Performance evaluation of deep learning image reconstruction algorithm for dual-energy spectral CT imaging: A phantom study.

OBJECTIVES: To evaluate the performance of deep learning image reconstruction (DLIR) algorithm in dual-energy spectral CT (DEsCT) as a function of radiation dose and image energy level, in comparison with filtered-back-projection (FBP) and adaptive statistical iterative reconstruction-V (ASIR-V) algorithms. METHODS: An ACR464 phantom was scanned with DEsCT at four dose levels (3.5 mGy, 5 mGy, 7.5 mGy, and 10 mGy). Virtual monochromatic images were reconstructed at five energy levels (40 keV, 50 keV, 68 keV, 74 keV, and 140 keV) using FBP, 50% and 100% ASIR-V, DLIR at low (DLIR-L), medium (DLIR-M), and high (DLIR-H) settings. The noise power spectrum (NPS), task-based transfer function (TTF) and detectability index (d') were computed and compared among reconstructions. RESULTS: NPS area and noise increased as keV decreased, with DLIR having slower increase than FBP and ASIR-V, and DLIR-H having the lowest values. DLIR had the best 40 keV/140 keV noise ratio at various energy levels, DLIR showed higher TTF (50%) than ASIR-V for all materials, especially for the soft tissue-like polystyrene insert, and DLIR-M and DLIR-H provided higher d' than DLIR-L, ASIR-V and FBP in all dose and energy levels. As keV increases, d' increased for acrylic insert, and d' of the 50 keV DLIR-M and DLIR-H images at 3.5 mGy (7.39 and 8.79, respectively) were higher than that (7.20) of the 50 keV ASIR-V50% images at 10 mGy. CONCLUSIONS: DLIR provides better noise containment for low keV images in DEsCT and higher TTF(50%) for the polystyrene insert over ASIR-V. DLIR-H has the lowest image noise and highest detectability in all dose and energy levels. DEsCT 50 keV images with DLIR-M and DLIR-H show potential for 65% dose reduction over ASIR-V50% withhigher d'.

BART-D2 subtype of EBV encoded BART miRNA cluster 1 region is strongly associated with endemic nasopharyngeal carcinoma.

Epstein-Barr virus (EBV)-encoded BamHI A rightward transcript (BART) microRNAs (miRNAs) play important roles in viral infection and tumorigenesis. The association of sequence variations in the BART miRNA cluster 1 region with diseases remains unclear. Herein, 6 types and 11 subtypes of BART cluster 1 were identified in 354 tumors and healthy donors (HDs) from nasopharyngeal carcinoma (NPC)-endemic and nonendemic China (genotyped data), and 905 EBV genomes retrieved from GenBank from diseased and normal people from around the world (archived data). The distributions of BART cluster 1 types/subtypes between NPC-endemic and nonendemic China; between Asian regions and Africa/Europe & Australia & United States; and among Asian regions (NPC-endemic China, NPC-nonendemic East Asia and Southeast Asia) were significantly different (p < 0.001). The subtype BART-D2 was not found outside Asia and was only common in NPC-endemic China. More importantly, BART-D2 had a higher frequency in NPCs than in HDs in NPC-endemic China (genotyped data, 78.0% vs. 44.1%, p < 0.001; achieved data, 89.3% vs. 43.7%, p < 0.001), and was also more frequent in NPCs than in HDs, gastric carcinomas, and lymphomas in NPC-nonendemic China (genotyped data, 27.9% vs. 1.9%, 2.4%, and 0.0%, p < 0.001). BART-D2 was preferentially linked with the high-risk subtypes for NPC previously reported, 162476C or 163364T, in the BALF2 gene, and was associated with NPC risk (p < 0.01). In vitro experiments showed that BART-D2 affected the expression of some mature BART miRNAs. These findings demonstrate geographically restricted variations of BART cluster 1 and identify distinct subtype that is confined to NPC-endemic China and is associated with NPC.

