Plane-wave medical image reconstruction based on dynamic Criss-Cross attention and multi-scale convolution.

BACKGROUND: Plane-wave imaging is widely employed in medical imaging due to its ultra-fast imaging speed. However, the image quality is compromised. Existing techniques to enhance image quality tend to sacrifice the imaging frame rate. OBJECTIVE: The study aims to reconstruct high-quality plane-wave images while maintaining the imaging frame rate. METHODS: The proposed method utilizes a U-Net-based generator incorporating a multi-scale convolution module in the encoder to extract information at different levels. Additionally, a Dynamic Criss-Cross Attention (DCCA) mechanism is proposed in the decoder of the U-Net-based generator to extract both local and global features of plane-wave images while avoiding interference caused by irrelevant regions. RESULTS: In the reconstruction of point targets, the experimental images achieved a reduction in Full Width at Half Maximum (FWHM) of 0.0499 mm, compared to the Coherent Plane-Wave Compounding (CPWC) method using 75-beam plane waves. For the reconstruction of cyst targets, the simulated image achieved a 3.78% improvement in Contrast Ratio (CR) compared to CPWC. CONCLUSIONS: The proposed model effectively addresses the issue of unclear lesion sites in plane-wave images.

Proteomics-Based Discovery of First-in-Class Chemical Probes for Programmed Cell Death Protein 2 (PDCD2).

Chemical probes are essential tools for understanding biological systems and for credentialing potential biomedical targets. Programmed cell death 2 (PDCD2) is a member of the B-cell lymphoma 2 (Bcl-2) family of proteins, which are critical regulators of apoptosis. Here we report the discovery and characterization of 10 e, a first-in-class small molecule degrader of PDCD2. We discovered this PDCD2 degrader by serendipity using a chemical proteomics approach, in contrast to the conventional approach for making bivalent degraders starting from a known binding ligand targeting the protein of interest. Using 10 e as a pharmacological probe, we demonstrate that PDCD2 functions as a critical regulator of cell growth by modulating the progression of the cell cycle in T lymphoblasts. Our work provides a useful pharmacological probe for investigating PDCD2 function and highlights the use of chemical proteomics to discover selective small molecule degraders of unanticipated targets.

ARU-GAN: U-shaped GAN based on Attention and Residual connection for super-resolution reconstruction.

Plane-wave ultrasound imaging technology offers high-speed imaging but lacks image quality. To improve the image spatial resolution, beam synthesis methods are used, which often compromise the temporal resolution. Herein, we propose ARU-GAN, a super-resolution reconstruction model based on residual connectivity and attention mechanisms, to address this issue. ARU-GAN comprises a Full-scale Skip-connection U-shaped Generator (FSUG) with an attention mechanism and a Residual Attention Patch Discriminator (RAPD). The former captures global and local features of the image by using full-scale skip-connections and attention mechanisms. The latter focuses on changes in the image at different scales to enhance its discriminative ability at the patch level. ARU-GAN was trained using a combined loss function on the Plane-Wave Imaging Challenge in Medical Ultrasound (PICMUS) 2016 dataset, which includes three types of targets: point targets, cyst targets, and in-vivo targets. Compared to Coherent Plane-Wave Compounding (CPWC), ARU-GAN achieved a reduction in Full Width at Half Maximum (FWHM) by 5.78%-20.30% on point targets, improved Contrast (CR) by 7.59-11.29 percentage points, and Contrast to Noise Ratio (CNR) by 30.58%-45.22% on cyst targets. On in-vivo target, ARU-GAN improved the Peak Signal-to-Noise Ratio (PSNR) by 11.94%, the Complex-Wavelet Structural Similarity Index Measurement (CW-SSIM) by 17.11%, and the Normalized Cross Correlation (NCC) by at least 2.17% compared to existing deep learning methods. In conclusion, ARU-GAN is a promising model for the super-resolution reconstruction of plane-wave medical ultrasound images. It provides a novel solution for improving image quality, which is essential for clinical practice.

Directed SN2 Glycosylation Employing an Amide-Functionalized 1-Naphthoate Platform Featuring a Selectivity-Safeguarding Mechanism.

This work implements a catalytic SN2 glycosylation by employing an amide-functionalized 1-naphthoate platform as a latent glycosyl leaving group. Upon gold-catalyzed activation, the amide group enables the SN2 process by directing the attack of the glycosyl acceptor via H-bonding interaction, which results in stereoinversion at the anomeric center. Unique in this approach is that the amide group also enables a novel safeguarding mechanism by trapping oxocarbenium intermediates and, hence, minimizing stereorandom SN1 processes. The strategy is applicable to the synthesis of a broad range of glycosides with high to excellent levels of stereoinversion from anomerically pure/enriched glycosyl donors. These reactions are generally high-yielding, and their applications in the synthesis of challenging 1,2-cis-linkage-rich oligosaccharides are demonstrated.

