tbuckley/cabot-search huggingface dataset:
Hepatitis B virus transgenic mice: Insights into the virus and the disease*1
Authors: F CHISARI
Journal: Hepatology (1995)

Hepatitis B virus (HBV) is a member of the Hepadnaviridae family and infects hepatocytes, leading to liver pathology in acutely and chronically infected individuals. Co-infection with Hepatitis D virus (HDV), which requires the surface proteins of HBV to replicate, can exacerbate this disease progression. Thus, the >250 million people living with chronic HBV infection, including 13 million co-infected with HDV, would significantly benefit from an effective and affordable curative treatment. Animal models are crucial to the development of innovative disease therapies, a paradigm repeated again and again throughout the fields of immunology, neurology, reproduction, and development. Unfortunately, HBV has a highly-restricted species tropism, infecting limited species including humans, chimpanzees, and treeshrews. The first experimentally controlled studies of HBV infection were following inoculation of human volunteers in 1942, which identified the transmissibility of hepatitis through serum transfer and led to the hypothesis that the etiological agent was viral. Subsequent research in chimpanzees (Desmyter et al., 1971; Lichter, 1969) and later in other species, such as the treeshrews (Walter et al., 1996; Yan et al., 1996), further confirmed the viral origin of hepatitis B. Shortly thereafter, HBV-like viral infections were identified in woodchucks (Summers et al., 1978; Werner et al., 1979) and ducks, and much of our understanding of HBV replication can be attributed to these important models. However, with the exodus of chimpanzees from research and the limited reagents and historical data for treeshrews and other understudied species, there remains an urgent need to identify physiologically relevant models of chronic HBV infection. While large strides have been made in generating such models, particularly over the past two decades, there is still no available model that faithfully recapitulates the immunity and pathogenesis of HBV infection. Here, we discuss recent advancements in the generation of murine and non-human primate (NHP) models of HBV/HDV infection.
Anisotropic conduction in monolayers of neonatal rat heart cells cultured on collagen substrate.
Authors: V G Fast, A G Kléber
Journal: Circulation Research (1994)

Anisotropic impulse conduction was studied in neonatal rat heart cell monolayers produced by culturing cells on a growth-directing substrate of collagen. Monolayers consisting of parallel-oriented cells without visible intercellular clefts were selected for experiments; cell lengths and widths were 65.8 +/- 12.5 and 12.2 +/- 3.2 microns (n = 49), respectively. Action potential upstrokes were measured by using 12 photodiodes selected within a 10x10 diode array and a voltage-sensitive dye (RH-237). The size of the area sensed by a single diode was 14 x 14 microns. High-density multiple recordings (resolution, up to 15 microns) demonstrated the variability of local activation delays and of the maximal rate of rise of the action potential upstroke (Vmax), which are presumably related to the microscopic cellular architecture. Mean macroscopic conduction velocities measured over distances of 135 microns were 34.6 +/- 4.5 and 19.0 +/- 4.3 cm/s (mean +/- SD, n = 13, P &lt; .0001) in longitudinal and transverse directions, respectively. The anisotropic velocity ratio was 1.89 +/- 0.38 (n = 13). Mean Vmax was not significantly different in two directions (122.0 +/- 17.4 V/s longitudinally versus 125.2 +/- 15.6 V/s transversely, n = 13, P = NS). In conclusion, we developed an anisotropic cell culture model suitable for studying impulse conduction with cellular resolution. The anisotropic velocity ratio was close to values measured in vivo. By contrast, Vmax was not dependent on the direction of propagation.
Paracrine Receptor Activation by Microenvironment Triggers Bypass Survival Signals and ALK Inhibitor Resistance in EML4-ALK Lung Cancer Cells
Authors: Tadaaki Yamada, Shinji Takeuchi, Junya Nakade, Kenji Kita, Takayuki Nakagawa, Shigeki Nanjo, Takahiro Nakamura, Kunio Matsumoto, Manabu Soda, Hiroyuki Mano, Toshimitsu Uenaka, Seiji Yano
Journal: Clinical Cancer Research (2012)