Application of deep learning image reconstruction algorithm to improve image quality in CT angiography of children with Takayasu arteritis.

BACKGROUND: The inflammatory indexes of children with Takayasu arteritis (TAK) usually tend to be normal immediately after treatment, therefore, CT angiography (CTA) has become an important method to evaluate the status of TAK and sometime is even more sensitive than laboratory test results. OBJECTIVE: To evaluate image quality improvement in CTA of children diagnosed with TAK using a deep learning image reconstruction (DLIR) in comparison to other image reconstruction algorithms. METHODS: hirty-two TAK patients (9.14±4.51 years old) underwent neck, chest and abdominal CTA using 100 kVp were enrolled. Images were reconstructed at 0.625 mm slice thickness using Filtered Back-Projection (FBP), 50%adaptive statistical iterative reconstruction-V (ASIR-V), 100%ASIR-V and DLIR with high setting (DLIR-H). CT number and standard deviation (SD) of the descending aorta and back muscle were measured and contrast-to-noise ratio (CNR) for aorta was calculated. The vessel visualization, overall image noise and diagnostic confidence were evaluated using a 5-point scale (5, excellent; 3, acceptable) by 2 observers. RESULTS: There was no significant difference in CT number across images reconstructed using different algorithms. Image noise values (in HU) were 31.36±6.01, 24.96±4.69, 18.46±3.91 and 15.58±3.65, and CNR values for aorta were 11.93±2.12, 15.66±2.37, 22.54±3.34 and 24.02±4.55 using FBP, 50%ASIR-V, 100%ASIR-V and DLIR-H, respectively. The 100%ASIR-V and DLIR-H images had similar noise and CNR (all P > 0.05), and both had lower noise and higher CNR than FBP and 50%ASIR-V images (all P < 0.05). The subjective evaluation suggested that all images were diagnostic for large arteries, however, only 50%ASIR-V and DLIR-H met the diagnostic requirement for small arteries (3.03±0.18 and 3.53±0.51). CONCLUSION: DLIR-H improves CTA image quality and diagnostic confidence for TAK patients compared with 50%ASIR-V, and best balances image noise and spatial resolution compared with 100%ASIR-V.

Application of a deep learning image reconstruction (DLIR) algorithm in head CT imaging for children to improve image quality and lesion detection.

BACKGROUND: To evaluate the performance of a Deep Learning Image Reconstruction (DLIR) algorithm in pediatric head CT for improving image quality and lesion detection with 0.625 mm thin-slice images. METHODS: Low-dose axial head CT scans of 50 children with 120 kV, 0.8 s rotation and age-dependent 150-220 mA tube current were selected. Images were reconstructed at 5 mm and 0.625 mm slice thickness using Filtered back projection (FBP), Adaptive statistical iterative reconstruction-v at 50% strength (50%ASIR-V) (as reference standard), 100%ASIR-V and DLIR-high (DL-H). The CT attenuation and standard deviation values of the gray and white matters in the basal ganglia were measured. The clarity of sulci/cisterns, boundary between white and gray matters, and overall image quality was subjectively evaluated. The number of lesions in each reconstruction group was counted. RESULTS: The 5 mm FBP, 50%ASIR-V, 100%ASIR-V and DL-H images had a subjective score of 2.25 ± 0.44, 3.05 ± 0.23, 2.87 ± 0.39 and 3.64 ± 0.49 in a 5-point scale, respectively with DL-H having the lowest image noise of white matter at 2.00 ± 0.34 HU; For the 0.625 mm images, only DL-H images met the diagnostic requirement. The 0.625 mm DL-H images had similar image noise (3.11 ± 0.58 HU) of the white matter and overall image quality score (3.04 ± 0.33) as the 5 mm 50% ASIR-V images (3.16 ± 0.60 HU and 3.05 ± 0.23). Sixty-five lesions were recognized in 5 mm 50%ASIR-V images and 69 were detected in 0.625 mm DL-H images. CONCLUSION: DL-H improves the head CT image quality for children compared with ASIR-V images. The 0.625 mm DL-H images improve lesion detection and produce similar image noise as the 5 mm 50%ASIR-V images, indicating a potential 85% dose reduction if current image quality and slice thickness are desired.

