tbuckley/cabot-search huggingface dataset:
Passively Acquired Antibody-Dependent Cellular Cytotoxicity (ADCC) Activity in HIV-Infected Infants Is Associated with Reduced Mortality
Authors: Caitlin Milligan, Barbra A. Richardson, Grace John-Stewart, Ruth Nduati, Julie Overbaugh
Journal: Cell Host & Microbe (2015)

In addition to direct effects on virus infectivity, antibodies mediate antibody-dependent cellular cytotoxicity (ADCC), the killing of an antibody-coated virus-infected cell by cytotoxic effector cells. Although ADCC has been suggested to protect against HIV, the relationship between HIV-specific ADCC antibodies at the time of HIV exposure and infection outcome in humans remains to be assessed. We evaluated the ADCC activity of passively acquired antibodies in infants born to HIV-infected mothers. ADCC levels were higher in uninfected than infected infants, although not significantly. Increase in ADCC antibody activity in infected infants was associated with reduced mortality risk. Infant ADCC positively correlated with the magnitude of IgG1 binding, and IgG1 levels were associated with survival in infected infants. Infant IgG3-binding antibodies were not associated with infected infant survival. These data suggest a therapeutic benefit of pre-existing HIV-specific ADCC antibodies and support a role for eliciting ADCC-mediating IgG1 in HIV vaccines.
Binding and regulation of cellular functions by monoclonal antibodies against human tumor necrosis factor receptors.
Authors: M R Shalaby, A Sundan, H Loetscher, M Brockhaus, W Lesslauer, T Espevik
Journal: The Journal of Experimental Medicine (1990)

The present study was undertaken to further characterize the interaction of monoclonal antibodies (mAbs) against tumor necrosis factor (TNF) receptors with different targets, and to assess their ability to influence TNF effects on U937 and human endothelial cell (HEC) functions. Actions of recombinant TNF-alpha on U937 and HEC were effectively inhibited by Htr-5 and Utr-1, and to a greater extent by a combination of both mAbs. These observations indicate that TNF interaction with antigenically different components of membrane receptors (p55 and p75) represents a crucial step in transduction of signals for TNF toxicity against U937 and TNF activation of HEC functions.
Langerhans cells are negative regulators of the anti-<i>Leishmania</i> response
Authors: Kordula Kautz-Neu, Madelon Noordegraaf, Stephanie Dinges, Clare L. Bennett, Dominik John, Björn E. Clausen, Esther von Stebut
Journal: The Journal of Experimental Medicine (2011)

Migratory skin dendritic cells (DCs) are thought to play an important role in priming T cell immune responses against Leishmania major, but DC subtypes responsible for the induction of protective immunity against this pathogen are still controversial. In this study, we analyzed the role of Langerin+ skin-derived DCs in the Leishmania model using inducible in vivo cell ablation. After physiologically relevant low-dose infection with L. major (1,000 parasites), mice depleted of all Langerin+ DCs developed significantly smaller ear lesions with decreased parasite loads and a reduced number of CD4+ Foxp3+ regulatory T cells (T reg cells) as compared with controls. This was accompanied by increased interferon γ production in lymph nodes in the absence of Langerin+ DCs. Moreover, selective depletion of Langerhans cells (LCs) demonstrated that the absence of LCs, and not Langerin+ dermal DC, was responsible for the reduced T reg cell immigration and the enhanced Th1 response, resulting in attenuated disease. Our data reveal a unique and novel suppressive role for epidermal LCs in L. major infection by driving the expansion of T reg cells. A better understanding of the various roles of different DC subsets in cutaneous leishmaniasis will improve the development of a potent therapeutic/prophylactic vaccine.
A New Family of Ferritin Genes from Lupinus luteus--Comparative Analysis of Plant Ferritins, Their Gene Structure, and Evolution
Authors: P. M. Strozycki, M. Szymanski, A. Szczurek, J. Barciszewski, M. Figlerowicz
Journal: Molecular Biology and Evolution (2009)