Cancer cell microenvironments, including host cells, can critically affect cancer cell behaviors, including drug sensitivity. Although crizotinib, a dual tyrosine kinase inhibitor (TKI) of ALK and Met, shows dramatic effect against EML4-ALK lung cancer cells, these cells can acquire resistance to crizotinib by several mechanisms, including ALK amplification and gatekeeper mutation. We determined whether microenvironmental factors trigger ALK inhibitor resistance in EML4-ALK lung cancer cells.We tested the effects of ligands produced by endothelial cells and fibroblasts, and the cells themselves, on the susceptibility of EML4-ALK lung cancer cell lines to crizotinib and TAE684, a selective ALK inhibitor active against cells with ALK amplification and gatekeeper mutations, both in vitro and in vivo.EML4-ALK lung cancer cells were highly sensitive to ALK inhibitors. EGF receptor (EGFR) ligands, such as EGF, TGF-α, and HB-EGF, activated EGFR and triggered resistance to crizotinib and TAE684 by transducing bypass survival signaling through Erk1/2 and Akt. Hepatocyte growth factor (HGF) activated Met/Gab1 and triggered resistance to TAE684, but not crizotinib, which inhibits Met. Endothelial cells and fibroblasts, which produce the EGFR ligands and HGF, respectively, decreased the sensitivity of EML4-ALK lung cancer cells to crizotinib and TAE684, respectively. EGFR-TKIs resensitized these cells to crizotinib and Met-TKI to TAE684 even in the presence of EGFR ligands and HGF, respectively.Paracrine receptor activation by ligands from the microenvironment may trigger resistance to ALK inhibitors in EML4-ALK lung cancer cells, suggesting that receptor ligands from microenvironment may be additional targets during treatment with ALK inhibitors.
Pressure-Dependent Heterogeneity of Renal Cortical Blood Flow in Dogs
Authors: JOHN L. MCNAY, YOUICHI ABE
Journal: Circulation Research (1970)

We determined the effect of perfusion pressure on the distribution of blood flow within the renal cortex of the anesthetized dog. Total blood flow to the denervated kidney was measured by an electromagnetic flowmeter and perfusion pressure was manipulated over the autoregulatory range (136 to 81 mm Hg) by an aortic clamp. Distribution of cortical blood flow was determined by the radioactive microsphere technique. Tissue perfusion rates of four cortical zones of equal thickness differed significantly from each other at normal arterial pressure. In sequence from superficial to deep, perfusion of the cortex zones averaged 4.18, 6.80, 3.07, and 1.68 ml . g -1 . min -1 . Aortic constriction significantly reduced perfusion of the outer cortical zone and augmented perfusion of the inner two cortex zones. Twelve percent of total renal blood flow was redistributed by pressure reduction. Atropine, 1 mg/kg, had no effect on cortical perfusion rates at either pressure. The influence of microsphere diameter and density on cortex perfusion rates was systematically studied and found to be minor. This observation implies that the microsphere method is valid for measuring distribution of blood flow within the renal cortex. We conclude that zones of the renal cortex are perfused at different rates and respond differently to changes in arterial pressure.
Atherosclerosis across 4000 years of human history: the Horus study of four ancient populations
Authors: Randall C Thompson, Adel H Allam, Guido P Lombardi, L Samuel Wann, M Linda Sutherland, James D Sutherland, Muhammad Al-Tohamy Soliman, Bruno Frohlich, David T Mininberg, Janet M Monge, Clide M Vallodolid, Samantha L Cox, Gomaa Abd el-Maksoud, Ibrahim Badr, Michael I Miyamoto, Abd el-Halim Nur el-din, Jagat Narula, Caleb E Finch, Gregory S Thomas
Journal: The Lancet (2013)
Phosphorylcholine‐Coated Semiconducting Polymer Nanoparticles as Rapid and Efficient Labeling Agents for In Vivo Cell Tracking
Authors: Kanyi Pu, Adam J. Shuhendler, Maija P. Valta, Lina Cui, Matthias Saar, Donna M. Peehl, Jianghong Rao
Journal: Advanced Healthcare Materials (2014)

