tbuckley/cabot-search huggingface dataset:
DEPRESSANT EFFECTS OF HIGH CONCENTRATIONS OF INSPIRED OXYGEN ON ERYTHROCYTOGENESIS. OBSERVATIONS ON PATIENTS WITH SICKLE CELL ANEMIA WITH A DESCRIPTION OF THE OBSERVED TOXIC MANIFESTATIONS OF OXYGEN 12
Authors: Edward H. Reinhard, Carl V. Moore, Reubenia Dubach, Leo J. Wade
Journal: Journal of Clinical Investigation (1944)

This report describes the effect of the continu- ous inhalation of 70 to 100 per cent oxygen for 8 to 20 days on the cellular elements of the blood of patients with sickle cell anemia.The investi- gation was originally begun in an effort to reduce the degree of intravascular sickling of red blood cells.There were two reasons for trying to pro- duce this result: (1) Diggs (1) and Bauer (2) have suggested that the pain of sickle cell crises may result from anoxia of tissues caused by oc- clusion of blood vessels with elongated clumped cells, and (2) the increased rate of hemolysis in sickle cell anemia might possibly be due to the greater trauma to which sickled cells are sub- jected during circulation.Therefore, if the ab- normal shape could be corrected, the pain of crises might be relieved, the rate of hemolysis decreased, and the degree of anemia lessened.It is well known that in vitro the erythrocytes of patients with sickle cell anemia will become bi- concave discs when they are exposed to air or oxygen, and become sickled when they are ex- posed to carbon dioxide (3, 4).Sherman (4), furthermore, demonstrated that there are fewer sickled cells in arterial than in venous blood.But, when this study was begun, no one had shown that the oxygen tension of arterial blood could be increased sufficiently to influence the degree of intravascular sickling.That this re- sult might be accomplished, however, seemed likely since (1) Boothby, Lovelace, and Uihlein (5) were able to increase alveolar oxygen tension to more than 500 mm.Hg, and (2) Behnke (6)
Pharmacogenomics of hepatitis C infections: personalizing therapy
Authors: David R Booth, Golo Ahlenstiel, Jacob George
Journal: Genome Medicine (2012)

It is a widely held view that drug response genes have not proved as useful in clinical practice as anticipated at the start of the genomic era. An exception is in the treatment for chronic hepatitis C virus (HCV) genotype 1 infection with pegylated interferon α and ribavirin. In 2009, four independent genome-wide analyses identified IL28B polymorphisms that predict drug response in chronic hepatitis C (CHC). This discovery had immediate clinical impact. First, the IL28B genotype could be used to personalize therapy. In the 2 years since discovery, most of the more than 100,000 CHC patients commencing therapy for CHC in the West will have considered IL28B genotype testing. Second, the discovery has supported clinical trials for the use of the protein encoded by the gene known as interferon lambda. Third, it is expected that new insights into HCV pathogenesis will follow from studies of how IL28B affects HCV viral clearance and, ultimately, this will lead to new therapeutic strategies for CHC. This review discusses how IL28B genotyping is now used in personalizing therapy and, with the dramatically changing clinical landscape in CHC, with the advent of direct-acting antivirals, the prospects ahead.
The Evaluation of Recombinant, Chimeric, Tetravalent Antihuman CD22 Antibodies
Authors: Ruiqi Meng, Joan E. Smallshaw, Laurentiu M. Pop, Michael Yen, Xiaoyun Liu, Lien Le, Maria-Ana Ghetie, Ellen S. Vitetta, Victor Ghetie
Journal: Clinical Cancer Research (2004)

