bluuebunny/crossref_metadata_2025 huggingface dataset:
A corundum-quartz assemblage in altered volcanic rocks, Bond Range, Tasmania
Authors: Bottrill R. S.
Published: July 2002

Unusual corundum-bearing rocks occur in the Bond Range, northern Tasmania, in a hydrothermally altered Cambrian quartz porphyry. The assemblage exhibits quartz and corundum in mutual contact, a rare phenomenon, in association with andalusite, pyrophyllite, diaspore and other minerals. This metastable assemblage apparently resulted from advanced argillic alteration at moderate temperature and low pressure, followed by rapid depressurisation accompanying boiling of hydrothermal, granite-derived fluids. This corundum occurrence appears to be unrelated to the sapphires in placer deposits in Tasmania.
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

Chronic 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

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

To 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

Limited 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.
Hematopoietic responses to stress conditions in young dogs compared with elderly dogs
Authors: Zaucha J. Maciej , Yu Cong , Mathioudakis George , Seidel Kristy , Georges George , Sale George , Little Marie-Térèse , Torok-Storb Beverly , Storb Rainer
Published: July 2002

Clinical observations show that older patients do not tolerate high-dose chemoradiotherapy as well as younger patients. It is unclear whether this is due to age-related differences in their responses to hematopoietic injury or to differential toxicities to other organs. In the present study, 6 young (0.5 years) and 6 elderly (8 years) dogs were challenged with 7 repeated nonlethal doses of 50 or 100 cGy total body irradiation (TBI) each (total 550 cGy), and 21 days of recombinant canine granulocyte–colony stimulating factor (rcG-CSF) after the last TBI dose. Recoveries of absolute neutrophil, platelet, and lymphocyte counts after each TBI dose, responses to rcG-CSF treatment, and telomere lengths in neutrophils were compared before and after the study. No differences were found in recoveries of neutrophils, platelets, or in responses to rcG-CSF among young and old dogs. In contrast, recoveries were suggestively worse in younger dogs. After rcG-CSF, platelet recoveries were poor in both groups compared with previous platelet recoveries (P < .01). Consequently, 2 old and 3 young dogs were euthanized because of persistent thrombocytopenia and bleeding. At the study's completion, marrow cellularities and peripheral blood counts of the remaining young and elderly dogs were equivalent. The telomere lengths in both groups were significantly reduced after the study versus beforehand (P = .03), but the median attritions of telomeres were not different. It was concluded that aging does not appear to affect hematopoietic cell recoveries after repeated low-dose TBI, suggesting that poor tolerance of radiochemotherapy regimens in older patients may be due to nonhematopoietic organ toxicities rather than age-related changes in hematopoietic stem cells reserves.
Thrombocytopenic c-mpl−/− mice can produce a normal level of platelets after administration of 5-fluorouracil: the effect of age on the response
Authors: Levin Jack , Cocault Laurence , Demerens Corinne , Challier Cécile , Pauchard Michèle , Caen Jacques , Souyri Michèle
Published: July 2002

Administration of 5-fluorouracil (5-FU) to mice results in a marked increase in the level of circulating platelets in 10 days. Mice lacking Mpl, the receptor for thrombopoietin (TPO), are thrombocytopenic. To gain insight into the mechanism by which 5-FU produces such a substantial stimulation of platelet production, this study investigated whether 5-FU (150 mg/kg) produced thrombocytosis in c-mpl−/− mice, thus establishing whether TPO was required for this response. A 5- to 6-fold increase in platelet levels in c-mpl−/− mice (to approximately 1000 × 109/L) was observed on days 20 and 25 after 5-FU injection. Thus, at the peak of the response, c-mpl−/− mice had platelet levels comparable to those in normal mice. Administration of 5-FU also produced thrombocytosis in previously splenectomized c-mpl−/− mice. Comparison of the platelet response to 5-FU in young (6-12 weeks) and old (33-46 weeks) c-mpl−/− mice found that older mice produced a much more marked response than younger mice, with a mean maximum platelet level of approximately 1700 × 109/L. To determine whether this increase in circulating platelets was preceded by an increase in hematopoietic progenitors, serial cultures of bone marrow and spleen were evaluated. A considerable increase in all colony types studied was observed on days 15 and 20 in spleens of c-mpl−/− mice, but no similar elevations were detected in bone marrow. These results indicate that c-mpl−/− mice can achieve a normal level of platelets after 5-FU injection, by means of a TPO-independent mechanism, and that they respond to 5-FU myelosuppression by producing large numbers of megakaryocytic, myeloid, and erythroid progenitors.
Extracorporeal photopheresis in Sézary syndrome: hematologic parameters as predictors of response
Authors: Evans Alun V. , Wood Blair P. , Scarisbrick Julia J. , Fraser-Andrews Elizabeth A. , Chinn Sue , Dean Alan , Watkins Philip , Whittaker Sean J. , Russell-Jones Robin
Published: July 2002

Data were analyzed from 23 patients with Sézary syndrome (defined by erythroderma, more than 10% circulating atypical mononuclear cells, and peripheral blood T-cell clone) undergoing monthly extracorporeal photopheresis as the sole therapy for up to 1 year. The cohort showed a significant reduction of skin scores during treatment (P = .001). Thirteen patients (57%) achieved a reduction in skin score greater than 25% from baseline at 3, 6, 9, or 12 months (responders). Reduction in skin score correlated with reduction in the Sézary cell count as a percentage of total white cell count (P = .03). Responders and nonresponders were compared. None of the measured parameters was significantly different between the 2 groups. It was assessed whether any of the baseline parameters predicted outcome. A higher baseline lymphocyte count was significantly associated with a decrease in skin score at 6 months (P < .05). A higher baseline Sézary cell count as a percentage of total white cell count predicted a subject was more likely to be a responder after 6 months of treatment (P = .021). No other parameters predicted responder status. These data show that the modest falls in CD4, CD8, and Sézary cell counts were seen in all patients and might have resulted from lymphocyte apoptosis. This mechanism could explain the more favorable response seen in patients with higher percentages of Sézary cells in the peripheral blood. Alternatively, minimum tumor burden might be required for the induction of a cytotoxic response. Analysis of tumor-specific cytotoxic T cells is needed to investigate these possibilities further.
Control of leukocyte rolling velocity in TNF-α–induced inflammation by LFA-1 and Mac-1
Authors: Dunne Jessica L. , Ballantyne Christie M. , Beaudet Arthur L. , Ley Klaus
Published: July 2002

Previously it was shown that β2-integrins are necessary for slow leukocyte rolling in inflamed venules. In this study, mice that are deficient for either one of the β2-integrins, αLβ2 (LFA-1) or αMβ2 (Mac-1), were used to determine which of the β2-integrins are responsible for slowing rolling leukocytes. The cremaster muscles of these mice were treated with tumor necrosis factor-α and prepared for intravital microscopy. The average rolling velocities in venules were elevated in LFA-1−/−mice (11.0 ± 0.7 μm/s) and Mac-1−/− mice (10.1 ± 1.1 μm/s) compared to wild-type mice (4.8 ± 0.3 μm/s;P < .05), but were lower than in CD18−/−mice (28.5 ± 2.1 μm/s). When both LFA-1 and Mac-1 were absent or blocked, rolling velocity became dependent on shear rate and approached that of CD18−/− mice. In addition, leukocyte adhesion efficiency was decreased in LFA-1−/− mice to near CD18−/− levels, but decreased only slightly in Mac-1−/− mice. Thus, both LFA-1 and Mac-1 contribute to slowing down rolling leukocytes, although LFA-1 is more important than Mac-1 in efficiently inducing firm adhesion.
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

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

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

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

Importance

Immune 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.

Objectives

To 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 Participants

This 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.

Exposures

Treatment 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 Measures

Overall 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.

Results

The 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 Relevance

In 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

Importance

Many older women are screened for breast cancer beyond guideline-recommended thresholds. Messaging holds promise to reduce overscreening.

Objective

To investigate the effect of a message on older women’s support for and intentions of stopping breast cancer screening.

Design, Setting, and Participants

A 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.

Intervention

A 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 Measures

Support 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.

Results

A 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 < .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 < .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 Relevance

In 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 Registration

ClinicalTrials.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

Importance

Anti-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.

Objective

To 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, Participants

The 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.

Exposure

The binding properties of lecanemab were assessed in brain tissue.

Main Outcome

The primary outcome was the extent of lecanemab binding to amyloid plaques and brain blood vessels.

Results

Tissue 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 Relevance

These 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

Objective

Autoimmune 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.

Methods

This 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.

Results

Among 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.

Conclusion

Rural 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.

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High‐Density Arrangement of Biomimetic Plasmonic Nanoprobes Guided by DNA Nanoroller based Cleaving‐Rolling Process for SERS Sensing Analysis
Authors: Xu Xinlin , Li Tiantian , Liu Yue , Xu Yang , Zhao Jingjing , Chen Wenhan , Luo Yu , Han Linping , Song Weiling , Yang Richard (Chunhui) , He Peng , Wang Yichao , Zhou Hong
Published: August 2024

DNA walker nanomachines are in fast development for biosensing, medical diagnostics, and food safety monitoring. For practical application, the issues of slow dynamics and low operational efficiency hinder its widespread application. Inspired by the high efficiency of agricultural cooperative machinery, a unique cleaving‐rolling‐assembly integrated nanodevice (CRAIN) is constructed for the high‐performance detection of various biomolecules. In the design, DNA nanotubes are introduced as building loaders to engineer polyoriented walking DNA nanorollers with blocked DNAzyme‐based walking strands and thus to increase the reaction direction and local concentration. Through target‐specific recognition, the activated nanorollers can autonomously and progressively cleave and roll along directional hairpin tracks on a gold substrate, significantly accelerating the reaction rate. Moreover, using nucleic acid‐encoded urchin‐shaped multispike gold‐silver composite nanospheres (nMGSs) as SERS‐enhanced probes, the engineered assembly of nMGSs probes induced by the cleaving‐rolling process promotes the formation of high‐density hotspot domains, further improving the detection sensitivity. With rational design, the CRAIN system can be extended to perform highly sensitive analyses of various analytes, such as microRNA‐21, butyrylcholinesterase activity and organophosphorus pesticides. This integrated assembly strategy can provide new perspectives for clinical diagnosis, biomedical engineering, and environmental science.
Photocatalytic CO2‐to‐CH4 Conversion with Ultrahigh Selectivity of 95.93% on S‐Vacancy Modulated Spatial In2S3/In2O3 Heterojunction
Authors: Lai Kezhen , Sun Yuxin , Li Ning , Gao Yangqin , Li Hui , Ge Lei , Ma Tianyi
Published: August 2024

Photocatalytic conversion of CO2 to methane faces challenges due to the stability of CO2, unpredictable intermediates, and complex electron transfer steps. Herein, a spatial In2S3/In2O3 heterojunction with abundant S vacancies (ISIO(VS)) is obtained through facile Polyvinylpyrrolidone (PVP) treatment to reach a methane yield of 16.52 µmol·g−1·h−1 with a selectivity of 95.93%, which is the highest among reported In2S3 and In2O3 based catalysts. The work function (Wf), differential charge density, and Kelvin Probe Force Microscopy (KPFM) results confirm that S vacancies strengthen the built‐in electric field (BEF) of In2S3/In2O3 (ISIO) heterojunctions, improving carrier separation. Density functional theory (DFT) calculations reveal that S vacancies induce electron redistribution, facilitating adsorption and activation of CO2 and *CO intermediate, thus promoting hydrogenation to yield *CHO. The reaction pathway of photocatalytic CO2 reduction is revealed by in situ diffuse reflectance infrared Fourier transform spectroscopy (DRIFTS) and Gibbs free energy (ΔG). The S vacancies modify electronic orbitals and the highest occupied molecular orbital (HOMO) of In atom, resulting in a stronger interaction between the catalyst and *CHO, which reduces ΔG*CHO and regulates the selectivity of CH4. This study paves a new avenue for the design of photocatalysts with highly selective reduction of CO2 to CH4 through defect engineering.
The Dawn of a New Pharmaceutical Epoch: Can AI and Robotics Reshape Drug Formulation?
Authors: Bannigan Pauric , Hickman Riley J. , Aspuru‐Guzik Alán , Allen Christine
Published: August 2024

Over the last four decades, pharmaceutical companies’ expenditures on research and development have increased 51‐fold. During this same time, clinical success rates for new drugs have remained unchanged at about 10 percent, predominantly due to lack of efficacy and/or safety concerns. This persistent problem underscores the need to innovate across the entire drug development process, particularly in drug formulation, which is often deprioritized and under‐resourced.
Phototactic/Photosynthetic/Magnetic‐Powered Chlamydomonas Reinhardtii‐Metal‐Organic Frameworks Micro/Nanomotors for Intelligent Thrombolytic Management and Ischemia Alleviation
Authors: Chiang Chia‐Che , Liu Chia‐Hung , Rethi Lekshmi , Nguyen Hieu Trung , Chuang Andrew E.‐Y.
Published: August 2024

Thrombosis presents a critical health threat globally, with high mortality and incidence rates. Clinical treatment faces challenges such as low thrombolytic agent bioavailability, thrombosis recurrence, ischemic hypoxia damage, and neural degeneration. This study developed biocompatible Chlamydomonas Reinhardtii micromotors (CHL) with photo/magnetic capabilities to address these needs. These CHL micromotors, equipped with phototaxis and photosynthesis abilities, offer promising solutions. A core aspect of this innovation involves incorporating polysaccharides (glycol chitosan (GCS) and fucoidan (F)) into ferric Metal‐organic frameworks (MOFs), loaded with urokinase (UK), and subsequently self‐assembled onto the multimodal CHL, forming a core‐shell microstructure (CHL@GCS/F‐UK‐MOF). Under light‐navigation, CHL@GCS/F‐UK‐MOF is shown to penetrate thrombi, enhancing thrombolytic biodistribution. Combining CHL@GCS/F‐UK‐MOF with the magnetic hyperthermia technique achieves stimuli‐responsive multiple‐release, accelerating thrombolysis and rapidly restoring blocked blood vessels. Moreover, this approach attenuates thrombi‐induced ischemic hypoxia disorder and tissue damage. The photosynthetic and magnetotherapeutic properties of CHL@GCS/F‐UK‐MOF, along with their protective effects, including reduced apoptosis, enhanced behavioral function, induced Heat Shock Protein (HSP), polarized M2 macrophages, and mitigated hypoxia, are confirmed through biochemical, microscopic, and behavioral assessments. This multifunctional biomimetic platform, integrating photo‐magnetic techniques, offers a comprehensive approach to cardiovascular management, advancing related technologies.
Targeting Osteoblast‐Osteoclast Cross‐Talk Bone Homeostasis Repair Microcarriers Promotes Intervertebral Fusion in Osteoporotic Rats
Authors: Zheng Jiancheng , Li Xiaoyan , Zhang Fangke , Li Changwei , Zhang Xingkai , Wang Fei , Qi Jin , Cui Wenguo , Deng Lianfu
Published: August 2024