Despite the pressing need to noninvasively monitor transplanted cells in vivo with fluorescence imaging, desirable fluorescent agents with rapid labeling capability, durable brightness, and ideal biocompatibility remain lacking. Here, phosphorylcholine‐coated near‐infrared (NIR) fluorescent semiconducting polymer nanoparticles (SPNs) are reported as a new class of rapid, efficient, and cytocompatible labeling nanoagents for in vivo cell tracking. The phosphorylcholine coating results in efficient and rapid endocytosis and allows the SPN to enter cells within 0.5 h in complete culture medium apparently independent of the cell type, while its NIR fluorescence leads to a tissue penetration depth of 0.5 cm. In comparison to quantum dots and Cy5.5, the SPN is tolerant to physiologically ubiquitous reactive oxygen species (ROS), resulting in durable fluorescence both in vitro and in vivo. These desirable physical and physiological properties of the SPN permit cell tracking of human renal cell carcinoma (RCC) cells in living mice at a lower limit of detection of 10 000 cells with no obvious alteration of cell phenotype after 12 d. SPNs thus can provide unique opportunities for optimizing cellular therapy and deciphering pathological processes as a cell tracking label.
Mortality from overdose among injecting drug users recently released from prison: database linkage study
Authors: S R Seaman, R P Brettle, S M Gore
Journal: BMJ (1998)

<h3>Abstract</h3> <b>Objective:</b> To assess whether injecting drug users have a higher than usual risk of death from overdose in the 2 weeks after release from prison. <b>Design:</b> Soundex coding of surnames and information on date of birth were used to link entry and release dates from the local prison between 1983 and 1994 with clinical data from Edinburgh City Hospital9s cohort of male injecting drug users who are infected with HIV. <b>Setting:</b> Edinburgh City Hospital and Edinburgh Prison. <b>Subjects:</b> 316/332 male injecting drug users infected with HIV in the City Hospital HIV cohort; 16 were excluded because they were enrolled after developing AIDS or because their precise date of death was not available. <b>Main outcome measure:</b> Relative risk of dying from overdose before developing AIDS and relative risk of dying of all causes before developing AIDS during the 2 weeks after release from prison; this was compared with relative risks of death during other time at liberty. <b>Results:</b> 238/316 (75%) injecting drug users served time in the prison between 1983 and 1994. 33 out of 316 injecting drug users who were infected with HIV died before developing AIDS during 517 177 days at risk. 20 of these men died of an overdose; 6 of these deaths occurred within 2 weeks of release during 5903 days at risk. Death rates from overdose before the development of AIDS were 1.02/1000 days during the 2 weeks after release (recently released) and 0.029/1000 days during other times of liberty. The relative risk of death from overdose became 7.7 (1.5 to 39.1) after temporal matching (when the comparison was limited to the first 2 weeks after release <i>v</i> the next 10 weeks). The crude relative risk in an analysis combining stratified prison term and the 2 weeks after release was 4.5 (1.7 to 11.7) for death from overdose. After temporal matching these risks became 1.8 (0.4 to 9.2). <b>Conclusion:</b> Prisons should evaluate interventions to reduce the risk of death from overdose after release. <h3>Key messages</h3> Overall, imprisonment does not seem to increase injecting drug users9 risks of dying from an overdose Between 1983 and 1994 the risk of death from overdose was eight times higher within 2 weeks after release from prison among injecting drug users infected with HIV than it was during the next 10 weeks after release Further studies will need to determine if the estimate of 1 death from overdose per 1000 days spent recently released can be generalised to those who are not infected with HIV, and to dependent drug users who do not inject drugs Deaths from overdose occurring in the 2 weeks after release from prison may outnumber the deaths from suicide in Scottish prisons by 3 to 1 Lives could be saved by implementing prison based, randomised trials of interventions to reduce the number of deaths from overdose that occur soon after release
Randomized Phase III Trial Exploring the Use of Long-Acting Release Octreotide in the Prevention of Chemotherapy-Induced Diarrhea in Patients With Colorectal Cancer: The LARCID Trial
Authors: Paulo M. Hoff, Daniel F. Saragiotto, Carlos H. Barrios, Auro del Giglio, Anelisa K. Coutinho, Aline C. Andrade, Carolina Dutra, Nora M. Forones, Mariangela Correa, Maria do Socorro O. Portella, Vanessa Q. Passos, Renata N. Chinen, Brigitte van Eyll
Journal: Journal of Clinical Oncology (2014)

