SwinCross: Cross-modal Swin transformer for head-and-neck tumor segmentation in PET/CT images.

BACKGROUND: Radiotherapy (RT) combined with cetuximab is the standard treatment for patients with inoperable head and neck cancers. Segmentation of head and neck (H&N) tumors is a prerequisite for radiotherapy planning but a time-consuming process. In recent years, deep convolutional neural networks (DCNN) have become the de facto standard for automated image segmentation. However, due to the expensive computational cost associated with enlarging the field of view in DCNNs, their ability to model long-range dependency is still limited, and this can result in sub-optimal segmentation performance for objects with background context spanning over long distances. On the other hand, Transformer models have demonstrated excellent capabilities in capturing such long-range information in several semantic segmentation tasks performed on medical images. PURPOSE: Despite the impressive representation capacity of vision transformer models, current vision transformer-based segmentation models still suffer from inconsistent and incorrect dense predictions when fed with multi-modal input data. We suspect that the power of their self-attention mechanism may be limited in extracting the complementary information that exists in multi-modal data. To this end, we propose a novel segmentation model, debuted, Cross-modal Swin Transformer (SwinCross), with cross-modal attention (CMA) module to incorporate cross-modal feature extraction at multiple resolutions. METHODS: We propose a novel architecture for cross-modal 3D semantic segmentation with two main components: (1) a cross-modal 3D Swin Transformer for integrating information from multiple modalities (PET and CT), and (2) a cross-modal shifted window attention block for learning complementary information from the modalities. To evaluate the efficacy of our approach, we conducted experiments and ablation studies on the HECKTOR 2021 challenge dataset. We compared our method against nnU-Net (the backbone of the top-5 methods in HECKTOR 2021) and other state-of-the-art transformer-based models, including UNETR and Swin UNETR. The experiments employed a five-fold cross-validation setup using PET and CT images. RESULTS: Empirical evidence demonstrates that our proposed method consistently outperforms the comparative techniques. This success can be attributed to the CMA module's capacity to enhance inter-modality feature representations between PET and CT during head-and-neck tumor segmentation. Notably, SwinCross consistently surpasses Swin UNETR across all five folds, showcasing its proficiency in learning multi-modal feature representations at varying resolutions through the cross-modal attention modules. CONCLUSIONS: We introduced a cross-modal Swin Transformer for automating the delineation of head and neck tumors in PET and CT images. Our model incorporates a cross-modality attention module, enabling the exchange of features between modalities at multiple resolutions. The experimental results establish the superiority of our method in capturing improved inter-modality correlations between PET and CT for head-and-neck tumor segmentation. Furthermore, the proposed methodology holds applicability to other semantic segmentation tasks involving different imaging modalities like SPECT/CT or PET/MRI. Code:https://github.com/yli192/SwinCross_CrossModalSwinTransformer_for_Medical_Image_Segmentation.

Spach Transformer: Spatial and Channel-wise Transformer Based on Local and Global Self-attentions for PET Image Denoising.

Position emission tomography (PET) is widely used in clinics and research due to its quantitative merits and high sensitivity, but suffers from low signal-to-noise ratio (SNR). Recently convolutional neural networks (CNNs) have been widely used to improve PET image quality. Though successful and efficient in local feature extraction, CNN cannot capture long-range dependencies well due to its limited receptive field. Global multi-head self-attention (MSA) is a popular approach to capture long-range information. However, the calculation of global MSA for 3D images has high computational costs. In this work, we proposed an efficient spatial and channel-wise encoder-decoder transformer, Spach Transformer, that can leverage spatial and channel information based on local and global MSAs. