Browse Articles

Publisher Correction: Preliminary investigation on the establishment of a new meibomian gland obstruction model and gene expression

Self-referential belief shares common neural correlates with general belief

Abstract Belief processing and self-referential processing have been consistently associated with cortical midline structures, and cortical regions such as the vmPFC have been implicated in general belief processing. The neural correlates of self-referential belief are yet to be investigated. In this fMRI study, we presented 120 statements with trait adjectives to N = 27 healthy participants, who subsequently judged whether they believed these trait adjectives applied to themselves, a close person, or a public person. Thereafter, participants rated their certainty in this judgment. Expectedly, self-referential processing evoked a large cluster in the vmPFC, ACC, and dmPFC. For belief, we found a cluster in the vmPFC, ACC, and amPFC during statement presentation, partially overlapping with that for self-referential processing. The cluster for self-belief vs. disbelief was similar in location and size to that for general belief processing. For uncertainty, we found dmPFC activation. We replicated vmPFC involvement in belief processing and found a common neural correlate for belief and self-belief in the vmPFC. Furthermore, we replicated the role of the dmPFC in uncertainty, supporting a dual neural process model of belief and certainty.

HLA-I aberrations in cutaneous T-cell lymphoma

Daratumumab with lenalidomide as maintenance after transplant in newly diagnosed multiple myeloma: the AURIGA study

Abstract No randomized trial has directly compared daratumumab and lenalidomide (D-R) maintenance with standard-of-care lenalidomide (R) alone after transplant. Herein, we report the primary results of the phase 3 AURIGA study evaluating D-R vs R maintenance in patients with newly diagnosed multiple myeloma (NDMM) who had very good or better partial response, were minimal residual disease (MRD)-positive (10–5) and anti-CD38–naïve after transplant. Two hundred patients were randomly assigned (1:1) to D-R (n = 99) or R (n = 101) maintenance for up to 36 cycles. The MRD-negative (10–5) conversion rate by 12 months from start of maintenance (primary end point) was significantly higher for D-R than R (50.5% vs 18.8%; odds ratio [OR], 4.51; 95% confidence interval [CI], 2.37-8.57; P < .0001). MRD-negative (10–6) conversion rate was similarly higher with D-R (23.2% vs 5.0%; OR, 5.97; 95% CI, 2.15-16.58; P = .0002). At median follow-up (32.3 months), D-R achieved a higher overall MRD-negative (10–5) conversion rate (D-R, 60.6% vs R, 27.7%; OR, 4.12; 95% CI, 2.26-7.52; P < .0001) and complete response rate or better (75.8% vs 61.4%; OR, 2.00; 95% CI, 1.08-3.69; P = .0255) vs R. Progression-free survival (PFS) favored D-R vs R (hazard ratio, 0.53; 95% CI, 0.29-0.97); estimated 30-month PFS rates were 82.7% for D-R and 66.4% for R. Incidences of grade 3/4 cytopenias (54.2% vs 46.9%) and infections (18.8% vs 13.3%) were slightly higher with D-R than R. In conclusion, D-R maintenance achieved a higher MRD-negative conversion rate and improved PFS after transplant vs R, with no new safety concerns. This trial was registered at www.clinicaltrials.gov as #NCT03901963.

Genetic alteration of class I HLA in cutaneous T-cell lymphoma

Abstract Abnormalities involving class I HLA are frequent in many lymphoma subtypes but have not yet been extensively studied in cutaneous T-cell lymphomas (CTCLs). We characterized the occurrence of class I HLA abnormalities in 65 patients with advanced mycosis fungoides or Sézary syndrome. Targeted DNA sequencing, including coverage of HLA loci, revealed at least 1 HLA abnormality in 26 of 65 patients (40%). Twelve unique somatic HLA mutations were identified across 9 patients, and loss of heterozygosity or biallelic loss of HLA was found to affect 24 patients. Although specific HLA alleles were commonly disrupted, these events did not associate with a decrease in the total class I HLA expression. Genetic events preferentially disrupted HLA alleles capable of presenting greater numbers of putative neoantigens. HLA abnormalities co-occurred with other genetic immune evasion events and were associated with worse progression-free survival. Single-cell analyses demonstrated that HLA abnormalities were frequently subclonal. Through analysis of serial samples, we observed that disrupting class I HLA events change dynamically over the disease course. The dynamics of HLA disruption are highlighted in a patient who received pembrolizumab and in whom resistance to pembrolizumab was associated with the elimination of an HLA mutation. Overall, our findings show that genomic class I HLA abnormalities are common in advanced CTCL and may be an important consideration in understanding the effects of immunotherapy in CTCL.