Balancing osteoblast‐osteoclast (OB‐OC) cross‐talk is crucial for restoring bone tissue structure and function. Current clinical drugs targeting either osteogenesis or osteoclastogenesis fail to effectively regulate cross‐talk, impeding efficient bone repair in osteoporosis patients. Ubiquitin‐specific protease 26 (USP26) is shown to coordinate OB‐OC cross‐talk by independently regulating β‐catenin and Iκb‐α. However, effective drugs for activating USP26 are still lacking. Here, they constructed bone homeostasis repair microcarriers (BHRC) that encapsulate Usp26 mRNA‐loaded lipid nanoparticles (mRNA@LNP) within MMPs‐responsive GelMA hydrogel microspheres. These microcarriers target the osteoporotic microenvironment and regulate OB‐OC cross‐talk, thereby facilitating intervertebral fusion in osteoporotic rats. Results demonstrate that mRNA@LNP exhibits uniform particle size and high transfection efficiency, while GelMA hydrogel microspheres possess excellent biocompatibility and MMP responsiveness, providing favorable cell survival space and controllable release of mRNA@LNP. The released LNP upregulates USP26 protein expression, effectively promoting osteogenesis while suppressing osteoclast formation. In vivo experiments show that injecting BHRC into the defect site of intervertebral discs in osteoporotic rats significantly promotes tail vertebrae fusion by responding to the microenvironment and regulating cell‐to‐cell cross‐talk. Thus, the BHRC holds great potential in regulating osteoporotic homeostasis, particularly in challenging bone defects such as intervertebral fusion in osteoporotic environments.
Ionic Covalent Organic Framework Solid‐State Electrolytes
Authors: Kim Yoonseob , Li Chen , Huang Jun , Yuan Yufei , Tian Ye , Zhang Wei
Published: August 2024

Rechargeable secondary batteries, widely used in modern technology, are essential for mobile and consumer electronic devices and energy storage applications. Lithium (Li)‐ion batteries are currently the most popular choice due to their decent energy density. However, the increasing demand for higher energy density has led to the development of Li metal batteries (LMBs). Despite their potential, the commonly used liquid electrolyte‐based LMBs present serious safety concerns, such as dendrite growth and the risk of fire and explosion. To address these issues, using solid‐state electrolytes in batteries has emerged as a promising solution. In this Perspective, recent advancements are discussed in ionic covalent organic framework (ICOFs)‐based solid‐state electrolytes, identify current challenges in the field, and propose future research directions. Highly crystalline ion conductors with polymeric versatility show promise as the next‐generation solid‐state electrolytes. Specifically, the use of anionic or cationic COFs is examined for Li‐based batteries, highlight the high interfacial resistance caused by the intrinsic brittleness of crystalline ICOFs as the main limitation, and presents innovative ideas for developing all‐ and quasi‐solid‐state batteries using ICOF‐based solid‐state electrolytes. With these considerations and further developments, the potential for ICOFs is optimistic about enabling the realization of high‐energy‐density all‐solid‐state LMBs.
Revolutionizing Sulfur Polymerization with a Biogenic Catalyst Approach
Authors: Mousavi Masoumeh , Hou Ke‐Xin , Kazemi Mohammadjavad , Li Cheng‐Hui , Fini Elham H.
Published: August 2024

This study introduces a novel biogenic catalyst derived from silver grass (SG) that could revolutionize sulfur polymerization, addressing the critical challenge of sulfur waste management. The oil refining industry generates large quantities of sulfur byproducts, which pose significant environmental risks. Inverse vulcanization offers a promising method to convert this waste into valuable polymers, but it traditionally relies on costly and environmentally harmful catalysts. The development of benign, sustainable catalysts is essential to making sulfur polymerization more eco‐friendly and scalable. This research demonstrates the effectiveness of the SG biogenic catalyst compared to the conventional chemical catalyst zinc diethyldithiocarbamate (Zn(DTC)2). Rheological characterizations reveal that the SG catalyst not only outperforms Zn(DTC)2 at elevated temperatures but also provides superior moisture resistance, enhancing polymer durability. Additionally, the SG‐catalyzed polymer exhibits better elasticity and structural integrity under mechanical stress. A density functional theory (DFT)‐based study further supports these findings, showing that the SG biochar matrix enables stronger Zn‐S coordination, resulting in improved polymer properties. These results highlight the potential of this biogenic catalyst to revolutionize sulfur polymerization, paving the way for more sustainable practices in the chemical industry by converting waste sulfur into valuable polymer resources.
Artificial Bacteriophages for Treating Oral Infectious Disease via Localized Bacterial Capture and Enhanced Catalytic Sterilization
Authors: Liu Xiaocan , Luo Danfeng , Dai Shuang , Cai Yanting , Chen Tianyan , Bao Xingfu , Hu Min , Liu Zhen
Published: August 2024