Inhibition of cIAP1 as a strategy for targeting c-MYC-driven oncogenic activity.

Protooncogene c-MYC, a master transcription factor, is a major driver of human tumorigenesis. Development of pharmacological agents for inhibiting c-MYC as an anticancer therapy has been a longstanding but elusive goal in the cancer field. E3 ubiquitin ligase cIAP1 has been shown to mediate the activation of c-MYC by destabilizing MAD1, a key antagonist of c-MYC. Here we developed a high-throughput assay for cIAP1 ubiquitination and identified D19, a small-molecule inhibitor of E3 ligase activity of cIAP1. We show that D19 binds to the RING domain of cIAP1 and inhibits the E3 ligase activity of cIAP1 by interfering with the dynamics of its interaction with E2. Blocking cIAP1 with D19 antagonizes c-MYC by stabilizing MAD1 protein in cells. Furthermore, we show that D19 and an improved analog (D19-14) promote c-MYC degradation and inhibit the oncogenic function of c-MYC in cells and xenograft animal models. In contrast, we show that activating E3 ubiquitin ligase activity of cIAP1 by Smac mimetics destabilizes MAD1, the antagonist of MYC, and increases the protein levels of c-MYC. Our study provides an interesting example using chemical biological approaches for determining distinct biological consequences from inhibiting vs. activating an E3 ubiquitin ligase and suggests a potential broad therapeutic strategy for targeting c-MYC in cancer treatment by pharmacologically modulating cIAP1 E3 ligase activity.

Performance evaluation of a deep learning image reconstruction (DLIR) algorithm in "double low" chest CTA in children: a feasibility study.

BACKGROUND: Chest CT angiography (CTA) is a convenient clinical examination for children with an increasing need to reduce both radiation and contrast medium doses. Iterative Reconstruction algorithms are often used to reduce image noise but encounter limitations under low radiation dose and conventional 100 kVp tube voltage may not provide adequate enhancement under low contrast dose. PURPOSE: To evaluate the performance of a deep learning image reconstruction (DLIR) algorithm in conjunction with lower tube voltage in chest CTA in children under reduced radiation and contrast medium (CM) dose. MATERIALS AND METHODS: 46 Children (age 5.9 ± 4.2 years) in the study group underwent chest CTA with 70 kVp and CM dose of 0.8-1.2 ml/kg. Images were reconstructed at 0.625 mm using a high setting DLIR (DLIR-H). The control group consisted of 46 age-matching children scanned with 100 kVp, CM dose of 1.3-1.8 ml/kg and images reconstructed with 50% and 100% adaptive statistical iterative reconstruction-V. Two radiologists evaluated images subjectively for overall image noise, vessel contrast and vessel margin clarity separately on a 5-point scale (5, excellent and 1, not acceptable). CT value and image noise of aorta and erector spinae muscle were measured. RESULTS: Compared to the control group, the study group reduced the dose-length-product by 11.2% (p = 0.01) and CM dose by 24% (p < 0.001), improved the enhancement in aorta (416.5 ± 113.1HU vs. 342.0 ± 57.6HU, p < 0.001) and reduced noise (15.1 ± 3.5HU vs. 18.6 ± 4.4HU, p < 0.001). The DLIR-H images provided acceptable scores on all 3 aspects of the qualitative evaluation. CONCLUSION: "Double low" chest CTA in children using 70 kVp and DLIR provides high image quality with reduced noise and improved vessel enhancement for diagnosis while further reduces radiation and CM dose.

Application of 70 kVp in abdominal CT angiography to reduce both radiation and contrast dosage and improve patient comfort for children.

