tbuckley/cabot-search huggingface dataset:
Remission of Proteinuria Improves Prognosis in IgA Nephropathy
Authors: Heather N. Reich, Ste[Combining Acute Accent]phan Troyanov, James W. Scholey, Daniel C. Cattran
Journal: Journal of the American Society of Nephrology (2007)

Proteinuria has been shown to be an adverse prognostic factor in IgA nephropathy. The benefit of achieving a partial remission of proteinuria, however, has not been well described. We studied 542 patients with biopsy-proven primary IgA nephropathy in the Toronto Glomerulonephritis Registry and found that glomerular filtration rate (GFR) declined at −0.38 ± 0.61 ml/min per 1.73 m2/mo overall, with 30% of subjects reaching end-stage renal disease. Multivariate analysis revealed that proteinuria during follow-up was the most important predictor of the rate of GFR decline. Among the 171 patients with <1 g/d of sustained proteinuria, the rate of decline was 90% slower than the mean rate. The rate of decline increased with the amount of proteinuria, such that those with sustained proteinuria >3 g/d (n = 121) lost renal function 25-fold faster than those with <1 g/d. Patients who presented with ≥3 g/d who achieved a partial remission (<1 g/d) had a similar course to patients who had ≤1 g/d throughout, and fared far better than patients who never achieved remission. These results underscore the relationship between proteinuria and prognosis in IgA nephropathy and establish the importance of remission.
Pneumococcal vaccination decreases atherosclerotic lesion formation: molecular mimicry between Streptococcus pneumoniae and oxidized LDL
Authors: Christoph J Binder, Sohvi Hörkkö, Asheesh Dewan, Mi-Kyung Chang, Emily P Kieu, Carl S Goodyear, Peter X Shaw, Wulf Palinski, Joseph L Witztum, Gregg J Silverman
Journal: Nature Medicine (2003)
Activation of the PD-1 Pathway Contributes to Immune Escape in EGFR-Driven Lung Tumors
Authors: Esra A. Akbay, Shohei Koyama, Julian Carretero, Abigail Altabef, Jeremy H. Tchaicha, Camilla L. Christensen, Oliver R. Mikse, Andrew D. Cherniack, Ellen M. Beauchamp, Trevor J. Pugh, Matthew D. Wilkerson, Peter E. Fecci, Mohit Butaney, Jacob B. Reibel, Margaret Soucheray, Travis J. Cohoon, Pasi A. Janne, Matthew Meyerson, D. Neil Hayes, Geoffrey I. Shapiro, Takeshi Shimamura, Lynette M. Sholl, Scott J. Rodig, Gordon J. Freeman, Peter S. Hammerman, Glenn Dranoff, Kwok-Kin Wong
Journal: Cancer Discovery (2013)

The success in lung cancer therapy with programmed death (PD)-1 blockade suggests that immune escape mechanisms contribute to lung tumor pathogenesis. We identified a correlation between EGF receptor (EGFR) pathway activation and a signature of immunosuppression manifested by upregulation of PD-1, PD-L1, CTL antigen-4 (CTLA-4), and multiple tumor-promoting inflammatory cytokines. We observed decreased CTLs and increased markers of T-cell exhaustion in mouse models of EGFR-driven lung cancer. PD-1 antibody blockade improved the survival of mice with EGFR-driven adenocarcinomas by enhancing effector T-cell function and lowering the levels of tumor-promoting cytokines. Expression of mutant EGFR in bronchial epithelial cells induced PD-L1, and PD-L1 expression was reduced by EGFR inhibitors in non-small cell lung cancer cell lines with activated EGFR. These data suggest that oncogenic EGFR signaling remodels the tumor microenvironment to trigger immune escape and mechanistically link treatment response to PD-1 inhibition.We show that autochthonous EGFR-driven lung tumors inhibit antitumor immunity by activating the PD-1/PD-L1 pathway to suppress T-cell function and increase levels of proinflammatory cytokines. These findings indicate that EGFR functions as an oncogene through non-cell-autonomous mechanisms and raise the possibility that other oncogenes may drive immune escape.
Continued Reduction in the Prevalence of Retinopathy in Adolescents With Type 1 Diabetes
Authors: Elizabeth Downie, Maria E. Craig, Stephen Hing, Janine Cusumano, Albert K.F. Chan, Kim C. Donaghue
Journal: Diabetes Care (2011)