Combined targeted modality in cHL: a risky bet?

Brentuximab vedotin, nivolumab, doxorubicin, and dacarbazine for advanced-stage classical Hodgkin lymphoma

Abstract Treatment options for stage I/II bulky and advanced-stage disease have recently extensively changed. For decades in North America, ABVD (doxorubicin hydrochloride [Adriamycin], bleomycin sulfate, vinblastine sulfate, and dacarbazine) has been a frontline standard-of-care option for patients with advanced classical Hodgkin lymphoma (cHL). Recent data on combining brentuximab vedotin, doxorubicin, vinblastine, and dacarbazine demonstrated improved overall survival compared with ABVD but increased adverse events (AEs). We hypothesized that replacing vinblastine with nivolumab (brentuximab vedotin and nivolumab [AN] + doxorubicin and dacarbazine [AD]; AN+AD) may improve efficacy and safety. This phase 2, open-label multipart, multicenter study enrolled patients with treatment-naive stage II bulky or III/IV cHL. Patients received ≤6 cycles of AN+AD; granulocyte-colony stimulating factor (G-CSF) prophylaxis was optional, per institutional guidelines. At the time of planned analysis (N = 57), complete response (CR) and objective response rates were 88% (95% confidence interval [CI], 76.3-94.9) and 93% (95% CI, 83.0-98.1), respectively. With a median follow-up of 24.2 months (95% CI, 23.4-26.9), the 2-year progression-free survival rate was 88% (95% CI, 75.7-94.6); 88% (95% CI, 75.7-94.6) had a response lasting >2 years. Most common grade ≥3 treatment-related AEs were alanine aminotransferase increased (11%) and neutropenia (9%); 44% had treatment-related peripheral sensory neuropathy (grade 1/2, 40%; grade 3, 4%). No febrile neutropenia occurred; 49% received G-CSF prophylaxis. AN+AD led to a high CR rate and favorable safety profile. Further evaluation of programmed death receptor 1 inhibitor and CD30 antibody–drug conjugate combination regimens in frontline advanced-stage cHL is warranted. This trial was registered at www.clinicaltrials.gov as #NCT03646123 and www.clinicaltrialsregister.eu as #EudraCT 2020-004027-17.

IFN-I promotes T-cell–independent immunity and RBC autoantibodies via modulation of B-1 cell subsets in murine SCD

Abstract The pathophysiology of sickle cell disease (SCD) is characterized by hemolytic anemia and vaso-occlusion, although its impact on the adaptive immune responses remains incompletely understood. To comprehensibly profile the humoral immune responses, we immunized SCD mice with T-cell–independent (TI) and T-cell–dependent (TD) antigens (Ags). Our study showed that SCD mice have significantly enhanced type 2 TI (TI-2) immune responses in a manner dependent on the level of type I interferons (IFN-I), while maintaining similar or decreased TD immune responses depending on the route of Ag administration. Consistent with the enhanced TI-2 immune responses in SCD mice, the frequencies of B-1b cells (B-1 cells in humans), a major cell type responding to TI-2 Ags, were significantly increased in both the peritoneal cavity and spleens of SCD mice and in the blood of patients with SCD. In support of expanded B-1 cells, elevated levels of anti–red blood cell (anti-RBC) autoantibodies were detected in both SCD mice and patients. Both the levels of TI-2 immune responses and anti-RBC autoantibodies were significantly reduced after IFN-I receptor (IFNAR) antibody blockades and in IFNAR1–deficient SCD mice. Moreover, the alterations of B-1 cell subsets were reversed in IFNAR1–deficient SCD mice, uncovering a critical role for IFN-I in the enhanced TI-2 immune responses and the increased production of anti-RBC autoantibodies by modulating the innate B-1 cell subsets in SCD. Overall, our study provides experimental evidence that the modulation of B-1 cells and IFN-I can regulate TI immune responses and the levels of anti-RBC autoantibodies in SCD.