BACKGROUND: Low-tube voltage scanning improves CT attenuation value of contrast medium (CM). Thus, we hypothesized that 70 kVp in pediatric abdominal CT angiography (CTA) could be used to reduce both radiation and CM dose and improve patient comfort at the same time. OBJECTIVE: To evaluate the feasibility of using 70 kVp in pediatric abdominal CTA to reduce radiation dose and CM dose and improve patient care for children. MATERIALS AND METHODS: Forty-six children needing abdominal CTA were enrolled in the study group using low-dose scanning protocol with 70 kVp and 0.7-1.1 ml/kg contrast dose, and reconstructed with 50%ASIR-V. They were compared with other 46 children in control group with matching body weight and underwent conventional CT scans with 100 kVp, 1.2-1.8 ml/kg contrast dose and reconstructed using 50%ASIR. Image quality of large vessels was evaluated using a 5-point scale. CT value and standard deviation of descending aorta (Ao) was measured, and signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) were calculated. Radiation dose, contrast dose, the maximum injection pressure between the two groups were also compared. RESULTS: Score for displaying large vessels by 70 kVp images was 3.91±0.28, lower than that (4.17±0.38) of the control group (p < 0.05), but fully met the diagnostic requirements. CT value of Ao was 390.87±86.79HU in study group, which is higher than 343.93±49.94HU in control group, while there was no difference in SNR and CNR between two groups; the radiation dose, contrast dosage and injection pressure of the study group were 1.23±0.39mGy, 12.67±7.27 ml and 43.83±17.16psi, respectively, which are significantly lower than the 1.95±0.37mGy, 22.67±7.39 ml, and 77.59±19.68psi of control group. CONCLUSION: Use of 70 kVp in pediatric abdominal CTA provides diagnostic quality images while significantly reduce radiation and contrast dose, as well as injection pressure to improve patient comfort for children.

Further Improving Image Quality of Cardiovascular Computed Tomography Angiography for Children With High Heart Rates Using Second-Generation Motion Correction Algorithm.

BACKGROUND: The state-of-art motion correction algorithm is inadequate for correcting motion artifacts in coronary arteries in cardiovascular computed tomography angiography (CCTA) for children with high heart rates, and even less effective for heart structures beyond coronary arteries. PURPOSE: This study aimed to evaluate the effectiveness of a second-generation, whole-heart motion correction algorithm in improving the heart image quality of CCTA for children with high heart rates. MATERIALS AND METHODS: Forty-two consecutive symptomatic cardiac patients with high heart rates (122.6 ± 18.8 beats/min) were enrolled. All patients underwent CCTA on a 256-row CT using a prospective electrocardiogram-triggered single-beat protocol. Images were reconstructed using a standard algorithm (STD), state-of-the-art first-generation coronary artery motion correction algorithm (MC1), and second-generation, whole-heart motion correction algorithm (MC2). The image quality of the origin of left coronary, right coronary, aortic valve, pulmonary valve, mitral valve, tricuspid valve, aorta root, pulmonary artery root, ventricular septum (VS), and atrial septum (AS) was assessed by 2 experienced radiologists using a 4-point scale (1, nondiagnostic; 2, detectable; 3, measurable; and 4, excellent); nonparametric test was used to analyze and compare the differences among 3 groups; and post hoc multiple comparisons were used between different methods. RESULTS: There were group differences for cardiac structures except VS and AS, with MC2 having the best image quality and STD having the worst image quality. Post hoc multiple comparisons showed that MC2 was better than MC1 and STD in all structures except VS and AS where all 3 algorithms performed equally, whereas MC1 was better than STD only in the origin of left coronary, right coronary, and mitral valve. CONCLUSIONS: A second-generation, whole-heart motion correction algorithm further significantly improves cardiac image quality beyond the coronaries in CCTA for pediatric patients with high heart rates.

Enzymatic preparation of chitooligosaccharides and their anti-obesity application.