Chemotherapy-induced diarrhea (CID) is a relatively common adverse event in the treatment of patients with colorectal cancer. The LAR for Chemotherapy-Induced Diarrhea (LARCID) trial evaluated the efficacy and safety of long-acting release octreotide (octreotide LAR) for the prevention of CID in this population.Patients with colorectal cancer starting adjuvant or first-line treatment with a chemotherapy combination containing fluorouracil, capecitabine, and/or irinotecan were randomly assigned to receive octreotide LAR 30 mg intramuscularly every 4 weeks (experimental arm) or the physician's treatment of choice in case of diarrhea (control arm).A total of 139 patients were randomly assigned, most of whom received fluorouracil- and oxaliplatin-containing chemotherapy regimens. The rate of diarrhea was 76.1% in the experimental group (n = 68) and 78.9% in the control group (n = 71). Treatment with octreotide LAR did not prevent or reduce the severity of CID. Treatment choices for diarrhea management included loperamide in the majority of patients. No benefit from octreotide LAR was identified in terms of need for diarrhea treatment, opioids, or intravenous hydration or in the rate of hospitalization or quality of life.This study could not prove the efficacy of octreotide LAR in the prevention of CID.
Advances in the treatment of late stage melanoma
Authors: L. A. Walkington, P. Lorigan, S. J. Danson
Journal: BMJ (2013)

Immunotherapies and targeted treatments: the future of cancer therapy

Patients diagnosed with thin cutaneous melanoma usually have a good prognosis after surgical resection, but prognosis is poor for those who present with, or develop, metastatic malignant melanoma (stage IV disease). Average survival is less than 12 months, and this has remained unchanged for more than 20 years.1 The mainstay of treatment in advanced melanoma has been dacarbazine chemotherapy, which has a poor response rate of 8-10%.1 However, the past three years have seen important advances in systemic treatment options for patients with this disease. Two treatment strategies, based on immunotherapy and genomics, now offer real hope of improved quality of life and prolonged survival, albeit with a serious risk of side effects and high drug costs.

It is now clear that the immune system has an important influence on the outcome of several cancers not previously thought to be immunogenic.2 Melanoma is an immunogenic tumour in that it expresses melanoma specific antigens, and a clinical response to immunotherapy has been shown. Better understanding of the complex molecular interactions needed to generate an immune response has led to the development of effective new immunotherapy agents.

Cytotoxic T lymphocyte associated antigen 4 (CTLA-4) is a key negative regulatory molecule. It is expressed on the surface of T cells shortly after activation by antigen presenting cells and inhibits the immune response. Ipilimumab is a fully humanised monoclonal antibody that competitively binds CTLA-4, resulting in increased T cell activation and proliferation. 

A phase III trial randomised patients with metastatic …
Bowel preparation for colonoscopy: relevant for the gut’s microbiota?
Authors: Volker Mai, O Colin Stine
Journal: Gut (2015)

Potential contributions of the host-associated gut microbiota to human physiology continue to receive extensive research interest. While various lines of evidence support a role of the microbiota in maintaining human health, perturbations in normal microbiota composition have been correlated with various dietary changes and disease states,1 particularly diarrhoea.2 We have long known that close interactions between microbiota and the host’s immune system occur in the distal small intestine and that microbes are highly metabolically active in the proximal large intestine. Recent global efforts have accumulated a wealth of data on the diversity of human gut-associated microbiota. These studies confirmed that even in healthy individuals a large degree of intraindividual as well as interindividual variation in microbiota composition and although to a lesser degree, microbial activities occur. However, what represents ‘normal’ gut microbiota is still not fully understood, which is largely due to the observed variation within and among individuals. While recent work based on phylogenetic analysis of both the small subunit (16S) of ribosomal RNA as well as metagenomic datasets suggests the existence of …
Erythropoietic Protoporphyria: Lipid Peroxidation and Red Cell Membrane Damage Associated with Photohemolysis
Authors: Bernard D. Goldstein, Leonard C. Harber
Journal: Journal of Clinical Investigation (1972)