Structure-Based Design of Y-Shaped Covalent TEAD Inhibitors.

Transcriptional enhanced associate domain (TEAD) proteins together with their transcriptional coactivator yes-associated protein (YAP) and transcriptional coactivator with the PDZ-binding motif (TAZ) are important transcription factors and cofactors that regulate gene expression in the Hippo pathway. In mammals, the TEAD families have four homologues: TEAD1 (TEF-1), TEAD2 (TEF-4), TEAD3 (TEF-5), and TEAD4 (TEF-3). Aberrant expression and hyperactivation of TEAD/YAP signaling have been implicated in a variety of malignancies. Recently, TEADs were recognized as being palmitoylated in cells, and the lipophilic palmitate pocket has been successfully targeted by both covalent and noncovalent ligands. In this report, we present the medicinal chemistry effort to develop MYF-03-176 (compound 22) as a selective, cysteine-covalent TEAD inhibitor. MYF-03-176 (compound 22) significantly inhibits TEAD-regulated gene expression and proliferation of the cell lines with TEAD dependence including those derived from mesothelioma and liposarcoma.

Positive and Negative Themes Depicted in Television Shows Targeted Toward Adolescents.

The American Academy of Pediatrics has previously expressed concerns about the thematic content of television (TV) and the amount of time children spend viewing TV. The objective of this study was to determine the positive and negative themes depicted in a select number of TV shows targeted toward adolescents. We analyzed the thematic content depicted in the first season of 26 Netflix TV shows. The mean occurrences/h for positive and negative themes were 39.53 and 47.20, respectively. The most common positive themes were "encouragement from a friend/peer," "demonstrating honesty," and "staying true to oneself" (5.98, 5.38, and 3.72 mean occurrences/h, respectively). The most common negative themes were "dishonesty," "cursing," and "selfishness," (5.30, 4.96, and 4.85 mean occurrences/h, respectively). We suggest that health care providers become aware of TV thematic content and promote media education, and we encourage co-viewing and active mediation by parents/guardians with their children.

Ultrasound-based radiomics XGBoost model to assess the risk of central cervical lymph node metastasis in patients with papillary thyroid carcinoma: Individual application of SHAP.

Objectives: A radiomics-based explainable eXtreme Gradient Boosting (XGBoost) model was developed to predict central cervical lymph node metastasis (CCLNM) in patients with papillary thyroid carcinoma (PTC), including positive and negative effects. Methods: A total of 587 PTC patients admitted at Binzhou Medical University Hospital from 2017 to 2021 were analyzed retrospectively. The patients were randomized into the training and test cohorts with an 8:2 ratio. Radiomics features were extracted from ultrasound images of the primary PTC lesions. The minimum redundancy maximum relevance algorithm and the least absolute shrinkage and selection operator regression were used to select CCLNM positively-related features and radiomics scores were constructed. Clinical features, ultrasound features, and radiomics score were screened out by the Boruta algorithm, and the XGBoost model was constructed from these characteristics. SHapley Additive exPlanations (SHAP) was used for individualized and visualized interpretation. SHAP addressed the cognitive opacity of machine learning models. Results: Eleven radiomics features were used to calculate the radiomics score. Five critical elements were used to build the XGBoost model: capsular invasion, radiomics score, diameter, age, and calcification. The area under the curve was 91.53% and 90.88% in the training and test cohorts, respectively. SHAP plots showed the influence of each parameter on the XGBoost model, including positive (i.e., capsular invasion, radiomics score, diameter, and calcification) and negative (i.e., age) impacts. The XGBoost model outperformed the radiologist, increasing the AUC by 44%. Conclusions: The radiomics-based XGBoost model predicted CCLNM in PTC patients. Visual interpretation using SHAP made the model an effective tool for preoperative guidance of clinical procedures, including positive and negative impacts.

Generation and Screening of Antigen-Specific Nanobodies from Mammalian Cells Expressing the BCR Repertoire Library Using Droplet-Based Microfluidics.

Nanobodies, also known as VHHs, originate from the serum of Camelidae. Nanobodies have considerable advantages over conventional antibodies, including smaller size, more modifiable, and deeper tissue penetration, making them promising tools for immunotherapy and antibody-drug development. A high-throughput nanobody screening platform is critical to the rapid development of nanobodies. To date, droplet-based microfluidic systems have exhibited improved performance compared to the traditional phage display technology in terms of time and throughput. In realistic situations, however, it is difficult to directly apply the technology to the screening of nanobodies. Requirements of plasma cell enrichment and high cell viability, as well as a lack of related commercial reagents, are leading causes for impeding the development of novel methods. We overcame these obstacles by constructing a eukaryotic display system that secretes nanobodies utilizing homologous recombination and eukaryotic transformation technologies, and the significant advantages are that it is independent of primary cell viability and it does not require plasma cell enrichment in advance. Next, a signal capture system of "SA-beads + Biotin-antigen + nanobody-6 × His + fluorescence-labeled anti-6 × His (secondary antibody)" was designed for precise localization of the eukaryotic-expressed nanobodies in a droplet. Based on this innovation, we screened 293T cells expressing anti-PD-L1 nanobodies with a high positive rate of targeted cells (up to 99.8%). Then, single-cell transcriptomic profiling uncovered the intercellular heterogeneity and BCR sequence of target cells at a single-cell level. The complete complementarity determining region (CDR3) structure was obtained, which was totally consistent with the BCR reference. This study expanded the linkage between microfluidic technology and nanobody applications and also showed potential to accelerate the rapid transformation of nanobodies in the large-scale market.

An SN2-Type Strategy toward 1,2-cis-Furanosides.

The stereoselective construction of 1,2-cis furanosidic linkage is synthetically challenging. A strategy that applies to all furanose types remains elusive. In this work, a solution is developed based on gold catalysis and the deployment of the directing-group-on-leaving-group strategy, where a basic oxazole group in the gold-activated leaving group facilitates the stereoinvertive attack by glycosyl acceptors. In addition to exhibiting good to excellent 1,2-cis selectivities, these furanosylation reactions are high-yielding and mostly complete in 30 min to 2 h. A broad range of 1,2-cis-furanosides is prepared. Although some are uncommon, the ease of access enabled by this approach presents new opportunities to study their applications in medicine and materials research.

Dissecting the Landscape of Activated CMV-Stimulated CD4+ T Cells in Humans by Linking Single-Cell RNA-Seq With T-Cell Receptor Sequencing.

CD4+ T cells are crucial in cytomegalovirus (CMV) infection, but their role in infection remains unclear. The heterogeneity and potential functions of CMVpp65-reactivated CD4+ T cell subsets isolated from human peripheral blood, as well as their potential interactions, were analyzed by single-cell RNA-seq and T cell receptor (TCR) sequencing. Tregs comprised the largest population of these reactivated cells, and analysis of Treg gene expression showed transcripts associated with both inflammatory and inhibitory functions. The detailed phenotypes of CMV-reactivated CD4+ cytotoxic T1 (CD4+ CTL1), CD4+ cytotoxic T2 (CD4+ CTL2), and recently activated CD4+ T (Tra) cells were analyzed in single cells. Assessment of the TCR repertoire of CMV-reactivated CD4+ T cells confirmed the clonal expansion of stimulated CD4+ CTL1 and CD4+ CTL2 cells, which share a large number of TCR repertoires. This study provides clues for resolving the functions of CD4+ T cell subsets and their interactions during CMV infection. The specific cell groups defined in this study can provide resources for understanding T cell responses to CMV infection.

A "Traceless" Directing Group Enables Catalytic SN2 Glycosylation toward 1,2-cis-Glycopyranosides.

Generally applicable and stereoselective formation of 1,2-cis-glycopyranosidic linkage remains a long sought after yet unmet goal in carbohydrate chemistry. This work advances a strategy to this challenge via stereoinversion at the anomeric position of 1,2-trans glycosyl ester donors. This SN2 glycosylation is enabled under gold catalysis by an oxazole-based directing group optimally tethered to a leaving group and achieved under mild catalytic conditions, in mostly excellent yields, and with good to outstanding selectivities. The strategy is also applied to the synthesis of oligosaccharides.

Obesity and malnutrition in critically ill patients with acute myeloid leukemia: Prevalence and impact on mortality.