Abstract Purpose: The purpose of this study was to prepare chimeric antihuman CD22 tetravalent monoclonal antibodies (MAbs) with high functional affinity, long persistence in the circulation, increased antitumor activity, and conserved effector function in vitro. Experimental Design: We investigated the association/dissociation rates of these tetravalent antibodies using CD22+ Daudi lymphoma cells. We then tested their ability to interact with Fc receptors on a human cell line (U937), to mediate antibody-dependent cellular cytotoxicity with human natural killer cells, to bind human C1q, to inhibit the in vitro growth of CD22 Daudi cells, and to persist in the circulation. Results: The rate of dissociation of the tetravalent MAbs versus the divalent antibody was considerably slower. These tetravalent MAbs inhibited the in vitro proliferation of CD22 Daudi cells at a concentration that was at least 100-fold lower than that of the divalent murine antibody. The tetravalent MAbs containing both the CH2 and CH3 domains and a chimeric recombinant divalent antibody bound similarly to Fc receptor, C1q, and mediate antibody-dependent cellular cytotoxicity equally well with human natural killer cells. The persistence in the circulation of chimeric tetravalent MAbs was considerably longer than that of chemical homodimers. Conclusions: The tetravalent anti-CD22 MAbs with intact Fc regions should make effective therapeutic agents for B-cell tumors.
The GPx1-PTP1B-PP2A axis: A key determinant of airway inflammation and alveolar destruction
Authors: Patrick Geraghty, Andrew Hardigan, Alison Wallace, Oleg Mirochnitchenko, Jincy Thankachen, Jeanine D'Armiento, Robert Foronjy
Journal: European Respiratory Journal (2013)

Protein phosphatase 2A (PP2A) is a primary serine-threonine phosphatase that modulates inflammatory responses in asthma and COPD. Despite its importance, the mechanisms that regulate lung PP2A activity remain to be determined. The redox-sensitive enzyme protein tyrosine phosphatase 1B (PTP1B) activates PP2A by dephosphorylating the catalytic subunit of the protein at tyrosine 307. This study aimed to identify how the interaction between the intracellular antioxidant glutathione peroxidase-1 (GPx-1) and PTP1B impacted on lung PP2A activity and airway inflammation. Studies using gene silencing techniques in mouse lung or human small airway epithelial (SAE) cells determined that knocking down PTP1B expression blocked GPx-1’s activation of PP2A and negated the anti-inflammatory effects of GPx-1 protein in the lung. Similarly, the expression of human GPx-1 in transgenic mice significantly increased PP2A and PTP1B activities and prevented chronic cigarette smoke-induced airway inflammation and alveolar destruction. GPx-1 knockout mice, however, exhibited an exaggerated emphysema phenotype, correlating with a non-responsive PP2A pathway. Importantly, GPx-1-PTP1B-PP2A signaling becomes inactivated in advanced lung diseases. Indeed, PTP1B protein was oxidized in the lungs of advanced emphysema subjects and, unlike normal lung epithelial cells, cigarette smoke did not increase PTP1B activity within epithelial cells isolated from COPD subjects. These findings establish that the GPx-1-PTP1B-PP2A axis plays a critical role in countering the inflammatory and proteolytic responses that result in lung tissue destruction in response to cigarette smoke exposure.
The Signal Perceived by the Macula Densa during Changes in Renin Release
Authors: RONALD H. FREEMAN, JAMES O. DAVIS, ROBERT W. GOTSHALL, J. ALAN JOHNSON, WILLIAM S. SPIELMAN
Journal: Circulation Research (1974)

