bluuebunny/crossref_metadata_2025_split huggingface dataset:
Autosomal recessive chronic granulomatous disease caused by defects in NCF-1, the gene encoding the phagocyte p47-phox: mutations not arising in theNCF-1 pseudogenes
Authors: Noack Deborah , Rae Julie , Cross Andrew R. , Ellis Beverly A. , Newburger Peter E. , Curnutte John T. , Heyworth Paul G. 
Published: July 2002

AbstractChronic granulomatous disease (CGD) is a primary immunodeficiency caused by defects in any one of 4 genes encoding phagocyte NADPH oxidase subunits. Unlike other CGD subtypes, in which there is great heterogeneity among mutations, 97% of affected alleles in patients previously reported with A470 CGD carry a single mutation, a GT deletion (ΔGT) in exon 2 of the p47-phox gene, NCF-1. This unusually high incidence results from recombination events between NCF-1and its highly homologous pseudogenes, in which ΔGT originates. In 50 consecutive patients with A470 CGD, 4 were identified who were heterozygous for ΔGT in NCF-1, and for the first time, 2 were identified whose DNA appeared normal at this position. To avoid co-amplification of pseudogene sequence and to enable the identification of mutations in these patients, allele-specific polymerase chain reaction was used to amplify alleles not containing ΔGT. In each of the 4 patients who were heterozygous for ΔGT, an additional novel mutation was identified. These were 2 missense mutations, G125 → A in exon 2 (predicting Arg42 → Gln) and G784 → A in exon 8 (Gly262 → Ser), and 2 splice junction mutations at the 5′ end of intron 1, gt → at and gtg → gtt. The first of 2 patients who appeared normal at the GT position was a compound heterozygote with the G125 → A transition on one allele and a deletion of G811 on the other. In the second of these patients, only a single defect was detected, G574 → A, which predicts Gly192 → Ser but is likely to result in defective splicing because it represents the final nucleotide of exon 6.
Apoptosis of tumoral and nontumoral lymphoid cells is induced by both mdm2 and p53 antisense oligodeoxynucleotides
Authors: Capoulade Corinne , Mir Lluis M. , Carlier Karine , Lécluse Yann , Tétaud Cécile , Mishal Zohair , Wiels Joëlle 
Published: July 2002

Abstract
Following stress signals, the p53 tumor suppressor protein plays a critical role in regulation of cell proliferation, mainly through induction of growth arrest or apoptosis. Therefore, this protein needs to be strictly regulated and numerous studies have shown that the MDM2 protein is an essential element for p53 regulation in normal cells and, most importantly, that overexpression of MDM2 is responsible for p53 inactivation in various types of tumors. A previous study showed that this is the case in some Burkitt lymphoma (BL) cell lines, where enhanced translation of mdm2 messenger RNA results in overexpression of the protein that complexes and inactivates wild-type p53. To further investigate the role of the p53/MDM2 complex in these BL cells, as well as in other lymphoid cells that do not overexpress MDM2, this study used antisense oligodeoxynucleotides directed either against mdm2 or against p53. Results show that the mdm2 antisense oligodeoxynucleotide induces apoptosis of cells that express a high or low level of MDM2 protein, only if they contain wild-type p53. Moreover, apoptosis is independent of the accumulation of p53 following mdm2 antisense treatment. Finally, the p53 antisense oligodeoxynucleotide, which inhibits the expression of wild-type p53, also induces a decrease of the MDM2 level in cells, whether or not they overexpress this protein, and causes apoptosis of these cells. These results indicate that decreasing the MDM2 protein level by directly or indirectly targeting its biosynthesis is a potent tool for the induction of apoptosis.
Plasma glucosylceramide deficiency as potential risk factor for venous thrombosis and modulator of anticoagulant protein C pathway
Authors: Deguchi Hiroshi , Fernández JoséA. , Pabinger Ingrid , Heit John A. , Griffin John H. 
Published: July 2002