OBJECTIVES: Obese patients have an increased risk of developing acute myeloid leukemia (AML), which in turn predisposes to malnutrition. Obesity has been associated with improved survival in critically ill patients (obesity paradox), but this effect seems to disappear when adjusting for malnutrition. How obesity and malnutrition interplay to affect mortality in critically ill patients with AML has not been addressed and was the objective of this study. METHODS: This was a retrospective chart review of adult patients with AML who were admitted to the medical intensive care unit and had a nutrition consultation between 2011 and 2018. Demographic characteristics, comorbidities, severity scores, and laboratory parameters, as well as data on vital organ support, hospital mortality, and long-term survival were collected. Obesity was defined by a body mass index of ≥30 kg/m2 and malnutrition per the American Society for Parenteral and Enteral Nutrition criteria. Patients were compared based on nutrition and weight status, and hospital and long-term mortality were analyzed with logistic regression and Kaplan-Meier curves. RESULTS: We included 145 patients (57% obese, 30% malnourished) in the study. As time from AML diagnosis elapsed, obesity was less frequent and malnutrition more prevalent, with 25% of obese patients also presenting with malnutrition. Hospital mortality was 40% and associated with malnutrition in nonobese patients (odds ratio: 5.1; 95% confidence interval, 1.3-21.8; P = 0.02) and sequential organ failure assessment severity score (odds ratio: 1.5; 95% confidence interval, 1.3-1.7; P < 0.0001). Sensitivity analyses confirmed the association between malnutrition, but not obesity, and hospital mortality. Obese malnourished patients had lower long-term survival, but this was not significant (P = 0.25). CONCLUSIONS: Critically ill patients with AML have a high prevalence of malnutrition and obesity, which are sometimes associated. Malnutrition, but not obesity, was associated with hospital mortality.

A randomized phase II, open-label and multicenter study of combination regimens of bortezomib at two doses by subcutaneous injection for newly diagnosed multiple myeloma patients.

PURPOSE: Combinations of bortezomib (Velcade), cyclophosphamide and dexamethasone have shown significant efficacy and safety for patients of newly diagnosed multiple myeloma (NDMM). In this study, we compared the efficacy and safety of modified VCD regimens with novel changes in bortezomib dose and schedule for NDMM. METHODS: Eighty-five NDMM patients from multiple centers were randomly assigned to a high-dose (1.6 mg/m2) (group A) or a low-dose (1.3 mg/m2) (group B) bortezomib, administrated on days 1, 6, 11, and 16 subcutaneously in a 4-week cycle for nine cycles, combined with 40 mg dexamethasone on bortezomib days and cyclophosphamide 300 mg/m2 on days 1-3 intravenously. RESULTS: After four cycles, complete response (CR) or better in group A (43.6%) was higher than that in group B (12.8%) (P = 0.002). During induction, for patients with R-ISS stage III, the CR or better rate in group A was superior to that in group B (P = 0.01). Of patients < 65, the CR or better rate of group A was superior to that of group B (P = 0.004). Rapid onset of CR occurred in group A (P < 0.01). Meanwhile, rate of 3-4 diarrhea was higher in group A (P = 0.03), which caused higher rate of dose reduction for patients ≥ 65 (P = 0.041). No significant difference between the two groups in PFS and OS. CONCLUSIONS: The studied high-dose VCD as induction regimen had an improved CR rate, especially in patients < 65 or with R-ISS stage III, and is feasible for young and high-risk patients. Trial registration ClinicalTrials.gov: NCT02086942.

Modulating the function of ATP-binding cassette subfamily G member 2 (ABCG2) with inhibitor cabozantinib.

Cabozantinib (XL184) is a small molecule tyrosine kinase receptor inhibitor, which targets c-Met and VEGFR2. Cabozantinib has been approved by the Food and Drug Administration to treat advanced medullary thyroid cancer and renal cell carcinoma. In the present study, we evaluated the ability of cabozantinib to modulate the function of the ATP-binding cassette subfamily G member 2 (ABCG2) by sensitizing cells that are resistant to ABCG2 substrate antineoplastic drugs. We used a drug-selected resistant cell line H460/MX20 and three ABCG2 stable transfected cell lines ABCG2-482-R2, ABCG2-482-G2, and ABCG2-482-T7, which overexpress ABCG2. Cabozantinib, at non-toxic concentrations (3 or 5µM), sensitized the ABCG2-overexpressing cells to mitoxantrone, SN-38, and topotecan. Our results indicate that cabozantinib reverses ABCG2-mediated multidrug resistance by antagonizing the drug efflux function of the ABCG2 transporter instead of downregulating its expression. The molecular docking analysis indicates that cabozantinib binds to the drug-binding site of the ABCG2 transporter. Overall, our findings demonstrate that cabozantinib inhibits the ABCG2 transporter function and consequently enhances the effect of the antineoplastic agents that are substrates of ABCG2. Cabozantinib may be a useful agent in anticancer treatment regimens for patients who are resistant to ABCG2 substrate drugs.