Renin secretion was studied in acute experiments in dogs during occlusion of the ureter alone (experiment 1), ureteral occlusion with a superimposed intrarenal infusion of papaverine (experiment 2), or ureteral occlusion with a superimposed intravenous ethacrynic acid injection (experiment 3) and following release of the ureteral occlusion (all three experiments). In all three experiments, ureteral occlusion increased renin secretion four- to fivefold. In experiment 2, papaverine, an inhibitor of smooth muscle contractility, was infused intrarenally during the last 20 minutes of ureteral occlusion, but renin secretion was unchanged by the infusion. Renin secretion decreased rapidly and was at the control level 5, 12½, and 27½ minutes after release of the occlusion, but urinary sodium concentration and excretion rate increased markedly during this period. In experiment 3, a superimposed injection of ethacrynic acid failed to alter renin secretion during ureteral occlusion. After release of the ureter, renin secretion remained unchanged for the first 5 minutes. Although renin secretion had decreased 12½ and 27½ minutes after release of the occlusion, it was still elevated twofold above the control level. Again, sodium excretion increased markedly and urinary sodium concentration was high after ureteral release. These findings support the hypothesis that the rate of renin release is inversely related to the rate of sodium transport by the macula densa cells.
Nutrient Supply and Mitochondrial Function
Authors: T Y Aw, D P Jones
Journal: Annual Review of Nutrition (1989)

MITOCHONDRIAL PLASTICITy  230 Organization and Function of Mitochondria   230 Expression of Enzyme Activities in Mitochondria     231 Tissue-Specific Mitochondrial Distribution  233 MODULATION OF MITOCHONDRIAL FORM AND FUNCTION BY NUTRIENTS 234 Nutrient Supply and Maintenance of Functional Mitochondria  234 Nutrient Supply and Optimal Mitochondrial Function  .... . . . . . . . . . . 238 CONCLUSIONS AND PERSPECTiVE   245
Prognostic Implication of Persistent Human Papillomavirus Type 16 DNA Detection in Oral Rinses for Human Papillomavirus–Related Oropharyngeal Carcinoma
Authors: Eleni M. Rettig, Alicia Wentz, Marshall R. Posner, Neil D. Gross, Robert I. Haddad, Maura L. Gillison, Carole Fakhry, Harry Quon, Andrew G. Sikora, William J. Stott, Jochen H. Lorch, Christine G. Gourin, Yingshi Guo, Weihong Xiao, Brett A. Miles, Jeremy D. Richmon, Peter E. Andersen, Krzysztof J. Misiukiewicz, Christine H. Chung, Jennifer E. Gerber, Shirani D. Rajan, Gypsyamber D’Souza
Journal: JAMA Oncology (2015)

<h3>Importance</h3> Human papillomavirus–related oropharyngeal carcinoma (HPV-OPC) is increasing in incidence in the United States. Although HPV-OPC has favorable prognosis, 10% to 25% of HPV-OPCs recur. Detection of human papillomavirus (HPV) DNA in oral rinses is associated with HPV-OPC, but its potential as a prognostic biomarker is unclear. <h3>Objective</h3> To determine whether HPV DNA detection in oral rinses after treatment for HPV-OPC is associated with recurrence and survival. <h3>Design, Setting, and Participants</h3> Prospective cohort study of patients with incident HPV-OPC diagnosed from 2009 to 2013 at 4 academic tertiary referral cancer centers in the United States. Oral rinse samples were collected at diagnosis and after treatment (9, 12, 18, and 24 months after diagnosis), and evaluated for HPV DNA. Among an initial cohort of 157 participants with incident HPV-OPC treated with curative intent, 124 had 1 or more posttreatment oral rinses available and were included in this study. <h3>Main Outcomes and Measures</h3> Disease-free survival (DFS) and overall survival (OS) were estimated by the Kaplan-Meier method, and the association of HPV DNA detection in oral rinses with survival was evaluated using Cox regression analysis. <h3>Results</h3> Oral HPV type 16 (HPV16) DNA was common at diagnosis (67 of 124 participants [54%]). In contrast, oral HPV16 DNA was detected in only 6 participants after treatment (5%), including 5 with HPV16 DNA also detected at diagnosis (persistent oral HPV16 DNA). Two-year DFS and OS were 92% (95% CI, 94%-100%) and 98% (95% CI, 93%-99%). Persistent oral HPV16 DNA was associated with worse DFS (hazard ratio, 29.7 [95% CI, 9.0-98.2]) and OS (hazard ratio, 23.5 [95% CI, 4.7-116.9]). All 5 participants with persistent oral HPV16 DNA developed recurrent disease, 3 with local disease involvement. In contrast, just 9 of 119 participants (8%) without persistent oral HPV16 DNA developed recurrent disease, only 1 (11%) with local disease involvement. Median (range) time from earliest posttreatment oral HPV16 DNA detection to recurrence was 7.0 (3.7-10.9) months. <h3>Conclusions and Relevance</h3> Human papillomavirus type 16 DNA in oral rinses is common at diagnosis but rare after treatment for HPV-OPC. Our data suggest that, although infrequent, persistent HPV16 DNA in posttreatment oral rinses is associated with poor prognosis and is a potential tool for long-term tumor surveillance, perhaps more so for local recurrence.
Peri-Operative Complications and Pain After the Suburethral Sling Procedure for Urinary Stress Incontinence: A French Prospective Randomised Multicentre Study Comparing the Retropubic and Transobturator Routes
Authors: Emmanuel David-Montefiore, Jean-Louis Frobert, Marielle Grisard-Anaf, Jean Lienhart, Karine Bonnet, Christophe Poncelet, Emile Daraï
Journal: European Urology (2005)
The need for macrolides in hospitalised community-acquired pneumonia: propensity analysis
Authors: M. Paul, A. D. Nielsen, A. Gafter-Gvili, E. Tacconelli, S. Andreassen, N. Almanasreh, E. Goldberg, R. Cauda, U. Frank, L. Leibovici
Journal: European Respiratory Journal (2007)

