the synovial cavity either directly during bacteraemia or by transport within lymphoid cells or monocytes. This may stimulate the immune system excessively, triggering arthritis. Some forms of ReA correspond to slow infectious arthritis due to the persistence of microbes and some to an infection triggered arthritis linked to an extra-articular site of infection.
Histamine self control
Authors: Heather L. Van Epps
Journal: The Journal of Experimental Medicine (2005)

Allergy-provoking histamine keeps itself under control, according to a study on page 387. Schneider and colleagues show that basophil precursor cells pump released histamine back into themselves. Once inside, the histamine shuts off its own production and that of allergy-promoting T helper (Th) 2 cytokines.






Figure 

Histamine pumped back into basophil precursor cells inhibits further synthesis of histamine.




Basophils and mast cells are the primary histamine producers of the immune system. In mature cells, histamine is stored in intracellular granules and is rapidly released when the cells are stimulated. Once released, histamine triggers acute allergy symptoms by binding to its receptors on vascular endothelial cells and bronchial smooth muscle cells. Histamine can also be produced by nongranular cells, including macrophages and dendritic cells, which secrete the molecule immediately after synthesis.

This group previously described a population of low-granule basophil precursor cells in the bone marrow that produce histamine and Th2 cytokines. This cell population increases in size during worm infections and may help resolve infection by promoting a protective Th2 response. The authors had noted that these cells could take up histamine from the external environment, but neither the mechanism nor the consequences of this uptake were understood. Schneider et al. now show that the uptake of histamine by these cells triggers a negative feedback loop that inhibits additional histamine synthesis and the production of allergy-promoting cytokines.

Histamine transport was dependent on a cation transporter protein (organic cation transporter 3, or OCT3), which was known to transport histamine in brain cells but had never been identified on basophils. The authors speculate the reverse histamine transport may help limit the severity of allergic responses. They are now testing this idea by assessing allergic responses in OCT3-deficient mice.
Intracellular enzymatic histochemistry of the human stomach with special reference to atrophic gastritis.
Authors: H Ragins, M Dittbrenner
Journal: Gut (1965)

EDITORIAL SYNOPSIS These studies demonstrate an altered pattern of cellular enzymic activity in patients with atrophic gastritis.The interesting and orginal supposition is put forward that this may possibly represent a change in function from a primarily secretory mucosa to a primarily absorptive epithelium.
Duplication and selection in the evolution of primate β-defensin genes
Authors: Colin AM Semple, Mark Rolfe, Julia R Dorin
Journal: Genome biology (2003)

Innate immunity is the first line of defense against microorganisms in vertebrates and acts by providing an initial barrier to microorganisms and triggering adaptive immune responses. Peptides such as beta-defensins are an important component of this defense, providing a broad spectrum of antimicrobial activity against bacteria, fungi, mycobacteria and several enveloped viruses. Beta-defensins are small cationic peptides that vary in their expression patterns and spectrum of pathogen specificity. Disruptions in beta-defensin function have been implicated in human diseases, including cystic fibrosis, and a fuller understanding of the variety, function and evolution of human beta-defensins might form the basis for novel therapies. Here we use a combination of laboratory and computational techniques to characterize the main human beta-defensin locus on chromosome 8p22-p23.
A comparison of associations of alanine aminotransferase and gamma-glutamyltransferase with fasting glucose, fasting insulin, and glycated hemoglobin in women with and without diabetes
Authors: Abigail Fraser, Shah Ebrahim, George Davey Smith, Debbie A. Lawlor
Journal: Hepatology (2007)