To examine trends in microvascular complications in adolescents with type 1 diabetes between 1990 and 2009 in Sydney, Australia.We used analysis of complications in 1,604 adolescents (54% female, aged 12-20 years, median duration 8.6 years), stratified by four time periods using Generalized Estimation Equations as follows: T1 (1990-1994), T2 (1995-1999), T3 (2000-2004), and T4 (2005-2009). Early retinopathy was detected using seven-field fundal photography, albumin excretion rate (AER) using timed overnight urine collections, and albumin-to-creatinine ratio (ACR) and peripheral nerve function using thermal and vibration threshold.Retinopathy declined (53, 38, 23, and 12%; P < 0.001), as did borderline elevation of AER/ACR (45, 30, 26, and 30%; P < 0.001) and microalbuminuria (8, 4, 3, and 3%; P = 0.006). Multiple daily injections (MDI)/continuous subcutaneous insulin infusion (CSII) use increased (17, 54, 75, and 88%; P < 0.001), median HbA(1c) decreased (9.1, 8.9, 8.5, and 8.5%; P < 0.001), and severe hypoglycemia was unchanged (6, 8, 10, and 7%; P = 0.272). Retinopathy was associated with diabetes duration (odds ratio [OR] 1.12 [95% CI 1.08-1.17]), age (1.13 [1.06-1.20]), HbA(1c) (1.16 [1.08-1.25]), systolic blood pressure (BP) SDS (1.31 [1.16-1.48]), socioeconomic disadvantage (1.42 [1.04-1.95]), and 1 to 2 injections per day (vs. MDI/CSII; 1.35 [1.05-1.73]); borderline AER/ACR with male sex (1.32 [1.02-1.70]), age (1.19 [1.12-1.26]), HbA(1c) (1.18 [1.08-1.29]), weight SDS (1.31 [1.21-1.53]), insulin dose per kilograms (1.64 [1.13-2.39]), 1 to 2 injections per day (1.41 [1.08-1.84]), and socioeconomic disadvantage (1.68 [1.23-2.31]); and microalbuminuria with age (1.14 [1.01-1.29]), HbA(1c) (1.20 [1.05-1.37]), diastolic BP SDS (1.76 [1.26-2.46]), and 1 to 2 injections per day (1.95 [1.11-3.41]).The decline in retinopathy supports contemporary guidelines that recommend lower glycemic targets and use of MDI/CSII in children and adolescents with type 1 diabetes.
FORMATION OF A HEMOLYTICALLY ACTIVE CELLULAR INTERMEDIATE BY THE INTERACTION BETWEEN PROPERDIN FACTORS B AND D AND THE ACTIVATED THIRD COMPONENT OF COMPLEMENT
Authors: Douglas T. Fearon, K. Frank Austen, Shaun Ruddy
Journal: The Journal of Experimental Medicine (1973)

The present studies demonstrate that the factor B-dependent C3 convertase can be affixed to an erythrocyte by use of an intermediate bearing C3b and that this convertase brings the hemolytic reaction to completion with an efficiency comparable to that of classical convertase. The evidence that the EAC43 intermediate was lysed by a new pathway includes requirements for factors B and D and cell-bound C3b for subsequent lysis by the terminal components, C3-C9. The linear stoichiometry of the effective molecule titrations of C3b and factor B, and the first-order kinetics displayed by the generation and decay of the factor B-dependent hemolytic site are characteristics consistent with the one-hit theory as initially developed for the classical complement system. The use of hemolytically active cellular intermediates to examine the reactions occurring with C3b and factors B and D has allowed extension of the one-hit theory to this molecular sequence, development of effective molecule titrations, recognition of the analogies to the functional characteristics of the classical C3 convertase, and discrimination of the probable mechanism of terminal complement activation from reactive lysis.
Gut mucosal mast cells. Origin, traffic, and differentiation.
Authors: D Guy-Grand, M Dy, G Luffau, P Vassalli
Journal: The Journal of Experimental Medicine (1984)