<h3>Abstract</h3> Clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9 technology provides potential advantages in high-throughput functional genomics analysis in prokaryotes over previously established platforms based on recombineering or transposon mutagenesis. In this work, as a proof-of-concept to adopt CRISPR/Cas9 method as a pooled functional genomics analysis platform in prokaryotes, we developed a CRISPR interference (CRISPRi) library consisting of 3,148 single guide RNAs (sgRNAs) targeting the open reading frame (ORF) of 67 genes with known knockout phenotypes and performed pooled screens under two stressed conditions (minimal and acidic medium) in <i>Escherichia coli</i>. Our approach confirmed most of previously described gene-phenotype associations while maintaining &lt; 5% false positive rate, suggesting that CRISPRi screen is both sensitive and specific. Our data also supported the ability of this method to narrow down the candidate gene pool when studying operons, a unique structure in prokaryotic genome. Meanwhile, assessment of multiple loci across treatments enables us to extract several guidelines for sgRNA design for such pooled functional genomics screen. For instance, sgRNAs locating at the first 5% upstream region within ORF exhibit enhanced activity and 10 sgRNAs per gene is suggested to be enough for robust identification of gene-phenotype associations. We also optimized the hit-gene calling algorithm to identify target genes more robustly with even fewer sgRNAs. This work showed that CRISPRi could be adopted as a powerful functional genomics analysis tool in prokaryotes and provided the first guideline for the construction of sgRNA libraries in such applications. <h3>Importance</h3> To fully exploit the valuable resource of explosive sequenced microbial genomes, high-throughput experimental platform is needed to associate genes and phenotypes at the genome level, giving microbiologists the insight about the genetic structure and physiology of a microorganism. In this work, we adopted CRISPR interference method as a pooled high-throughput functional genomics platform in prokaryotes with <i>Escherichia coli</i> as the model organism. Our data suggested that this method was highly sensitive and specific to map genes with previously known phenotypes, potent to act as a new strategy for high-throughput microbial genetics study with advantages over previously established methods. We also provided the first guideline for the sgRNA library design by comprehensive analysis of the screen data. The concept, gRNA library design rules and open-source scripts of this work should benefit prokaryotic genetics community to apply high-throughput mapping of defined gene set with phenotypes in a broad spectrum of microorganisms.
Secondary oxalosis
Authors: A M Alkhunaizi, L Chan
Journal: Journal of the American Society of Nephrology (1996)