Abstract Associations between biomarkers of nonalcoholic fatty liver disease (NAFLD) alanine aminotransferase (ALT), and gamma-glutamyltransferase (GGT), with 3 separate measures of glucose homeostasis: fasting glucose, fasting insulin and glycated hemoglobin (HbA1c) were studied and compared between women with and without diabetes in order to gain insight into the documented associations between NAFLD, insulin resistance and diabetes. Data from the British Women's Health and Heart Study, a random sample of British women aged 60-79 years (N = 3394; 3086 without diabetes and 308 with diabetes) was used. Associations of ALT and GGT with fasting glucose and HbA1c and of ALT with fasting insulin (and homeostasis model assessment of insulin resistance [HOMA]) are stronger in women with diabetes compared to women without diabetes ( P for interaction &lt; 0.001). GGT is associated with fasting insulin (and HOMA) to the same extent in all women, irrespective of diabetes status. Results excluding hyperinsulinemic women, i.e., in the highest fourth of the fasting insulin distribution, were similar to those obtained for all non-diabetic women as were results excluding women in the highest quartile of the alcohol consumption distribution and for women with ALT and GGT levels within the normal range. Associations did not differ substantially between obese and non-obese non-diabetic women. Conclusion: elevation of liver enzymes and hepatic insulin resistance as reflected by fasting insulin occur in the early stages of insulin resistance and highlight the central role of the liver in insulin resistance in the general population. (HEPATOLOGY 2007;46:158–165.)
Alternatively Used Promoters and Distinct Elements Direct Tissue-Specific Expression of Nephrin
Authors: Olga Beltcheva, Sirpa Kontusaari, Sergueï Fetissov, Heli Putaala, Pekka Kilpeläinen, Tomas Hökfelt, Karl Tryggvason
Journal: Journal of the American Society of Nephrology (2003)

ABSTRACT. Nephrin, an essential component of the glomerular ultrafilter, the slit diaphragm, has also been found to be expressed in the central nervous system and pancreas. This study examined the regulation of the nephrin gene by analyzing the expression of different length nephrin promoter–lacZ reporter constructs in transgenic mice. An upstream segment between −4 kb and −4 bp was shown to be sufficient for driving expression in all three tissues. Surprisingly, a 5.7-kb construct lacking the transcription initiation site and the immediate upstream region of the gene could drive expression in the central nervous system. This led to the identification of a novel, alternatively used exon 1B located 1871 bp upstream of the ATG codon of the previously known first exon, now termed exon 1A. The existence and functionality of exon 1B was verified in nephrin knockout mice in which exon 1A is deleted. Deletion of exon 1B and its immediate surrounding sequence, introduced in the 4-kb promoter–lacZ reporter construct, abolished the expression of the transgene in pancreas and spinal cord but not in kidney and brain in transgenic mice. Analysis of five promoter–reporter gene constructs showed that regulatory elements driving expression encoded by exon 1A in kidney and brain are localized in the region between −4 kb and 2.1 kb. E-mail: [email protected]
A controlled study of bone mineral density in patients with inflammatory bowel disease.
Authors: J A Silvennoinen, T J Karttunen, S E Niemela, J J Manelius, J K Lehtola
Journal: Gut (1995)

To assess the prevalence of and risk factors for low bone mineral density in inflammatory bowel disease (IBD), 152 IBD patients and 73 healthy controls were studied. Sixty seven patients had ulcerative colitis, 78 had Crohn's disease (52 of them (66.7%) had ileal disease), and seven had indeterminate colitis. Bone mineral density values (g/cm2) measured by dual energy x ray absorbtiometry at the spine (L2-L4), the femoral neck, Ward's triangle, and the trochanter were 1.177, 0.948, 0.850, and 0.838 in the patients and 1.228 (p = 0.034), 1.001 (p = 0.009), 0.889 (NS), and 0.888 (p = 0.012) in the control group, respectively. The type or extent of the disease or previous small bowel resection did not have any significant effect on the bone mineral density values. There was a weak, but statistically significant negative correlation between bone mineral density and the total lifetime corticosteroid dose (in the lumbar spine r = -0.164, p = 0.04, the femoral neck r = -0.185, p = 0.02, Ward's triangle r = -0.167, p = 0.04, and the trochanter r = -0.237, p = 0.003). The patients whose lifetime corticosteroid dose (prednisone/prednisolone) was more than 10 g had especially low bone mineral density (p < 0.05 compared with the groups with no or less than 5 g of corticosteroid). The patients who had never taken peroral corticosteroids did not have decreased bone mineral density. In conclusion, IBD patients have significantly lower bone mineral density values than healthy controls, but the difference is not so great as has been reported previously. Low bone mineral density values in these patients are related to high lifetime corticosteroid doses.
Randomized Trial of Atopaxar in the Treatment of Patients With Coronary Artery Disease
Authors: Stephen D. Wiviott, Marcus D. Flather, Michelle L. O'Donoghue, Shinya Goto, Desmond J. Fitzgerald, Fernando Cura, Philip Aylward, Victor Guetta, Dariusz Dudek, Charles F. Contant, Dominick J. Angiolillo, Deepak L. Bhatt
Journal: Circulation (2011)