Gut mucosal mast cells (MMC), which are nearly absent in normal mice are abundant during nematode infection. In normal mice, study of MMC precursors (MMC-P: cells giving rise to MMC colonies in the presence of IL-3) show that: (a) their frequency, judged by limiting dilution is very high in bone marrow (BM) and gut, and very low in most lymphoid organs and thoracic duct lymph (TDL); (b) gut MMC-P are Thy-1- Lyt-1-2- and are not rapidly replicating; (c) they are the progeny of less differentiated BM MMC-P which are attracted from the blood to the gut mucosa by local factor(s), other than antigen and T cell factors (since normal amounts of gut MMC-P are found in germ-free, nude, and newborn mice). In mice bearing the Wehi 3 tumor (which releases enough IL-3 to produce detectable blood levels) spleen and mesenteric lymph nodes (LN) show increased MMC-P frequency, the greatest increase being in the gut and BM, where numerous differentiated MMC are found. In Nippostrongylus brasiliensis (Nb)-infested mice (known to develop a large, T cell-dependent, gut MMC infiltration), gut MMC-P proliferation is induced by IL-3 released from gut mucosal Thy-1+ Lyt-2- cells, whose in vitro IL-3 release capability is much higher than that of similar cells from normal mice. Both Nb-stimulated T blasts and proliferating MMC-P undergo cyclic traffic, migrating into the TDL and then seeding the whole length of the gut (a process which allows a widespread immune defense after a local antigenic stimulus). Experiments using 2-d interruption of this traffic and fetal gut grafts, suggest that the continuous homing of T blasts back to the gut which leads to permanent Nb-stimulated IL-3 release, is essential for the full maturation of MMC. Transfer experiments in the rat show that TDL circulating MMC-P rapidly mature into MMC when they home back to the Nb-infested gut. It is proposed that gut MMC arise after several stages of progressive differentiation of MMC-P, influenced both by IL-3 and unidentified gut factor(s).
Use of SPRAT for peer review of paediatricians in training
Authors: Julian C Archer, John Norcini, Helena A Davies
Journal: BMJ (2005)

To determine whether a multisource feedback questionnaire, SPRAT (Sheffield peer review assessment tool), is a feasible and reliable assessment method to inform the record of in-training assessment for paediatric senior house officers and specialist registrars.Trainees' clinical performance was evaluated using SPRAT sent to clinical colleagues of their choosing. Responses were analysed to determine variables that affected ratings and their measurement characteristics.Three tertiary hospitals and five secondary hospitals across a UK deanery.112 paediatric senior house officers and middle grades.95% confidence intervals for mean ratings; linear and hierarchical regression to explore potential biasing factors; time needed for the process per doctor.20 middle grades and 92 senior house officers were assessed using SPRAT to inform their record of in-training assessment; 921/1120 (82%) of their proposed raters completed a SPRAT form. As a group, specialist registrars (mean 5.22, SD 0.34) scored significantly higher (t = - 4.765) than did senior house officers (mean 4.81, SD 0.35) (P < 0.001). The grade of the doctor accounted for 7.6% of the variation in the mean ratings. The hierarchical regression showed that only 3.4% of the variation in the means could be additionally attributed to three main factors (occupation of rater, length of working relationship, and environment in which the relationship took place) when the doctor's grade was controlled for (significant F change < 0.001). 93 (83%) of the doctors in this study would have needed only four raters to achieve a reliable score if the intent was to determine if they were satisfactory. The mean time taken to complete the questionnaire by a rater was six minutes. Just over an hour of administrative time is needed for each doctor.SPRAT seems to be a valid way of assessing large numbers of doctors to support quality assurance procedures for training programmes. The feedback from SPRAT can also be used to inform personal development planning and focus quality improvements.
Global Climate Change and Emerging Infectious Diseases
Authors: Jonathan A. Patz, Paul R. Epstein, Thomas A. Burke, John M. Balbus
Journal: JAMA (1996)

Climatic factors influence the emergence and reemergence of infectious diseases, in addition to multiple human, biological, and ecological determinants. Climatologists have identified upward trends in global temperatures and now estimate an unprecedented rise of 2.0 degrees C by the year 2100. Of major concern is that these changes can affect the introduction and dissemination of many serious infectious diseases. The incidence of mosquito-borne diseases, including malaria, dengue, and viral encephalitides, are among those diseases most sensitive to climate. Climate change would directly affect disease transmission by shifting the vector's geographic range and increasing reproductive and biting rates and by shortening the pathogen incubation period. Climate-related increases in sea surface temperature and sea level can lead to higher incidence of water-borne infectious and toxin-related illnesses, such as cholera and shellfish poisoning. Human migration and damage to health infrastructures from the projected increase in climate variability could indirectly contribute to disease transmission. Human susceptibility to infections might be further compounded by malnutrition due to climate stress on agriculture and potential alterations in the human immune system caused by increased flux of ultraviolet radiation. Analyzing the role of climate in the emergence of human infectious diseases will require interdisciplinary cooperation among physicians, climatologists, biologists, and social scientists. Increased disease surveillance, integrated modeling, and use of geographically based data systems will afford more anticipatory measures by the medical community. Understanding the linkages between climatological and ecological change as determinants of disease emergence and redistribution will ultimately help optimize preventive strategies.
Cabazitaxel: More Than a New Taxane for Metastatic Castrate-Resistant Prostate Cancer?
Authors: Alain C. Mita, Robert Figlin, Monica M. Mita
Journal: Clinical Cancer Research (2012)