Comparison of progression risk of monoclonal gammopathy of undetermined significance by method of detection

Abstract Monoclonal gammopathy of undetermined significance (MGUS) is an asymptomatic premalignant disorder. The current standard of care is not to screen for MGUS, so it is often incidentally diagnosed in the clinic. It is unknown whether the outcomes of screened vs clinically detected MGUS differ. We compared the progression risk between screened vs clinical MGUS cohorts and assessed whether the MGUS detection method affected risk prediction of established clinical factors (score). We included 379 screened MGUS cases from the Olmsted County population-based study and 1384 patients with MGUS diagnosed during routine clinical evaluation at Mayo Clinic. Median follow-up time for the screened vs clinical cohort was 26.6 and 40.1 years, respectively. Accounting for death as a competing risk, the cumulative incidence of progression at 25 years was similar in the screened (11.1% [95% confidence interval [CI], 8.3-14.8]) vs clinical (10.1% [95% CI, 8.6-11.8]) MGUS cohorts, even when stratified by sex, age, or the baseline MGUS risk score. Overall, 0.9 (95% CI, 0.6-1.2) of patients with screened MGUS vs 1.0 (95% CI, 0.9-1.2) of those with clinically detected MGUS experienced disease progression for every 100 person-years of follow-up. MGUS detection method did not modify the association between MGUS risk score and progression risk (pinteraction = 0.217) and did not add to known risk factors for progression (likelihood ratio test; P = .839). Here, we show that progression risk among patients with screened vs clinically detected heavy-chain MGUS was similar. Future studies are needed to assess whether tailored follow-up of patients with screened MGUS affects clinical outcomes.

Daratumumab for maintenance in myeloma

Brentuximab vedotin and nivolumab for cHL

B-1 B cells lose self-control in SCD

How I treat older patients with relapsed/refractory diffuse large B-cell lymphoma

Abstract Diffuse large B-cell lymphoma (DLBCL) is an aggressive, yet curable, malignancy, but older patients are at higher risk of relapsed disease because they may not be eligible for full-intensity frontline chemoimmunotherapy or have comorbidities that limit standard treatments. Recent years have brought more treatment options than ever for this patient population, but it remains challenging to determine which can be safely and effectively offered to older patients. Formal determinations of fitness including geriatric assessments remain critical, but there is less guidance on how to best use this tool in the relapsed setting. Chimeric antigen receptor T-cell therapy is accessible to older patients, provided they can be supported through the intensive road to this treatment. If relapse occurs despite this or alternative therapies are preferred, many novel therapeutic options and combinations exist with some potential modifications for older adults, such as bispecific antibodies, tafasitamab and lenalidomide, polatuzumab-containing regimens, or loncastuximab tesirine. This article provides a summary of our approach to the management of this diverse population of older patients with relapsed or refractory DLBCL.

Is it time to screen for multiple myeloma?

Current myeloproliferative neoplasm scoring systems for clinical practice

Abstract BCR::ABL1-negative myeloproliferative neoplasms (MPNs) are clonal hematologic malignancies that are caused by the proliferation of myeloid cells that harbor a JAK-STAT pathway activating driver mutation. MPN management recommendations are based on the evaluation of different risks to prevent disease evolution–associated events while preserving patients’ quality of life. Such risks can be common across all MPNs or specific to each subtype (polycythemia vera [PV], essential thrombocythemia [ET], prefibrotic myelofibrosis [MF], and primary MF). Patients with MF harbor the worse prognosis, and hematopoietic stem cell transplantation (HSCT) is the only curative treatment at the expense of a high rate of morbidity and mortality. Therefore, accurate scoring systems to estimate overall survival are crucial for the management of patients with MF and the selection for HSCT. In PV and ET, the prediction of vascular events is prioritized given their higher incidence and related morbidity and mortality. Finally, quality of life evaluation is important for all subtypes. To predict these risks and adapt MPN therapeutic strategies, clinical risk scores have been developed over the past decades and more recently have incorporated molecular risk factors for more accurate risk stratification. The large number of scoring systems available, combined with disease heterogeneity and the necessity to predict diverse outcomes, make it difficult for clinicians to choose the most appropriate score to evaluate their patients’ risk in 2024. Here, we provide an overview of MPN disease evolution–associated event incidence and conduct an exhaustive comparative review of the scoring systems currently available for each risk. Finally, we propose an algorithm for the use of these scores in clinical practice in each MPN subtype.