Chitooligosaccharides (COS) are derived from chitosan, which can be used as nutraceuticals and functional foods. Because of their various biological activities, COS are widely used in the food, medicine, agriculture, and other fields. COS were prepared by chitosanase  from Pseudoalteromonas sp. SY39 and their anti-obesity activity was researched in mice in this study. The effects of hydrolysis time, temperature, the ratio of enzyme to chitosan, and pH on the productivity of COS were discussed. Preparation process of COS was established in a 5-L fermenter. COS were characterized and their anti-obesity activity was studied in animal experiments. The results showed that COS could effectively reduce serum lipid levels and obesity in mice, and have a good anti-obesity activity. The preparation technology and remarkable anti-obesity activity of COS further expand their applications in the food and pharmaceutical industries.

Microcystin-LR disrupts insulin signaling by hyperphosphorylating insulin receptor substrate 1 and glycogen synthase.

Microcystin-LR (MC-LR) is a cyanobacteria-derived heptapeptide that has been commonly characterized as a hepatotoxin. Although the liver is a primary organ in glucose homeostasis, the effect of MC-LR on glucose metabolism remains unclear. In this study, the human liver cell line HL7702 and ICR mice were exposed to various concentrations of MC-LR for 24 h, and the proteins involved in insulin signaling were investigated. The results showed that MC-LR treatment induced the hyperphosphorylation of insulin receptor substrate 1 (IRS1) at several serine sites, S307, S323, S636/639, and S1101 in HL7702 cells, and S302, S318, S632/635, and S1097 in mice livers. In addition, the activation of S6K1 was demonstrated to play an important role in MC-LR-induced IRS1 hyperphosphorylation at several serine sites. Decreased levels of total IRS1 were observed in the mice livers, but there was no significant change in HL7702 cells. MC-LR also induced glycogen synthase (GS) hyperphosphorylation at S641 (inactivating GS) both in vitro and in vivo, even glycogen synthase kinase 3, a well-known GS kinase, was inactivated after MC-LR treatment. Moreover, MC-LR could block insulin-induced GS activation. In addition, glucose transport in liver cells was not impacted by MC-LR either with or without insulin stimulation. Our study implies that MC-LR can interfere with the actions of IRS1 and GS in insulin signaling and may have a toxic effect on glucose metabolism in the liver.

Morphology, composition, and bioactivity of strontium-doped brushite coatings deposited on titanium implants via electrochemical deposition.

Surface modification techniques have been applied to generate titanium implant surfaces that promote osseointegration for use in dental applications. In this study, strontium-doped brushite coatings were deposited on titanium by electrochemical deposition. The phase composition of the coating was investigated by energy dispersive X-ray spectroscopy and X-ray diffraction. The surface morphologies of the coatings were studied through scanning electron microscopy, and the cytocompatibility and bioactivity of the strontium-doped brushite coatings were evaluated using cultured osteoblasts. Osteoblast proliferation was enhanced by the addition of strontium, suggesting a possible mechanism by which strontium incorporation in brushite coatings increased bone formation surrounding the implants. Cell growth was also strongly influenced by the composition of the deposited coatings, with a 10% Sr-doped brushite coating inducing the greatest amount of bone formation among the tested materials.

In defense of local descriptor-based few-shot object detection.

State-of-the-art image object detection computational models require an intensive parameter fine-tuning stage (using deep convolution network, etc). with tens or hundreds of training examples. In contrast, human intelligence can robustly learn a new concept from just a few instances (i.e., few-shot detection). The distinctive perception mechanisms between these two families of systems enlighten us to revisit classical handcraft local descriptors (e.g., SIFT, HOG, etc.) as well as non-parametric visual models, which innately require no learning/training phase. Herein, we claim that the inferior performance of these local descriptors mainly results from a lack of global structure sense. To address this issue, we refine local descriptors with spatial contextual attention of neighbor affinities and then embed the local descriptors into discriminative subspace guided by Kernel-InfoNCE loss. Differing from conventional quantization of local descriptors in high-dimensional feature space or isometric dimension reduction, we actually seek a brain-inspired few-shot feature representation for the object manifold, which combines data-independent primitive representation and semantic context learning and thus helps with generalization. The obtained embeddings as pattern vectors/tensors permit us an accelerated but non-parametric visual similarity computation as the decision rule for final detection. Our approach to few-shot object detection is nearly learning-free, and experiments on remote sensing imageries (approximate 2-D affine space) confirm the efficacy of our model.