Ferritins are one of the most important elements of cellular machinery involved in iron management. Despite extensive studies conducted during the last decade, many factors regulating the expression of ferritin genes in plants remain unknown. To broaden our knowledge about the mechanisms controlling ferritin production in plant cells, we have identified and characterized a new family of ferritin genes (from yellow lupine). We have also inventoried all available plant ferritins and their genes and subjected them to a complex bioinformatic analysis. It showed that the conservative structure of ferritin genes was established much earlier than it was thought before. The first introns in ferritin genes appeared already in green algae. The number and location of introns have been finally established in mosses, over 400 million years ago, and are strictly preserved in all plants from bryophytes to dicots. Comparison of ferritin gene promoters revealed that the 14-bp-long iron-dependent regulatory sequence (IDRS), identified earlier in Arabidopsis and maize, is characteristic for all higher plants. Moreover, we found that a highly conserved IDRS can be extended (extIDRS) up to 22 bp. Phylogenetic analysis of plant ferritins showed that polypeptides of the eudicot clade can be divided into two subclasses (eudicot-1 and eudicot-2). Interestingly, we found that genes encoding proteins classified as eudicot-1 and eudicot-2 are equipped with class-specific promoters. This suggests that eudicot ferritins are structurally and perhaps functionally diverse. Based on the above observations, we were able to identify conservative elements (ELEM1--6) other than extIDRS within plant ferritin gene promoters. We also found E-boxes and iron-responsive sequence elements FeRE1 and 2, characteristically distributed within ferritin promoters. Because most of the identified conserved sequences are located within or in close proximity of extIDRS, we named this fragment of the plant ferritin gene promoter the regulatory element rich region.
Twelve-Month Outcome of Adolescents With Bipolar Disorder Following First Hospitalization for a Manic or Mixed Episode
Authors: Melissa P. DelBello, Dennis Hanseman, Caleb M. Adler, David E. Fleck, Stephen M. Strakowski
Journal: American Journal of Psychiatry (2007)

Objective: Although adolescent-onset bipolar disorder is associated with significant morbidity, there have been few prospective outcome studies of this population. The aim of this study was to examine the 12-month outcome of bipolar adolescents following an initial hospitalization for a manic or mixed episode. Method: Bipolar adolescents (N=71) were recruited during their first hospitalization for a manic or mixed episode and were evaluated using diagnostic, symptomatic, and functional assessments. Patients were also evaluated at 1, 4, 8, and 12 months after hospitalization to assess syndromic, symptomatic, and functional outcomes. Predictors of each type of outcome were identified. Results: Kaplan-Meier estimates of the cumulative probabilities of syndromal, symptomatic, and functional recovery and syndromic recurrence during the first 12 months following initial hospitalization were 0.86, 0.43, 0.41, and 0.54, respectively. Only 35% of bipolar adolescents reported full medication adherence. Individual predictors of poor syndromic recovery included co-occurring attention deficit hyperactivity disorder (ADHD), anxiety disorders, and disruptive behavior disorders as well as nonadherence to psychotropic medication and lower socioeconomic levels. Co-occurring alcohol use disorders, treatment with antidepressants, and the absence of psychotherapeutic intervention predicted syndromic recurrence. Boys were more than twice as likely as girls to experience symptomatic recovery. Conclusions: Most bipolar adolescents experienced syndromic recovery following their first hospitalization. However, rates of symptomatic and functional recoveries were much lower. Future studies examining effective pharmacological and nonpharmacological treatment strategies for bipolar youth with co-occurring disorders and investigating factors that contribute to the development of substance use disorders and treatment adherence in bipolar youth are necessary to improve outcome.
Hepatitis C virus promotes t-helper (Th)17 responses through thymic stromal lymphopoietin production by infected hepatocytes
Authors: Hai-Chon Lee, Sung-Sang J. Sung, Peter D. Krueger, Yoon-Ah Jo, Hugo R. Rosen, Steven F. Ziegler, Young S. Hahn
Journal: Hepatology (2012)