AbstractTo assess the relationship between venous thrombosis and plasma glucosylceramide (GlcCer) or phosphatidylethanolamine (PE), plasma levels of GlcCer and PE were determined for 70 venous thrombosis patients referred for evaluation and 70 healthy blood donors. The mean GlcCer level, but not the PE level, was lower in patients versus controls (4.9 vs 6.5 μg/mL [P = .0007] and 66 vs 71 μg/mL [P = .48], respectively). As a measure of relative risk, the odds ratio for deep vein thrombosis in subjects with GlcCer levels below the 10th percentile of controls was 5.7 (95% CI, 2.3-14). To assess the influence of glycolipids on anticoagulant response to activated protein C (APC):protein S in modified prothrombin time assays, the effects of depleting endogenous plasma GlcCer by glucocerebrosidase treatment or of adding exogenous purified GlcCer or other neutral glycolipids to plasma were tested. Glucocerebrosidase treatment reduced plasma sensitivity to APC:protein S in parallel with GlcCer reduction. Exogenously added GlcCer and the homologous Glc-containing globotriaosylceramide (Gb3Cer), but not galactosylceramide, dose-dependently prolonged clotting times of normal plasma in the presence, but not absence, of APC:protein S, which suggests that GlcCer or Gb3Cer can enhance protein C pathway anticoagulant activity. In studies using purified proteins, inactivation of factor Va by APC:protein S was enhanced by GlcCer alone and by GlcCer in multicomponent vesicles containing phosphatidylserine and phosphatidylcholine. These results suggest that the neutral glycolipids GlcCer and Gb3Cer may directly contribute to the anticoagulant activity of the protein C pathway and that deficiency of plasma GlcCer may be a risk factor for venous thrombosis.
Dendritic cells from patients with myeloma are numerically normal but functionally defective as they fail to up-regulate CD80 (B7-1) expression after huCD40LT stimulation because of inhibition by transforming growth factor-β1 and interleukin-10
Authors: Brown Ross D. , Pope Belinda , Murray Allan , Esdale Warren , Sze Daniel M. , Gibson John , Ho P. Joy , Hart Derek , Joshua Doug 
Published: July 2002

AbstractLimited response to idiotype vaccination in patients with myeloma suggests that there is a need to develop better immunotherapy strategies. It has been determined that the number of high-potency CMRF44+CD14−CD19−dendritic cells (DCs) in the blood of patients with myeloma (range, 0.03%-0.8% of mononuclear cells [MNCs]; n = 26) was not significantly different from that in controls (range, 0.05%-0.8% of MNCs; n = 13). Expression of the costimulatory molecules CD80 and CD86 on DCs from these patients (mean, 29%±17% of MNCs and 85%±10% of MNCs, respectively) was also normal (mean, 29%±17% and 86%±16% of MNCs, respectively). Up-regulation of CD80 expression in response to stimulation by human (hu)CD40LT + interleukin (IL)-2 was significantly reduced on the DCs of patients with myeloma during stable disease (n = 9) and was absent during progressive stages (n = 7) of disease. Similar effects were seen on B cells but not on monocytes of the same group of patients. CD86 expression on DCs was high before (86%) and after (89%) stimulation. Inhibition of CD80 up-regulation was neutralized by either anti–transforming growth factor (TGF)–β1 or anti–IL-10. Up-regulation of CD80 on DCs of controls was inhibited by rTGF-β1 in a dose-dependent manner. Serum TGF-β1 and IL-10 levels were normal in most patients studied. Cytoplasmic TGF-β1 was increased in plasma cells during progressive disease. Thus patients with myeloma have normal numbers of DCs, but CD80 expression may fail to be up-regulated in the presence of huCD40LT because of tumor-derived TGF-β1 or IL-10. Autologous high-potency DCs may have to be tested for CD80 up-regulation and biologically modified ex vivo before idiotype priming for immunotherapy.
Mechanism of hypercalcemia in adult T-cell leukemia: overexpression of receptor activator of nuclear factor κB ligand on adult T-cell leukemia cells
Authors: Nosaka Kisato , Miyamoto Takeshi , Sakai Tatsunori , Mitsuya Hiroaki , Suda Toshio , Matsuoka Masao 
Published: July 2002