Nitrogen-cycling microbial communities respond differently to nitrogen addition under two contrasting grassland soil types.

Introduction: The impact of nitrogen (N) deposition on the soil N-transforming process in grasslands necessitates further investigation into how N input influences the structural composition and diversity of soil N-cycling microbial communities across different grassland types. Methods: In this study, we selected two types of grassland soils in northwest Liaoning, temperate steppe and warm-temperate shrub, and conducted short-term N addition experiments using organic N, ammonium N, and nitrate N as sources with three concentration gradients to simulate N deposition. Illumina MiSeq sequencing technology was employed to sequence genes associated with N-cycling microbes including N-fixing, ammonia-oxidizing and denitrifying bacteria, and ammonia-oxidizing archaea. Results and discussion: The results revealed significant alterations in the structural composition and diversity of the N-cycling microbial community due to N addition, but the response of soil microorganisms varied inconsistent among different grassland types. Ammonium transformation rates had a greater impact on soils from temperate steppes while nitrification rates were more influential for soils from warm-temperate shrubs. Furthermore, the influence of the type of N source on soil N-cycling microorganisms outweighed that of its quantity applied. The ammonium type of nitrogen source is considered the most influential driving factor affecting changes in the structure of the microbial community involved in nitrogen transformation, while the amount of low nitrogen applied primarily determines the composition of soil bacterial communities engaged in nitrogen fixation and nitrification. Different groups of N-cycling microorganisms exhibited distinct responses to varying levels of nitrogen addition with a positive correlation observed between their composition, diversity, and environmental factors examined. Overall findings suggest that short-term nitrogen deposition may sustain dominant processes such as soil-N fixation within grasslands over an extended period without causing significant negative effects on northwestern Liaoning's grassland ecosystems within the next decade.

Application of metal artifact reduction algorithm in reducing metal artifacts in post-surgery pediatric low radiation dose spine computed tomography (CT) images.

Background: The commonly used methods for removing metal-induced beam hardening artifacts often rely on the use of high energy photons with either high tube voltage or high energy virtual monoenergetic images in dual-energy computed tomography (CT), the radiation dose was usually relatively high in order to generate adequate signals. This retrospective study is designed to evaluate the application of a metal artifact reduction (MAR) algorithm in reducing pedicle screw metal-caused beam hardening artifacts in post-surgery pediatric low radiation dose spine CT images. Methods: Seventy-seven children (3-15 years) who had undergone a low dose CT with 140 or 100 kV were enrolled. The radiation dose was 1.40 mGy for the 3-8 years old and 2.61 mGy for 9-15 years old children. There were 116 pedicle screws evaluated. The raw data were reconstructed with adaptive statistical iterative reconstruction-V (ASIR-V) at 50% strength, ASIR-V with MAR (AV-MAR), deep learning image reconstruction (DLIR) at high strength and DLIR with MAR (DL-MAR). The image quality concerning pedicle screws was evaluated objectively in terms of the length of beam-hardening artifact (LHA) and artifact index (AI), and subjectively using a 4-point scale (4 points: best, 3 points: acceptable). Results: Both AV-MAR and DL-MAR significantly reduced metal-induced beam hardening artifacts with smaller LHA (15.76±10.12 mm, a reduction of 57.24% and 15.66±10.49 mm, a reduction of 57.40%, respectively), and AI value (62.50±33.51, a reduction of 64.65% and 61.03±32.61, a reduction of 65.01%, respectively) compared to ASIR-V and DLIR (all P<0.01), The subjective image quality scores concerning the screws were 3.37±0.49 and 3.47±0.50 with AV-MAR and DL-MAR, respectively, higher than the respective value of 1.73±0.44 and 1.76±0.43 without MAR (all P<0.01). Conclusions: MAR significantly reduces the low-density artifacts caused by metal screws in post-surgery pediatric low-dose spine CT images, across different tube voltages, radiation dose levels and reconstruction algorithms. Combining DL-MAR further improves the overall image quality under low radiation dose conditions.