Multiview attention networks for fine-grained watershed categorization via knowledge distillation

With the rapid development of artificial intelligence technology, an increasing number of village-related modeling problems have been addressed. However, first, the exploration of village-related watershed fine-grained classification problems, particularly the multi-view watershed fine-grained classification problem, has been hindered by dataset collection limitations; Second, village-related modeling networks typically employ convolutional modules for attentional modeling to extract salient features, yet they lack global attentional feature modeling capabilities; Lastly, the extensive number of parameters and significant computational demands render village-related watershed fine-grained classification networks infeasible for end-device deployment. To tackle these challenges, we introduce a multi-view attention mechanism designed for precise watershed classification, leveraging knowledge distillation techniques, abbreviated as MANet-KD. Specifically, first, we have developed the inaugural multi-view watershed classification dataset, termed MVWD.Second, we introduce a cross-view attention module (CVAM), which models salient features from intersecting views with global attention, enhancing the accuracy and precision of watershed classification. This module enhances fine-grained classification accuracy. Based on the above proposed CVAM, we propose a heavyweight MANet-Teacher and a lightweight MANet-Student, and finally, we introduce an Attention Knowledge Distillation (AKD) strategy that effectively transfers critical feature knowledge from the teacher network to the student network, utilizing the AKD approach for enhanced learning outcomes. The experimental results show that the proposed MANet-Teacher achieves state-of-the-art performance with 78.51% accuracy, and the proposed MANet-Student achieves comparable performance to MANet-Teacher with 6.64M parameters and 1.68G computation. The proposed MANet-KD achieves a good balance of performance and efficiency in the multi-view fine-grained watershed classification task. To facilitate further research in multi-view fine-grained watershed classification, all datasets, codes, and benchmark outcomes will be made available to the public. https://github.com/Jack13026212687/MANet-KD.

Extraction of coronary thrombus-derived exosomes from patients with acute myocardial infarction and its effect on the function of adventitial cells

Background Type I acute myocardial infarction (T1MI) has a very high morbidity and mortality rate. The role of thrombus-derived exosomes (TEs) in T1MI is unclear. Methods The objective of this study was to identify the optimal thrombolytic drug and concentration for extracting TEs. To this end, a series of time and concentration combinations were tested. Subsequently, the effect of TEs on thrombus-adjacent cells was investigated. Finally, we conducted lncRNA microarray analysis on the extracted TEs (GSE213115). Results TEs has been demonstrated to promote necrosis, autophagy, and ferroptosis of human cardiomyocytes, while inhibiting the proliferation and migration of human umbilical vein endothelial cells (HUVECs). Furthermore, TEs can stimulate the proliferation and migration of smooth muscle cells, and induce a transformation from a contractile to a secretory phenotype. Bioinformatics analysis revealed that five lncRNAs, AC068418.2, AC010186.3, AL031430.1, AC121333.1, and AL136526.1, exhibited significant differential expression in TE and regulated cell autophagy and ferroptosis by directly binding to TP53, TP63, and RELA, respectively. Conclusions We demonstrate that TEs as a potential target and research direction for the treatment of heart failure after T1MI. TEs may regulate ferroptosis and autophagy in thrombus-adjacent cells through the enrichment of certain lncRNAs.