Abstract The taxanes are recognized as a major class of chemotherapeutic agents; however, mechanisms of innate and acquired resistance can limit their usefulness. Cabazitaxel, a novel taxane with microtubule-stabilizing potency similar to docetaxel, exhibits activity against tumor cell lines resistant to paclitaxel and docetaxel. Cabazitaxel showed linear pharmacokinetics and a terminal elimination half-life comparable with that of docetaxel, findings which support dosing as a single infusion in three-week treatment cycles. Dose-ranging studies recommended doses of 20 or 25 mg/m2 every three weeks. Antitumor activity was shown in patients with advanced cancer and chemotherapy failure (including taxane failure). Other early studies investigated the efficacy of cabazitaxel in pretreated metastatic breast cancer, either as a single agent or in combination with capecitabine. Objective antitumor response rates of up to 24% and sustained tumor stabilizations were also observed. The TROPIC phase III study, conducted in patients with metastatic castrate-resistant prostate cancer previously treated with docetaxel, established cabazitaxel as the first chemotherapeutic agent to offer a survival advantage in this patient population. Across these studies, the dose-limiting hematologic toxicity was neutropenia (including febrile neutropenia), usually controllable with colony-stimulating factor/granulocyte-colony stimulating factor support. Clin Cancer Res; 18(24); 6574–9. ©2012 AACR.
Evaluating Nanoparticle Breakthrough during Drinking Water Treatment
Authors: Talia E. Abbott Chalew, Gaurav S. Ajmani, Haiou Huang, Kellogg J. Schwab
Journal: Environmental Health Perspectives (2013)

Background: Use of engineered nanoparticles (NPs) in consumer products is resulting in NPs in drinking water sources. Subsequent NP breakthrough into treated drinking water is a potential exposure route and human health threat.Objectives: In this study we investigated the breakthrough of common NPs—silver (Ag), titanium dioxide (TiO2), and zinc oxide (ZnO)—into finished drinking water following conventional and advanced treatment.Methods: NPs were spiked into five experimental waters: groundwater, surface water, synthetic freshwater, synthetic freshwater containing natural organic matter, and tertiary wastewater effluent. Bench-scale coagulation/flocculation/sedimentation simulated conventional treatment, and microfiltration (MF) and ultrafiltration (UF) simulated advanced treatment. We monitored breakthrough of NPs into treated water by turbidity removal and inductively coupled plasma–mass spectrometry (ICP-MS).Results: Conventional treatment resulted in 2–20%, 3–8%, and 48–99% of Ag, TiO2, and ZnO NPs, respectively, or their dissolved ions remaining in finished water. Breakthrough following MF was 1–45% for Ag, 0–44% for TiO2, and 36–83% for ZnO. With UF, NP breakthrough was 0–2%, 0–4%, and 2–96% for Ag, TiO2, and ZnO, respectively. Variability was dependent on NP stability, with less breakthrough of aggregated NPs compared with stable NPs and dissolved NP ions.Conclusions: Although a majority of aggregated or stable NPs were removed by simulated conventional and advanced treatment, NP metals were detectable in finished water. As environmental NP concentrations increase, we need to consider NPs as emerging drinking water contaminants and determine appropriate drinking water treatment processes to fully remove NPs in order to reduce their potential harmful health outcomes.Citation: Abbott Chalew TE, Ajmani GS, Huang H, Schwab KJ. 2013. Evaluating nanoparticle breakthrough during drinking water treatment. Environ Health Perspect 121:1161–1166; http://dx.doi.org/10.1289/ehp.1306574
Somatic <i>CEBPA</i> Mutations Are a Frequent Second Event in Families With Germline <i>CEBPA</i> Mutations and Familial Acute Myeloid Leukemia
Authors: Thomas Pabst, Marianne Eyholzer, Simon Haefliger, Julian Schardt, Beatrice U. Mueller
Journal: Journal of Clinical Oncology (2008)