Biodegradable microspheres come into sight: A promising biomaterial for delivering drug to the posterior segment of the eyeball.

Posterior segment disease acts as a major cause of irreversible visual impairments. Successful treatment of posterior segment disease requires the efficient delivery of therapeutic substances to the targeted lesion. However, the complex ocular architecture makes the bioavailability of topically applied drugs extremely low. Invasive delivery approaches like intravitreal injection may cause adverse complications. To enhance the efficiency, several biomedical engineering systems have been developed to increase the penetration efficiency and improve the bioavailability of drugs at the posterior segments. Advantageously, biodegradable microspheres are found to deliver the therapeutic agents in a controlled fashion. The microspheres prepared from novel biomaterials can realize the prolonged release at the posterior segment with minimum side effects. Moreover, it will be degraded automatically into products that are non-toxic to the human body without the necessity of secondary operation to remove the residual polymer matrix. Additionally, biodegradable microspheres have decent thermoplasticity, adjustable hydrophilicity, controlled crystallinity, and high tensile strength, which make them suitable for intraocular delivery. In this review, we introduce the latest advancements in microsphere production technology and elaborate on the biomaterials that are used to prepare microspheres. We discuss systematically the pharmacological characteristics of biodegradable microspheres and compare their potential advantages and limitations in the treatment of posterior segment diseases. These findings would enrich our knowledge of biodegradable microspheres and cast light into the discovery of effective biomaterials for ocular drug delivery.

CHD1, a multifaceted epigenetic remodeler in prostate cancer.

Chromatin remodeling proteins contribute to DNA replication, transcription, repair, and recombination. The chromodomain helicase DNA-binding (CHD) family of remodelers plays crucial roles in embryonic development, hematopoiesis, and neurogenesis. As the founding member, CHD1 is capable of assembling nucleosomes, remodeling chromatin structure, and regulating gene transcription. Dysregulation of CHD1 at genetic, epigenetic, and post-translational levels is common in malignancies and other human diseases. Through interacting with different genetic alterations, CHD1 possesses the capabilities to exert oncogenic or tumor-suppressive functions in context-dependent manners. In this Review, we summarize the biochemical properties and dysregulation of CHD1 in cancer cells, and then discuss CHD1's roles in different contexts of prostate cancer, with an emphasis on its crosstalk with diverse signaling pathways. Furthermore, we highlight the potential therapeutic strategies for cancers with dysregulated CHD1. At last, we discuss current research gaps in understanding CHD1's biological functions and molecular basis during disease progression, as well as the modeling systems for biology study and therapeutic development.

Alternative splicing of GSDMB modulates killer lymphocyte-triggered pyroptosis.