Hepatitis C virus (HCV) is a major cause of liver cirrhosis and hepatocellular carcinoma. Here we report that infection of hepatic cells by HCV stimulates nuclear factor kappa B (NFκB)-dependent production of thymic stromal lymphopoietin (TSLP). Hepatocyte-derived TSLP in turn conditions dendritic cells (DCs) to drive T-helper (Th)17 differentiation. The TSLP secreted by HCV-infected hepatoma cells is capable of activating human monocyte-derived DCs by up-regulating the expression of CD40, CD86, CCL17, CCL22, and CCL20 which are activating markers of DCs. In addition, the production of key cytokines for Th17 differentiation, transforming growth factor beta (TGF-β), interleukin (IL)-6, and IL-21, is enhanced by human monocytes upon coculture with HCV-infected cells. Importantly, the blockade of TSLP using neutralizing antibody prevented the activation and maturation of DCs as well as the production of Th17 differentiation cytokines. DC conditioning by TSLP secreted from HCV-infected cells activated naïve CD4+ T lymphocytes, resulting in Th17 differentiation. Furthermore, we can detect substantial levels of hepatocyte TSLP in fibrotic liver tissue from chronic HCV patients. Thus, blockade of TSLP released by HCV-infected hepatocytes may suppress the induction/maintenance of hepatic Th17 responses and halt the progression of chronic liver disease to fibrosis and liver failure.Hepatocyte-derived TSLP conditions DCs to drive Th17 differentiation. Treatment of TSLP neutralizing antibody in HCV-infected hepatocyte/DC coculture abrogates DC conditioning and thereby inhibits Th17 differentiation.
Medical audit and clinical competence.
Authors: S E Josse
Journal: BMJ (1980)

who continued treatment with tamoxifen alone did not have a response.We agree that tamoxifen-induced hyper- calcaemia probably is not uncommon, but as yet there is no firm evidence to support the suggestion that induced hypercalcaemia is indicative of a good response to tamoxifen or other additive hormones used in the treatment of breast cancer.
High Prevalence of Myocardial Perfusion Abnormalities on Positron Emission Tomography in Asymptomatic Persons With a Parent or Sibling With Coronary Artery Disease
Authors: Stefano Sdringola, Dhaval Patel, K. Lance Gould
Journal: Circulation (2001)

Background —We hypothesized that asymptomatic persons with a parent or sibling with coronary artery disease (CAD) have myocardial perfusion defects on positron emission tomography (PET) as markers of early CAD. Methods and Results —After medical and family histories were recorded, 90 subjects underwent rest-dipyridamole cardiac PET perfusion imaging, including 18 index cases (a subject with CAD documented by PET and arteriography), 32 asymptomatic adults without known CAD who had a parent or sibling with CAD among these index cases, 30 asymptomatic subjects with comparable coronary risk factors without CAD or a family history of CAD, and 10 volunteer control subjects with no risk factors and no family history. PET perfusion images were quantified with automated software for size of abnormalities as percent of the cardiac image outside 95% CIs of normal controls and for severity as the lowest quadrant average relative activity. Of asymptomatic subjects with a parent or sibling with CAD (first-degree relatives), 50% had dipyridamole-induced myocardial perfusion defects that involved ≥5% of the cardiac image outside normal 95% CIs with or without other risk factors. The size of perfusion defects was larger in first-degree relatives than in control subjects (11±13% versus 1±1%, P =0.02) and larger than in asymptomatic subjects with comparable risk factors but no family history of CAD (11±13% versus 5±6%, P =0.02). Conclusions —This study documents the presence of quantitative, statistically significant, dipyridamole-induced myocardial perfusion abnormalities on PET in 50% of asymptomatic persons with a parent or sibling with CAD, independent of other risk factors, indicating preclinical coronary atherosclerosis.
High prevalence of G1 and G2 TT-virus infection in subjects with high and low blood exposure risk: identification of G4 isolates in Italy
Authors: Piero Colombatto, Maurizia R. Brunetto, Joe Kansopon, Filippo Oliveri, Anna Maina, Ulises Aragon, Maria L. Bortoli, Fabrizio Scatena, Ugo Baicchi, Michael Houghton, Ferruccio Bonino, Amy J. Weiner
Journal: Journal of Hepatology (1999)
Trimethoprim-sulfamethoxazole induced hyperkalaemia in elderly patients receiving spironolactone: nested case-control study
Authors: T. Antoniou, T. Gomes, M. M. Mamdani, Z. Yao, C. Hellings, A. X. Garg, M. A. Weir, D. N. Juurlink
Journal: BMJ (2011)