UAV target tracking method based on global feature interaction and anchor-frame-free perceptual feature modulation

Target tracking techniques in the UAV perspective utilize UAV cameras to capture video streams and identify and track specific targets in real-time. Deep learning UAV target tracking methods based on the Siamese family have achieved significant results but still face challenges regarding accuracy and speed compatibility. In this study, in order to refine the feature representation and reduce the computational effort to improve the efficiency of the tracker, we perform feature fusion in deep inter-correlation operations and introduce a global attention mechanism to enhance the model’s field of view range and feature refinement capability to improve the tracking performance for small targets. In addition, we design an anchor-free frame-aware feature modulation mechanism to reduce computation and generate high-quality anchors while optimizing the target frame refinement computation to improve the adaptability to target deformation motion. Comparison experiments with several popular algorithms on UAV tracking datasets, such as UAV123@10fps, UAV20L, and DTB70, show that the algorithm balances speed and accuracy. In order to verify the reliability of the algorithm, we built a physical experimental environment on the Jetson Orin Nano platform. We realized a real-time processing speed of 30 frames per second.

Metastatic melanoma: An integrated analysis to identify critical regulators associated with prognosis, pathogenesis and targeted therapies

Metastatic melanoma causes a high rate of mortality. We conducted an integrated analysis to identify critical regulators associated with the prognosis, pathogenesis, and targeted therapies of metastatic-melanoma. A microarray dataset, GSE15605, including 12 metastatic-melanoma and sixteen normal skin (NS) samples, were obtained from the GEO database. After exploration of DEGs of NS and metastatic-melanoma, identification of relevant transcription factors (TFs) and kinases, the Gene Ontology (GO), and pathways analyses of DEGs were performed. Protein-protein interaction (PPI) networks were evaluated by the STRING and Cytoscape. Subsequently, the hub genes were selected using GEPIA. Survival analysis was performed using the TCGA. To identify microRNA and lncRNA DEGs of the melanoma-associated genes miRwalk and FANTOM6 were employed. In metastatic-melanoma samples 285 and 1173 genes were up and down-regulated, respectively. The upregulated genes were mostly involved in granulocyte chemotaxis, positive regulation of calcium ion transmembrane transport, and melanin biosynthetic process. Five hub genes including CXCL11, ICAM1, LEF1, MITF, and STAT1 were identified, SUZ12, SOX2, TCF3, NANOG, and SMAD4 were determined as the most significant TFs in metastatic-melanoma. Furthermore, CDK2, GSK3B, CSNK2A1, and CDK1 target the highest amounts of genes associated with disease. The DGIdb analysis results show the match drugs for five hub genes. MiRNAs analysis revealed hsa-miR-181c-5p, hsa-miR-30b-3p, hsa-miR-3680-3P, hsa-miR-4659a-3p, hsa-miR-4687-3P, and hsa-miR-6808-3P could regulate the hub genes, whereas RP11-553K8.5 and SRP14-AS1 were identified as the top significant lncRNA. The items recognized in the current study can be used as potential biomarkers for diagnostic, predictive, and might helpful to develop targeted combined therapies.

Achieving universal sanitation in Ghana: An analysis of key drivers of toilet ownership among property owners in Urban areas

Access to safe sanitation facilities remains a critical public health concern, especially in rapidly urbanizing countries like Ghana. This study investigates the determinants of household toilet ownership among property owners in three urban districts in Ghana. Using a cross-sectional survey design, data were collected from 1,256 property owners selected through a multi-stage stratified sampling procedure. Logistic regression analysis revealed that toilet ownership is significantly associated with the age and education level of property owners, community classification, building characteristics, and household income. Older property owners were more likely to own toilets (OR = 1.014 per year increase), as were those with higher education levels (OR = 1.752 for secondary, OR = 4.489 for tertiary education). Medium-class communities (OR = 2.013) completed buildings (OR = 2.625), and those constructed with sandcrete (OR = 12.755) were more likely to have toilets. Higher household income (OR = 1.00) correlated positively with toilet ownership. We conclude that enforcing building regulations requiring toilet facilities in all properties is crucial for improving sanitation in urban Ghana. Additionally, innovative sanitation financing interventions that subsidize the costs of sanitation facilities can be effective in addressing financial barriers and increasing household toilet ownership.