Abstract
Hypercalcemia is one of the most frequent and serious complications in patients with adult T-cell leukemia (ATL) and is due to marked bone resorption by accumulation of osteoclasts (OCLs). Although several cytokines such as interleukin 1 and parathyroid hormone–related protein are thought to be involved in the development of high serum Ca++ levels, its precise underlying mechanism remains unknown. This study analyzed the expression of various genes that are thought to regulate serum Ca++ levels in ATL and showed that the overexpression of the receptor activator of nuclear factor κB (RANK) ligand gene correlated with hypercalcemia. ATL cells from patients with hypercalcemia, which highly expressed the transcripts of the RANK ligand (RANKL) gene, induced the differentiation of human hematopoietic precursor cells (HPCs) into OCLs in vitro in the presence of macrophage colony-stimulating factor (M-CSF). In contrast, ATL cells from patients without hypercalcemia did not induce such differentiation, suggesting that the induction of the differentiation correlated with the expression of the RANKL gene in ATL cells. Cell differentiation was suppressed by osteoprotegerin/Fc, an inhibitor of RANKL, indicating that such differentiation occurred through the RANK-RANKL pathway. In addition, direct contact between ATL cells and HPCs was essential for the differentiation, suggesting that not the soluble form but membrane-bound RANKL played a role in this process. These results strongly suggested that ATL cells induce the differentiation of HPCs to OCLs through RANKL expressed on their surface, in cooperation with M-CSF, and ultimately cause hypercalcemia.
Contribution of parasite proteins to altered mechanical properties of malaria-infected red blood cells
Authors: Glenister Fiona K. , Coppel Ross L. , Cowman Alan F. , Mohandas Narla , Cooke Brian M. 
Published: July 2002

Abstract
Red blood cells (RBCs) parasitized by Plasmodium falciparum are rigid and poorly deformable and show abnormal circulatory behavior. During parasite development, knob-associated histidine-rich protein (KAHRP) and P falciparum erythrocyte membrane protein 3 (PfEMP3) are exported from the parasite and interact with the RBC membrane skeleton. Using micropipette aspiration, the membrane shear elastic modulus of RBCs infected with transgenic parasites (with kahrp or pfemp3 genes deleted) was measured to determine the contribution of these proteins to the increased rigidity of parasitized RBCs (PRBCs). In the absence of either protein, the level of membrane rigidification was significantly less than that caused by the normal parental parasite clone. KAHRP had a significantly greater effect on rigidification than PfEMP3, contributing approximately 51% of the overall increase that occurs in PRBCs compared to 15% for PfEMP3. This study provides the first quantitative information on the contribution of specific parasite proteins to altered mechanical properties of PRBCs.
Limiting transplantation-related mortality following unrelated donor stem cell transplantation by using a nonmyeloablative conditioning regimen
Authors: Chakraverty Ronjon , Peggs Karl , Chopra Rajesh , Milligan Donald W. , Kottaridis Panagiotis D. , Verfuerth Stephanie , Geary Johanne , Thuraisundaram Dharsha , Branson Kate , Chakrabarti Suparno , Mahendra Premini , Craddock Charles , Parker Anne , Hunter Ann , Hale Geoff , Waldmann Herman , Williams Catherine D. , Yong Kwee , Linch David C. , Goldstone Anthony H. , Mackinnon Stephen 
Published: July 2002