To characterise the risk of admission to hospital for hyperkalaemia in elderly patients treated with trimethoprim-sulfamethoxazole in combination with spironolactone.Population based nested case-control study.Ontario, Canada, from 1 April 1992 to 1 March 2010.Cases were residents of Ontario aged 66 years or above receiving chronic treatment with spironolactone and admitted to hospital with hyperkalaemia within 14 days of receiving a prescription for either trimethoprim-sulfamethoxazole, amoxicillin, norfloxacin, or nitrofurantoin. Up to four controls for each case were identified from the same cohort, matched on age, sex, and presence or absence of chronic kidney disease and diabetes, and required to have received one of the study antibiotics within 14 days before the case's index date.Odds ratio for association between admission to hospital with hyperkalaemia and receipt of a study antibiotic in the preceding 14 days, adjusted for conditions and drugs that may influence risk of hyperkalaemia.During the 18 year study period, 6903 admissions for hyperkalaemia were identified, 306 of which occurred within 14 days of antibiotic use. Of these, 248 (81%) cases were matched to 783 controls. 10.8% (17,859/165,754) of spironolactone users received at least one prescription for trimethoprim-sulfamethoxazole. Compared with amoxicillin, prescription of trimethoprim-sulfamethoxazole was associated with a marked increase in the risk of admission to hospital for hyperkalaemia (adjusted odds ratio 12.4, 95% confidence interval 7.1 to 21.6). The population attributable fraction was 59.7%, suggesting that approximately 60% of all cases of hyperkalaemia in older patients taking spironolactone and treated with an antibiotic for a urinary tract infection could be avoided if trimethoprim-sulfamethoxazole was not prescribed. Treatment with nitrofurantoin was also associated with an increase in the risk of hyperkalaemia (adjusted odds ratio 2.4, 1.3 to 4.6), but no such risk was found with norfloxacin (adjusted odds ratio 1.6, 0.8 to 3.4)Among older patients receiving spironolactone, treatment with trimethoprim-sulfamethoxazole was associated with a major increase in the risk of admission to hospital for hyperkalaemia. This drug combination should be avoided when possible.
Exome Chip Genotyping Reveals Association With PDE4C and Atopic Dermatitis In Populations Of European and African Descent
Authors: Nicholas M. Rafaels, Lili Huang, Donald Y.M. Leung, Lisa A. Beck, Candelaria I. Vergara, Mark Boguniewicz, Tissa Hata, Lynda C. Schneider, Jon M. Hanifin, Richard Gallo, Li Gao, Ingo Ruczinski, Rasika A. Mathias, Kathleen C. Barnes
Journal: Journal of Allergy and Clinical Immunology (2014)
The Three-Dimensional Structure of Peptide-MHC Complexes
Authors: Dean R. Madden
Journal: Annual Review of Immunology (1995)

The ability of MHC molecules to present a broad spectrum of peptide antigens for T cell recognition requires a compromise between high affinity and broad specificity. Three-dimensional atomic structures of several class I and class II MHC molecules reveal a unique structural solution to this problem: Tight binding to the peptide main chain is supplemented by more or less restrictive interactions with peptide side chains. In spite of these contacts, peptide side-chain and conformational variability ensures that the resulting peptide-MHC complex presents an antigenically unique surface to T cell receptors. Extension of this understanding to other peptide-MHC complexes, including agonist/antagonist peptides and the identification of antigenic peptides within protein sequences, however, requires a detailed analysis of the interactions that determine both peptide-MHC binding affinity and the conformations of bound peptides. While many of these interactions can be modeled by homology with known structures, their specificity can depend sensitively on subtle and long range structural effects. Structurally and immunologically important distinctions are also found between the class I and class II peptide-binding strategies. Taken together, these interactions ultimately determine the ability of an individual to respond successfully to immune challenges.
Safety and Effectiveness of Recombinant Human Bone Morphogenetic Protein-2 for Spinal Fusion
Authors: Mark C. Simmonds, Jennifer V.E. Brown, Morag K. Heirs, Julian P.T. Higgins, Richard J. Mannion, Mark A. Rodgers, Lesley A. Stewart
Journal: Annals of Internal Medicine (2013)