Oxalosis, or calcium oxalate deposition in the tissues, may develop in patients with inherited disorders of oxalate metabolism or can occur secondary to other diseases. In this study, a case of renal oxalosis probably secondary to excessive parenteral vitamin C administration in a patient with acute post-traumatic oliguric renal failure is reported. Oxalate deposits may have contributed to further worsening and delayed recovery of renal function. The elimination of the source of excess vitamin C and its presumed effect on oxalate production, together with enhanced removal of oxalate during aggressive dialysis, resulted in prompt recovery of renal function. Secondary oxalosis represents a possible cause of delayed recovery of renal function in patients with acute renal failure who are receiving vitamin C supplementation if excess dosage of that supplementation is given. Vitamin C supplementation, if utilized, should be carefully monitored in patients receiving artificial renal replacement therapy.
A novel missense mutation in RSPO4 gene underlies autosomal recessive congenital anonychia in a consanguineous Pakistani family
Authors: M.S. Chishti, N. Kausar, M.A. Rafiq, M. Amin, W. Ahmad
Journal: British Journal of Dermatology (2007)

Conflicts of interest: none declared. Developmental abnormalities involving nails range from slight change to complete absence of fingernails and toenails. They may appear as an isolated abnormality or as a feature of genetic syndromes. Isolated forms of nail dysplasia are rare and to date only a few cases have been reported. Recently, autosomal recessive congenital anonychia, a condition representing the absence of several or all fingernails and/or toenails since birth, was mapped to chromosome 20p13.1, 2 Further, mutations in RSPO4, encoding a member of the R‐spondin protein family, were independently identified by two different groups. The R‐spondin proteins are newly identified secreted molecules that activate β‐catenin signalling.3, 4 Four R‐spondin proteins (Rspo1–4) exist in vertebrates. Each of the four RSPO genes consists of five coding exons that are predicted to encode an N‐terminal signal peptide (exon 1), followed by two furin‐type cysteine‐rich domains (exons 2 and 3), a thrombospondin‐type domain (exon 4) and a C‐terminal basic region that scores highly as a nuclear localization signal. The furin‐like repeats encoded by exons 2 and 3 are believed to be required for activation and stabilization of β‐catenin.5 The Rspo proteins play important roles in vertebrate development, as they are expressed in temporal and tissue‐specific patterns during vertebrate development.3, 6, 7 Ligand‐type activities of these proteins overlap substantially with those of the canonical Wnt ligands in that both Rspo and canonical Wnt signalling result in the activation of β‐catenin and the T‐cell factor–lymphoid enhancer factor family transcription factor complex,8 by binding to the Frizzled family receptors and the low‐density lipoprotein‐related receptor LRP5 or LRP6 coreceptor which initiates downstream signalling events leading to the gene activation.4
Sinusoidal Ultrastructure Evaluated During the Revascularization of Regenerating Rat Liver
Authors: Kathryn E. Wack, Mark A. Ross, Vasthy Zegarra, Laura R. Sysko, Simon C. Watkins, Donna Beer Stolz
Journal: Hepatology (2001)

Sinusoidal endothelial cell (SEC) porosities were compared between the periportal (zone 1) and pericentral (zone 3) regions of the rat liver during regeneration following partial hepatectomy (PHx). SEC porosities and fenestration diameters were measured in control livers, as well as at 5 minutes, 24, 48, 72, 96, 120 hours, and 14 days following PHx. Bimodal maximums in both porosity and fenestration diameters were observed in both zones at 5 minutes and 5 days following PHx. SEC porosities increased significantly in both zones 1 and 3 within 5 minutes following PHx, but the increase was maintained only in zone 1 at 24 hours after resection. Following the initial rise, both zones displayed a gradual decrease to less than half their porosity values at 72 hr post–PHx. After 72 hours, porosities increased to over control levels and remained elevated until 14 days after PHx. The decrease in porosity at 72 hr post–PHx is accompanied by ultrastructural changes within the sinusoid at this time. Vascular corrosion casting and transmission electron microscopy (TEM) show sinusoid compression resulting from increased hepatic plate widths due to hepatocyte proliferation in the absence of SEC proliferation. Also at this time, we observed many SEC completely enveloped by stellate cells. The zonal variations observed for porosities throughout regeneration did not correlate with changes in laminin, collagen I and IV, or fibronectin deposition within the space of Disse. Taken together, the data reveal that SEC are dynamic regulators of porosity that respond rapidly and locally to environmental zonal stimuli during liver regeneration.
Conversion of immunity to suppression by in vivo administration of I-A subregion-specific antibodies.
Authors: L L Perry, M I Greene
Journal: The Journal of Experimental Medicine (1982)