Abstract
A nonmyeloablative conditioning regimen was investigated in 47 patients with hematological malignancy receiving allogeneic progenitor cells from matched, unrelated donors. The median patient age was 44 years. The majority of patients had high-risk features, including having failed a prior transplantation (29 individuals). Twenty of the transplants were mismatched for HLA class I and/or class II alleles. Recipient conditioning consisted of 20 mg CAMPATH-1H on days −8 to −4, 30 mg/m2fludarabine on days −7 to −3, and 140 mg/m2 melphalan on day −2. Graft-versus-host disease (GVHD) prophylaxis was with cyclosporine A alone. Primary graft failure occurred in only 2 of 44 evaluable patients (4.5%). Chimerism studies in 34 patients indicated that the majority (85.3%) attained initial full donor chimerism. Only 3 patients developed grade III to IV acute GVHD, and no patients have yet developed chronic extensive GVHD. The estimated probability of nonrelapse mortality at day 100 was 14.9% (95% confidence interval [CI], 4.7%-25.1%). With a median follow-up of 344 days (range, 79-830), overall and progression-free survivals at 1 year were 75.5% (95% CI, 62.8%-88.2%) and 61.5% (95% CI, 46.1%-76.8%), respectively. In summary, a nonmyeloablative regimen incorporating in vivo CAMPATH-1H is effective in promoting durable engraftment in most patients and in reducing the risk of severe GVHD following matched unrelated donor transplantation.
Overall Survival, Treatment Duration, and Rechallenge Outcomes With ICI Therapy for Recurrent or Metastatic HNSCC
Authors: Sun Lova , Cohen Roger B. , D’Avella Christopher A. , Singh Aditi P. , Schoenfeld Jonathan D. , Hanna Glenn J. 
Published: August 2024

ImportanceImmune checkpoint inhibition (ICI) is a frontline treatment for recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC), but questions remain surrounding optimal duration of therapy, benefits and risks of ICI rechallenge, and efficacy in first vs subsequent lines of therapy.ObjectivesTo estimate survival in US patients receiving ICI-based treatment for R/M HNSCC, compare outcomes associated with treatment discontinuation vs continuation at 1 or 2 years, and assess outcomes after immunotherapy rechallenge.Design, Setting, and ParticipantsThis retrospective, population-based cohort study included adult patients in the Flatiron Health nationwide oncology database treated with immunotherapy for R/M HNSCC from 2015 to 2023. Data cutoff was August 31, 2023; data analysis was conducted from December 2023 to February 2024.ExposuresTreatment continuation vs discontinuation at 1 and 2 years; rechallenge with ICI after at least a 60-day period off ICI therapy without intervening systemic treatment (immediate rechallenge), or with intervening systemic treatment (delayed rechallenge).Main Outcomes and MeasuresOverall survival (OS) from ICI initiation was analyzed using the Kaplan-Meier method. Cox multivariable regression was used to examine associations of key variables (line of therapy, human papillomavirus [HPV] status, Eastern Cooperative Oncology Group [ECOG] performance status) with survival.ResultsThe cohort included 4549 patients with R/M HNSCC who received ICI-containing therapy (median [IQR] age, 66 [59-72] years; 3551 [78.1%] male; 56 [1.2%] Asian, 260 [5.7%] Black or African American, 3020 [66.4%] White, 1213 [26.7%] other or unknown race; 3226 [70.9%] ECOG performance status 0 or 1). There were 3000 patients (65.9%) who received ICI in frontline and 1207 (26.5%) in second line; 3478 patients (76.5%) received ICI monotherapy. Median (IQR) OS was 10.9 (4.1-29.1) months and was longer in patients who received ICI in frontline therapy (12.2 [4.8-32.0] vs 8.7 [3.2-22.4] months), had HPV-positive cancer (16.6 [6.5-43.9] vs 8.8 [3.5-24.0] months), and had ECOG performance status 0 or 1 (13.5 [5.2-33.9] vs 5.5 [2.0-13.7] months). There were no survival differences on adjusted analysis between patients who stopped vs those who continued ICI at 1 or 2 years. Median (IQR) OS after ICI rechallenge was 15.7 (13.7-21.9) months in the immediate rechallenge group and 9.9 (3.7-18.1) months in the delayed rechallenge group.Conclusions and RelevanceIn this large cohort study of patients with R/M HNSCC receiving ICI-based therapy, survival estimates closely mirrored clinical trial results, both in frontline and later-line settings. Discontinuation of ICI in long-term responders at 1 or 2 years may be a reasonable strategy that does not appear to compromise survival. ICI rechallenge was associated with clinical benefit in a subset of patients.
Effect of Messaging on Support for Breast Cancer Screening Cessation Among Older US Women
Authors: Schoenborn Nancy L. , Gollust Sarah E. , Nagler Rebekah H. , Pollack Craig E. , Boyd Cynthia M. , Xue Qian-Li , Schonberg Mara A. 
Published: August 2024