Recombinant human bone morphogenetic protein-2 (rhBMP-2) is widely used to promote fusion in spinal surgery, but its safety has been questioned.To evaluate the effectiveness and safety of rhBMP-2.Individual-participant data obtained from the sponsor or investigators and data extracted from study publications identified by systematic bibliographic searches through June 2012.Randomized, controlled trials of rhBMP-2 versus iliac crest bone graft (ICBG) in spinal fusion surgery for degenerative disc disease and related conditions and observational studies in similar populations for investigation of adverse events.Individual-participant data from 11 eligible of 17 provided trials sponsored by Medtronic (Minneapolis, Minnesota) (n = 1302) and 1 of 2 other eligible trials (n = 106) were included. Additional aggregate adverse event data were extracted from 35 published observational studies.Primary outcomes were pain (assessed with the Oswestry Disability Index [ODI] or Short Form-36), fusion, and adverse events. At 24 months, ODI scores were 3.5% lower (better) with rhBMP-2 than with ICBG (95% CI, 0.5% to 6.5%) and radiographic fusion was 12% higher (CI, 2% to 23%). At or shortly after surgery, pain was more common with rhBMP-2 (odds ratio, 1.78 [CI, 1.06 to 2.95]). Cancer was more common after rhBMP-2 (relative risk, 1.98 [CI, 0.86 to 4.54]), but the small number of events precluded definite conclusions.The observational studies were diverse and at risk of bias.At 24 months, rhBMP-2 increases fusion rates, reduces pain by a clinically insignificant amount, and increases early postsurgical pain compared with ICBG. Evidence of increased cancer incidence is inconclusive.Yale University Open Data Access Project.
Independently derived murine glomerular immune deposit-forming anti-DNA antibodies are encoded by near-identical VH gene sequences.
Authors: M S Katz, M H Foster, M P Madaio
Journal: Journal of Clinical Investigation (1993)

To examine the influence of variable region sequences on the capacity of individual lupus autoantibodies (autoAb) to form glomerular immune deposits, the complete VH and VL region sequences of three anti-DNA mAb that produced morphologically similar immune deposits after administration to normal mice were determined. The Ig were independently derived from 1-mo-old (H238, IgM), 3-mo-old (H8, IgG2a), and 6-mo-old (H161, IgG3) MRL-lpr/lpr mice, and they all produced subendothelial and mesangial immune deposits after passive transfer to normal mice. In addition, H238 and H161 produced granular deposits in small extraglomerular vessels. The mAb had nearly identical VH gene sequences; H8 differed from H238 and H161 by a single nucleotide in FR1 that resulted in a histidine for glutamine substitution. This VH gene sequence was also > 99% homologous to another anti-DNA Ab (termed H241), that we previously reported to produce glomerular immune deposits in a similar morphologic pattern. H161 and H238 were encoded by DFL16 and JH2 genes, whereas H8 was encoded by a JH4 gene. Different Vk family genes were used to encode the three mAb, however H161 and H238 both used a Jk5 gene. The results indicate that an identical or highly related VH gene is used to encode a subgroup of murine lupus autoAb that share immune deposit forming properties. Furthermore, they raise the possibility that amino acid residues independent from those encoded by VH genes may be influential in immune deposit formation at extraglomerular sites.
Cancer Stem Cells and Chemosensitivity
Authors: Marcello Maugeri-Saccà, Paolo Vigneri, Ruggero De Maria
Journal: Clinical Cancer Research (2011)

Cancer lethality is mainly due to the onset of distant metastases and refractoriness to chemotherapy. Thus, the development of molecular targeted agents that can restore or increase chemosensitivity will provide valuable therapeutic options for cancer patients. Growing evidence indicates that a cellular subpopulation with stem cell-like features, commonly referred to as cancer stem cells (CSCs), is critical for tumor generation and maintenance. Recent advances in stem cell biology are revealing that this cellular fraction shares many properties with normal adult stem cells and is able to propagate the parental tumor in animal models. CSCs seem to be protected against widely used chemotherapeutic agents by means of different mechanisms, such as a marked proficiency in DNA damage repair, high expression of ATP-binding cassette drug transporters, and activation of PI3K/AKT and Wnt pathways. Moreover, microenvironmental stimuli such as those involved in the epithelial-mesenchymal transition and hypoxia indirectly contribute to chemoresistance by inducing in cancer cells a stem-like phenotype. Understanding how CSCs overcome chemotherapy-induced death stimuli, and integrating such knowledge into clinical research methodology, has become a priority in the process of identifying innovative therapeutic strategies aimed at improving the outcome of cancer patients.