The in vivo administration of antibodies specific for gene products of the I-A subregion represents an immunologically specific approach to the manipulation of Ly-1+ T cell responses to antigen. This has been demonstrated previously by the capacity of anti-I-A antibody treatment to abrogate T cell-mediated delayed-type hypersensitivity (DTH) responses to syngeneic tumor antigen, hapten, and non-H-2 histocompatibility antigens. Evidence obtained in these studies suggested that the primary action of antibody was related to its ability to interfere with macrophage-T cell interactions during antigen presentation, consistent with the demonstration that similar antibodies inhibit T cell binding to antigen-pulsed macrophages in vitro. Results presented in this report provide evidence for an additional consequence of in vivo antibody administration that may be secondary to any direct effects on I-A-restricted antigen presentation. Thus, animals treated with I-A subregion-specific antibodies also develop a population of antigen-specific suppressor T cells (Ts) capable of inhibiting recipient Ly-1+ T cell responses to tumor antigen. The induction of suppression appeared to be an essential component of the total biological activity of these antibodies, because elimination of Ts precursors by cyclophosphamide also abrogated the antibody-mediated inhibition of DTH responsiveness. These results are discussed with respect to the possible mechanisms of Ts activation by anti-I-A antibody administration, and the general applicability of this approach as a means of clinical immunotherapy to limit inappropriate T cell responses in human disease.
Endothelial Cell Loss and Visual Outcome of Deep Anterior Lamellar Keratoplasty versus Penetrating Keratoplasty: A Randomized Multicenter Clinical Trial
Authors: Yanny Y.Y. Cheng, Nienke Visser, Jan S. Schouten, Robert-Jan Wijdh, Elisabeth Pels, Hugo van Cleynenbreugel, Catharina A. Eggink, Michel J.W. Zaal, Wilhelmina J. Rijneveld, Rudy M.M.A. Nuijts
Journal: Ophthalmology (2010)
Pharmacology of Nicotine: Addiction, Smoking-Induced Disease, and Therapeutics
Authors: Neal L. Benowitz
Journal: The Annual Review of Pharmacology and Toxicology (2008)

Nicotine sustains tobacco addiction, a major cause of disability and premature death. Nicotine binds to nicotinic cholinergic receptors, facilitating neurotransmitter release and thereby mediating the complex actions of nicotine in tobacco users. Dopamine, glutamate, and gamma aminobutyric acid release are particularly important in the development of nicotine dependence, and corticotropin-releasing factor appears to contribute to nicotine withdrawal. Nicotine dependence is highly heritable. Genetic studies indicate roles for nicotinic receptor subtypes, as well as genes involved in neuroplasticity and learning, in development of dependence. Nicotine is primarily metabolized by CYP 2A6, and variability in rate of metabolism contributes to vulnerability to tobacco dependence, response to smoking cessation treatment, and lung cancer risk. Tobacco addiction is much more common in persons with mental illness and substance abuse disorders, representing a high proportion of current smokers. Pharmacotherapeutic approaches to tobacco addiction include nicotine replacement, bupropion, and varenicline, the latter a selective nicotine receptor partial agonist.