ImportanceMany older women are screened for breast cancer beyond guideline-recommended thresholds. Messaging holds promise to reduce overscreening.ObjectiveTo investigate the effect of a message on older women’s support for and intentions of stopping breast cancer screening.Design, Setting, and ParticipantsA 2-wave randomized clinical online survey trial using a nationally representative online panel was performed from May 12 to June 19, 2023. Women 65 years or older without breast cancer were eligible to participate.InterventionA pilot-tested breast cancer screening cessation message delivered to a hypothetical older woman with serious illnesses and functional impairment. The message was described as from 1 of 3 sources (clinician, news story, or family member). Participants were randomized into 4 groups: no message (group 1 [control]), a single message from a clinician at wave 1 and no message at wave 2 (group 2), a message from a news story (wave 1) and a clinician (wave 2) (group 3), and a message from a family member (wave 1) and a clinician (wave 2) (group 4).Main Outcomes and MeasuresSupport for stopping screening in the hypothetical older woman (primary) and screening intentions for oneself (secondary) were assessed on 7-point scales, with higher values indicating stronger support for and intentions to stop screening. Means were compared using analysis of variance. The message effect on screening intentions among participants 75 years or older and those with life expectancy of less than 10 years were also explored.ResultsA total of 3051 women participated in wave 1 of the trial. The mean (SD) age was 72.8 (5.9) years; 272 (8.9%) were non-Hispanic Black and 2506 (82.1%) were non-Hispanic White. Of these women, 2796 (91.6%) completed wave 2. Group 2 had significantly higher support for screening cessation in the hypothetical patient at wave 2 (mean score, 3.14 [95% CI, 2.99-3.29]) compared with group 1 (mean score, 2.68 [95% CI, 2.54-2.82]; P &amp;lt; .001). The effect was even stronger in group 3 (mean score, 4.23 [95% CI, 4.09-4.38]) and group 4 (mean score, 4.12 [95% CI, 3.97-4.27]) compared with both groups 1 and 2 (all P &amp;lt; .001). Message effects on self-screening intentions followed a similar pattern, with larger effects among participants 75 years or older or with limited life expectancy.Conclusions and RelevanceIn this randomized clinical trial, a breast cancer screening cessation message significantly increased older women’s support for and intentions of screening cessation. The strongest effects were observed when the message was delivered over time from multiple sources. Future work needs to engage potential message sources to examine the feasibility and acceptability of multilevel messaging strategies and their effect on screening behavior.Trial RegistrationClinicalTrials.gov Identifier: NCT05821023
Lecanemab and Vascular-Amyloid Deposition in Brains of People With Down Syndrome
Authors: Liu Lei , Saba Adriana , Pascual Jesse R. , Miller Michael B. , Hennessey Elizabeth L. , Lott Ira T. , Brickman Adam M. , Wilcock Donna M. , Harp Jordan P. , Schmitt Frederick A. , Selkoe Dennis J. , Chhatwal Jasmeer P. , Head Elizabeth 
Published: August 2024