The mechanism by which long wavelength ultraviolet light hemolyzes red cells obtained from patients with erythropoietic protoporphyria (EPP) was investigated. Previous studies had suggested that irradiation of these red cells with wavelengths of light capable of eliciting dermatological manifestations led to oxygen-dependent colloid osmotic hemolysis through the formation of peroxides. In the present report, lipid peroxidation during in vitro irradiation of EPP red cells with long ultraviolet light was demonstrated by: (a) the formation of 2-thiobarbituric acid reactants; (b) the presence of conjugated diene bonds in red cell lipid; and (c) the selective loss of unsaturated fatty acids proportional to the number of carbon-carbon double bonds in each. Irradiation of EPP red cells was also shown to result in the formation of hydrogen peroxide.Before photohemolysis there was a decline in cell membrane sulfhydryl groups and a loss in activity of the cell membrane enzyme acetylcholinesterase. These parameters provide further evidence suggesting that the cell membrane is a primary site of the photohemolytic effect of long ultraviolet light in EPP red cells. Further evaluation of the radiation-induced inactivation of EPP red cell acetylcholinesterase was performed by radiating mixtures containing bovine erythrocyte acetylcholinesterase and protoporphyrin IX. These studies revealed that the rate of decline in enzyme activity is accelerated by the addition of linoleic acid, an unsaturated fatty acid, but not by palmitic acid, a saturated fatty acid. Partial protection against both photohemolysis and acetylcholinesterase decline is provided by alpha-to-copherol. This lipid antioxidant loses its activity during the irradiation of EPP red cells suggesting that it is utilized in this process.
The Neurofibromatosis Type 1 Gene
Authors: D Viskochil, R White, R Cawthon
Journal: Annual Review of Neuroscience (1993)

The brain's default mode network consists of discrete, bilateral and symmetrical cortical areas, in the medial and lateral parietal, medial prefrontal, and medial and lateral temporal cortices of the human, nonhuman primate, cat, and rodent brains. Its ...Read More
Adjuvant postoperative fluorouracil-modulated chemotherapy combined with pelvic radiation therapy for rectal cancer: initial results of intergroup 0114.
Authors: J E Tepper, M J O'Connell, G R Petroni, D Hollis, E Cooke, A B Benson, B Cummings, L L Gunderson, J S Macdonald, J A Martenson
Journal: Journal of Clinical Oncology (1997)

PURPOSE The combination of radiation therapy with fluorouracil (5-FU)-based chemotherapy is generally accepted as appropriate postoperative therapy for patients with adenocarcinomas of the rectum that extend through the bowel wall or with lymph nodes positive for tumor. We attempted to determine whether the efficacy of this postoperative therapy could be improved by the addition of leucovorin and/or levamisole. METHODS A total of 1,696 patients were randomized and eligible for treatment with one of four treatment schemes. All patients received two cycles of bolus 5-FU-based systemic chemotherapy followed by pelvic radiation therapy with chemotherapy and two more cycles of the same systemic chemotherapy. Chemotherapy was either 5-FU alone, 5-FU with leucovorin, 5-FU with levamisole, or 5-FU with leucovorin and levamisole. RESULTS With a median follow-up duration of 48 months, there is no statistically significant advantage to any of the treatment regimens compared with bolus 5-FU alone. There is evidence of increased gastrointestinal toxicity with the three-drug combination compared with bolus 5-FU alone. Statistical analysis suggests it is very unlikely that either levamisole-containing combination will be shown to be of value with further follow-up evaluation. CONCLUSION There is no evidence at present for a beneficial effect of levamisole in the adjuvant treatment of rectal cancer. Definitive evaluation of the effect of the addition of leucovorin to 5-FU and pelvic radiation will require further follow-up evaluation.
Nuclear expression of the 50- and 65-kD Rel-related subunits of nuclear factor-kappa B is differentially regulated in human monocytic cells.
Authors: P A Kaufman, J B Weinberg, W C Greene
Journal: Journal of Clinical Investigation (1992)

The nuclear factor (NF)-kappa B transcription factor system is composed of at least four inducible nucleoprotein adducts termed p50, p55 (NF-kappa B p50), p75 (NF-kappa B p65), and p85 (c-Rel). These proteins are expressed in the nuclei of activated T cells in a distinctly biphasic fashion, with p55 and p75 induction occurring within minutes whereas the induction of p50 and p85 occurs after several hours. In contrast, p50 and p55 are constitutively expressed in the nuclei of U937 and THP-1 monocytic cells. However, cellular activation is required for the nuclear expression of p75 in these cells. Additionally, activation of monocytic cells does not result in a significant induction of p85. Tumor necrosis factor alpha induces the nuclear expression of p55 and p75 in these monocytic cells within 20 min, presumably reflecting the liberation of these proteins from I kappa B. In contrast, phorbol myristate acetate (PMA) induces the expression of these proteins with delayed kinetics, raising the possibility that PMA is incapable of mediating the efficient release of p55 and p75 from I kappa B in these cells. These findings highlight important differences in the regulation of these proteins in monocytic cells versus T cells and suggest that the induced expression of NF-kappa B p65 in monocytes may play a central role in the activation of HIV-1 gene expression.