With the rapid emergence of antibiotic‐resistant pathogens, nanomaterial‐assisted catalytic sterilization has been well developed to combat pathogenic bacteria by elevating the level of reactive oxygen species including hydroxyl radical (·OH). Although promising, the ultra‐short lifetime and limited diffusion distance of ·OH severely limit their practical antibacterial usage. Herein, the rational design and preparation of novel virus‐like copper silicate hollow spheres (CSHSs) are reported, as well as their applications as robust artificial bacteriophages for localized bacterial capture and enhanced catalytic sterilization in the treatment of oral infectious diseases. During the whole process of capture and killing, CSHSs can efficiently capture bacteria via shortening the distance between bacteria and CSHSs, produce massive ·OH around bacteria, and further iinducing the admirable effect of bacterial inhibition. By using mucosal infection and periodontitis as typical oral infectious diseases, it is easily found that the bacterial populations around lesions in animals after antibacterial treatment fall sharply, as well as the well‐developed nanosystem can decrease the inflammatory reaction and promote the hard or soft tissue repair. Together, the high Fenton‐like catalytic activity, strong bacterial affinity, excellent antibacterial activity, and overall safety of the nanoplatform promise its great therapeutic potential for further catalytic bacterial disinfection.
Analyzing the Effect of Electrolyte Quantity on the Aging of Lithium‐Ion Batteries
Authors: Lechtenfeld Christian‐Timo , Buchmann Julius , Hagemeister Jan , Bela Marlena M. , van Wickeren Stefan , Stock Sandro , Daub Rüdiger , Wiemers‐Meyer Simon , Winter Martin , Nowak Sascha
Published: August 2024

Despite a substantial impact on various economic and cell technology factors, the influence of electrolyte quantities is rarely addressed in research. This study examines the impact of varying electrolyte quantities on cell performance and aging processes using three different electrolytes: LP57 (1 M LiPF6 in ethylene carbonate:ethyl methyl carbonate (EC:EMC 3:7 w/w), LP572 (LP57+2 wt.% vinylene carbonate (VC)) and LP57 + absVC (18.351 mg VC). Comprehensive analytical post mortem investigations revealed that continuous excessive electrolyte decomposition determines the performance of cells using LP57, leading to enhanced irreversible lithium‐ion loss and interphase thickening with increasing electrolyte volume. Impedance rise due to the growth of the interphase was also identified as the cause of degrading cell performance with rising amounts of LP572, attributed to an increasingly pronounced consumption of VC rather than electrolyte aging effects. By varying the electrolyte quantity while maintaining a constant amount VC within the cell system, the differences in cell performance were minimized, and observed deteriorating effects were suppressed. This study demonstrates the sensitive interdependence of electrolyte volume and additive concentration, practically affecting aging behavior. Comprehensively understanding the characteristics of each individual electrolyte component and tailoring the electrolytes to cell‐specific cell properties proves to be crucial to optimize cell performance.
Lateral Piezoelectricity of Alzheimer's Aβ Aggregates
Authors: Jang Jinhyeong , Joo Soyun , Yeom Jiwon , Jo Yonghan , Zhang Jingshu , Hong Seungbum , Park Chan Beum
Published: August 2024

Alzheimer's disease (AD) is the most frequent neurodegenerative disorder in the elderly aged over 65. The extracellular accumulation of beta‐amyloid (Aβ) aggregates in the brain is considered as the major event worsening the AD symptoms, but its underlying reason has remained unclear. Here the piezoelectric characteristics of Aβ aggregates are revealed. The vector piezoresponse force microscopy (PFM) analysis results exhibit that Aβ fibrils have spiraling piezoelectric domains along the length and a lateral piezoelectric constant of 44.1 pC N‐1. Also, the continuous sideband Kelvin probe force microscopy (KPFM) images display that the increment of charge‐induced surface potential on a single Aβ fibril is allowed to reach above +1700 mV in response to applied forces. These findings shed light on the peculiar mechano‐electrical surface properties of pathological Aβ fibrils that exceed those of normal body components.