Thrombin is a key mediator of platelet activation. Atopaxar is a reversible protease-activated receptor-1 antagonist that interferes with thrombin-mediated platelet effects. The phase II Lessons From Antagonizing the Cellular Effect of Thrombin-Coronary Artery Disease (LANCELOT-CAD) trial examined the safety and tolerability of prolonged therapy with atopaxar in subjects with CAD.Subjects with a qualifying history were randomized in a double-blind fashion to 3 dosing regimens of atopaxar (50, 100, or 200 mg daily) or matching placebo for 24 weeks and followed up for an additional 4 weeks. The key safety end points were bleeding according to the Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) and Thrombolysis in Myocardial Infarction (TIMI) classifications. Secondary objectives included platelet aggregation and major adverse cardiac events. Seven hundred and twenty subjects were randomized. Overall bleeding rates tended to be higher with atopaxar compared with placebo by CURE criteria (placebo, 0.6%; atopaxar, 3.9%; relative risk, 6.82, P=0.03; 50 mg, 3.9%; 100 mg, 1.7%; 200 mg, 5.9%; P for trend=0.01) and TIMI criteria (placebo, 6.8%; atopaxar, 10.3%; relative risk, 1.52, P=0.17; 50 mg, 9.9%; 100 mg, 8.1%; 200 mg, 12.9%; P for trend=0.07). There was no difference in major bleeding. Major adverse cardiac events were numerically lower in the atopaxar subjects. All atopaxar regimens achieved high levels of platelet inhibition. A transient elevation in liver transaminases and dose-dependent QTc prolongation without apparent complications were observed in higher-dose atopaxar treatment groups.In this dose-ranging study of patients with CAD, treatment with atopaxar resulted in platelet inhibition, more minor bleeding, and numerically but not statistically fewer ischemic events. Larger-scale trials are needed to determine whether these patterns translate into clinically meaningful effects.URL: http://www.ClinicalTrials.gov. Unique identifier: NCT00312052.
Rapid Detection of Hendra Virus Using Magnetic Particles and Quantum Dots
Authors: Fabio Lisi, Paolo Falcaro, Dario Buso, Anita J. Hill, Jennifer A. Barr, Gary Crameri, Tich‐Lam Nguyen, Lin‐Fa Wang, Paul Mulvaney
Journal: Advanced Healthcare Materials (2012)

A proof-of-concept for the development of a fast and portable Hendra virus biosensor is presented. Hendra virus, a deadly emerging pathogen in Australia, can be co-localized, concentrated and revealed using simultaneously magnetic and luminescent functional particles. This method should be applicable for the early detection of any other virus by targeting the specific virus with the corresponding antibody.
Congenital myasthenia–related AChR δ subunit mutation interferes with intersubunit communication essential for channel gating
Authors: Xin-Ming Shen, Taku Fukuda, Kinji Ohno, Steven M. Sine, Andrew G. Engel
Journal: Journal of Clinical Investigation (2008)

Congenital myasthenias (CMs) arise from defects in neuromuscular junction–associated proteins. Deciphering the molecular bases of the CMs is required for therapy and illuminates structure-function relationships in these proteins. Here, we analyze the effects of a mutation in 1 of 4 homologous subunits in the AChR from a CM patient, a Leu to Pro mutation at position 42 of the δ subunit. The mutation is located in a region of contact between subunits required for rapid opening of the AChR channel and impedes the rate of channel opening. Substitutions of Gly, Lys, or Asp for δL42, or substitutions of Pro along the local protein chain, also slowed channel opening. Substitution of Pro for Leu in the ε subunit slowed opening, whereas this substitution had no effect in the β subunit and actually sped opening in the α subunit. Analyses of energetic coupling between residues at the subunit interface showed that δL42 is functionally linked to αT127, a key residue in the adjacent α subunit required for rapid channel opening. Thus, δL42 is part of an intersubunit network that enables ACh binding to rapidly open the AChR channel, which may be compromised in patients with CM.