Purpose The transcription factor CCAAT/enhancer binding protein-α (CEBPA) is crucial for normal myeloid differentiation. Mutations in the CEBPA gene are found in subsets of patients with acute myeloid leukemia (AML). Recently, three families were reported in whom several family members had germline CEBPA mutations and subsequently developed AML. Whereas familial AML is considered a rare event, the frequency of CEBPA germline mutations in AML is not known. Patients and Methods In this study, we screened 187 consecutive AML patients for CEBPA mutations at diagnosis. We detected 18 patients (9.6%) with CEBPA mutations. We then analyzed remission samples and constitutive DNA from these patients. Results We found that two (11.1%) of 18 AML patients with CEBPA mutations carried a germline N-terminal frameshift CEBPA mutation. Interestingly, additional members in the families of both of these patients have been affected by AML, and the germline CEBPA mutations were also observed in these patients. Additional somatic mutations in AML patients with germline CEBPA mutations in the two families comprised in-frame C-terminal CEBPA mutations in two patients, two nonsilent CEBPA point mutations in one patient, and monosomy 7 in one patient. Conclusion This study shows, for the first time to our knowledge, that germline CEBPA mutations are frequently observed among AML patients with CEBPA mutations. Including the families with germline CEBPA mutations reported previously, additional somatic CEBPA mutations represent a frequent second event in AML with germline CEBPA mutations. Our data strongly indicate that germline CEBPA mutations predispose to AML and that additional somatic CEBPA mutations contribute to the development of the disease.
Acknowledging a persistent truth: domestic violence in pregnancy
Authors: Joanna Cook, Susan Bewley
Journal: Journal of the Royal Society of Medicine (2008)

Violence against women has a devastating effect on women's sexual and reproductive health, and also affects the health of their children. Such behaviour is rooted in gender inequality, which is sadly persistent, arguably throughout all societies. This phenomenon is a serious health and development concern, in addition to a violation of a woman's human rights. Violence can begin or escalate in pregnancy and has significant consequences for the woman, fetus and child. Questioning pregnant women about the presence of violence and offering referral to a secondary agency can help to break the pattern of abuse.
In Vitro Antibodies: Strategies for Production and Application
Authors: Sherie L. Morrison
Journal: Annual Review of Immunology (1992)

The approaches to the production of antibodies (Ab) using the techniques of genetic engineering and expression are reviewed. Genetic engineering facilitates the production of proteins tailormade for an intended use. Bacterial and mammalian expression systems are commonly used for the production of Ab and Ab-like molecules. While genomic or cDNA cloning can be used to obtain the relevant variable regions, PCR-based cloning approaches facilitate the acquisition of additional binding specificities. Large numbers of different chimeric Abs with murine variable regions joined to constant regions from human and other species have been expressed and found to exhibit the expected binding specificities and effector functions. These molecules have been used to study the structural basis of effector functions such as complement activation and Fc receptor binding, and potentially they may be used as therapeutic agents. Carbohydrate has been shown to influence both variable and constant region function. Single-chain Abs and fusion proteins with Ab binding specificities joined to nonimmunoglobulin sequences provide a source of Ab-like molecules with novel properties, and genetically engineered Ab-like molecules provide a source of useful antigens. Combinatorial libraries produced in bacteriophage present an alternative to hybridomas for the production of Abs with desired combining specificities. Issues of the immunogenicity of the recombinant molecules are addressed.
Reply to Y. Mao et al
Authors: Chen Yuan, Brian M. Wolpin
Journal: Journal of Clinical Oncology (2015)

We appreciate the interest of Mao et al 1 in our article entitled, "Survival Among Patients With Pancreatic Cancer and Long-Standing or Recent-Onset Diabetes Mellitus." 2 In our study, we examined the association of long-standing (Ͼ 4 years) and recent-onset diabetes (Յ 4 years) with survival among patients with pancreatic cancer drawn from two prospective cohort studies 3,4 and one clinicbased study.We noted a consistent and statistically significant reduction in survival among patients with long-term diabetes in the cohort and clinic-based studies.However, we noted no statistically significant association of recent-onset diabetes with survival in any of the individual studies or in a meta-analysis of the three studies.Mao et al noted that the prevalence of recent-onset diabetes was relatively low in patients enrolled in the prospective cohorts, possibly because of lower ascertainment of diabetes status with the use of biennial questionnaires.We agree that a lower ascertainment of diabetes status near the time of cancer diagnosis is a potential limitation of the cohort study design.Nevertheless, we found no statistically significant heterogeneity (P heterogeneity ϭ .63) in the association of recent-onset diabetes with survival among patients from the prospective cohort studies and clinic-based case series with a meta-analysis hazard ratio (HR) of 1.12 (95% CI, 0.90 to 1.39).HRs for death for recent-onset diabetes were similar for clinic-based studies (HR, 1.13; 95% CI, 1.02 to 1.25) and prospective cohort studies (HR, 1.12; 95% CI, 0.95 to 1.32) in the unpublished meta-analyses presented by Mao et al.Therefore, the results from our three patient populations support a statistically significant association between long-term diabetes and survival.We agree that additional studies are warranted to better understand the relationship of diabetes with pancreatic cancer development and prognosis.