ImportanceAnti-β-amyloid immunotherapy using lecanemab is becoming increasingly available to patients with Alzheimer disease (AD). Individuals with Down syndrome (DS) develop AD neuropathology by age 40 years, representing a significant cohort of genetically determined AD.ObjectiveTo investigate the binding properties of lecanemab in the brains of people with DS, in anticipation of their inclusion in clinical trials or access to antiamyloid immunotherapies.Design, Setting, ParticipantsThe study included cases of postmortem brain tissue analysis from 15 individuals with DS aged 43 to 68 years that were acquired from Alzheimer Disease research centers at the University of California, Irvine and the University of Kentucky from 2008 to 2021. Data were analyzed from August 2023 through May 2024.ExposureThe binding properties of lecanemab were assessed in brain tissue.Main OutcomeThe primary outcome was the extent of lecanemab binding to amyloid plaques and brain blood vessels.ResultsTissue from 15 people (8 were female [53%]) with DS ranging in age from 43 to 68 (mean, 56.6) years were included in the study. Lecanemab-labeled amyloid plaques appeared in all 15 DS cases studied, indicating potential target engagement. However, extensive binding of lecanemab to brain blood vessels in DS was observed, raising significant safety concerns. These findings underscore the necessity for clinical trials of lecanemab in people with DS to evaluate both safety and efficacy, particularly in individuals older than 43 years.Conclusions and RelevanceThese findings suggest significant binding of lecanemab to cerebral amyloid angiopathy in DS. Lecanemab should be rigorously tested in clinical trials for AD in the DS population to determine its safety and efficacy, especially in those older than 43 years.
Long‐Term Mortality Following SARS‐CoV‐2 Infection in Rural Versus Urban Dwellers With Autoimmune or Inflammatory Rheumatic Disease: A Retrospective Cohort Analysis From the National COVID Cohort Collaborative
Authors: Anzalone A. Jerrod , Jackson Lesley E. , Singh Namrata , Danila Maria I. , Reisher Elizabeth , Patel Rena C. , Singh Jasvinder A. ,   the National COVID Cohort Collaborative Consortium
Published: August 2024

ObjectiveAutoimmune or inflammatory rheumatic diseases (AIRDs) increase the risk for poor COVID‐19 outcomes. Although rurality is associated with higher post–COVID‐19 mortality in the general population, whether rurality elevates this risk among people with AIRD is unknown. We assessed associations between rurality and post–COVID‐19 all‐cause mortality, up to two years post infection, among people with AIRD using a large nationally sampled US cohort.MethodsThis retrospective study used the National COVID Cohort Collaborative, a medical records repository containing COVID‐19 patient data. We included adults with two or more AIRD diagnostic codes and a COVID‐19 diagnosis documented between April 2020 and March 2023. Rural residency was categorized using patient residential zip codes. We adjusted for AIRD medications and glucocorticoid prescription, age, sex, race and ethnicity, tobacco or substance use, comorbid burden, and SARS‐CoV‐2 variant‐dominant periods. Multivariable Cox proportional hazards with inverse probability treatment weighting assessed associations between rurality and two‐year all‐cause mortality.ResultsAmong the 86,467 SARS‐CoV‐2–infected persons with AIRD, we observed a higher risk for two‐year post–COVID‐19 mortality in rural versus urban dwellers. Rural‐residing persons with AIRD had higher two‐year all‐cause mortality risk (adjusted hazard ratio 1.24, 95% confidence interval 1.19–1.29). Glucocorticoid, immunosuppressive, and rituximab prescriptions were associated with a higher risk for two‐year post–COVID‐19 mortality, whereas risk with nonbiologic or biologic disease‐modifying antirheumatic drugs was lower.ConclusionRural residence in people with AIRD was independently associated with higher two‐year post–COVID‐19 mortality in a large US cohort after adjusting for background risk factors. Policymakers and health care providers should consider these findings when designing interventions to improve outcomes in people with AIRD following SARS‐CoV‐2 infection, especially among high‐risk rural residents.image