Granzyme A from killer lymphocytes cleaves gasdermin B (GSDMB) and triggers pyroptosis in targeted human tumor cells, eliciting antitumor immunity. However, GSDMB has a controversial role in pyroptosis and has been linked to both anti- and protumor functions. Here, we found that GSDMB splicing variants are functionally distinct. Cleaved N-terminal (NT) fragments of GSDMB isoforms 3 and 4 caused pyroptosis, but isoforms 1, 2, and 5 did not. The nonfunctional isoforms have a deleted or modified exon 6 and therefore lack a stable belt motif. The belt likely contributes to the insertion of oligomeric GSDMB-NTs into the membrane. Consistently, noncytotoxic GSDMB-NTs blocked pyroptosis caused by cytotoxic GSDMB-NTs in a dominant-negative manner. Upon natural killer (NK) cell attack, GSDMB3-expressing cells died by pyroptosis, whereas GSDMB4-expressing cells died by mixed pyroptosis and apoptosis, and GSDMB1/2-expressing cells died only by apoptosis. GSDMB4 partially resisted NK cell-triggered cleavage, suggesting that only GSDMB3 is fully functional. GSDMB1-3 were the most abundant isoforms in the tested tumor cell lines and were similarly induced by interferon-γ and the chemotherapy drug methotrexate. Expression of cytotoxic GSDMB3/4 isoforms, but not GSDMB1/2 isoforms that are frequently up-regulated in tumors, was associated with better outcomes in bladder and cervical cancers, suggesting that GSDMB3/4-mediated pyroptosis was protective in those tumors. Our study indicates that tumors may block and evade killer cell-triggered pyroptosis by generating noncytotoxic GSDMB isoforms. Therefore, therapeutics that favor the production of cytotoxic GSDMB isoforms by alternative splicing may improve antitumor immunity.

Immune checkpoint B7-H3 is a therapeutic vulnerability in prostate cancer harboring PTEN and TP53 deficiencies.

Checkpoint immunotherapy has yielded meaningful responses across many cancers but has shown modest efficacy in advanced prostate cancer. B7 homolog 3 protein (B7-H3/CD276) is an immune checkpoint molecule and has emerged as a promising therapeutic target. However, much remains to be understood regarding B7-H3's role in cancer progression, predictive biomarkers for B7-H3-targeted therapy, and combinatorial strategies. Our multi-omics analyses identified B7-H3 as one of the most abundant immune checkpoints in prostate tumors containing PTEN and TP53 genetic inactivation. Here, we sought in vivo genetic evidence for, and mechanistic understanding of, the role of B7-H3 in PTEN/TP53-deficient prostate cancer. We found that loss of PTEN and TP53 induced B7-H3 expression by activating transcriptional factor Sp1. Prostate-specific deletion of Cd276 resulted in delayed tumor progression and reversed the suppression of tumor-infiltrating T cells and NK cells in Pten/Trp53 genetically engineered mouse models. Furthermore, we tested the efficacy of the B7-H3 inhibitor in preclinical models of castration-resistant prostate cancer (CRPC). We demonstrated that enriched regulatory T cells and elevated programmed cell death ligand 1 (PD-L1) in myeloid cells hinder the therapeutic efficacy of B7-H3 inhibition in prostate tumors. Last, we showed that B7-H3 inhibition combined with blockade of PD-L1 or cytotoxic T lymphocyte-associated protein 4 (CTLA-4) achieved durable antitumor effects and had curative potential in a PTEN/TP53-deficient CRPC model. Given that B7-H3-targeted therapies have been evaluated in early clinical trials, our studies provide insights into the potential of biomarker-driven combinatorial immunotherapy targeting B7-H3 in prostate cancer, among other malignancies.

Influence of normal forces on the frictional behavior in tribological systems made of different bracket types and wire dimensions.

The aim of the present work was measuring the effect of varying normal forces on frictional forces applied to different bracket types in combination with archwires made of NiTi and stainless steel of variable cross section. The measurements were carried out in artificial saliva. Three-way ANOVA and Bonferroni post-hoc tests (α=0.05) were applied. Except for one subgroup the combination of normal force, bracket system and wire dimension had significant effect on friction (p<0.001) as friction increased with increasing normal forces. Only moderately tied ligatures or passive self-ligating brackets generate low friction forces. There was a statistically significant order (0.016"×0.022"<0.018"×0.025"<0.019"×0.025") for stainless steel wire material. Finite element modeling simulation showed the increasing effect of active clip force on friction especially for 0.025" wire profiles. If compared to NiTi wires, stainless steel archwires delivered higher friction. Combinations between wire-type and ligation should be chosen carefully for the intended treatment step.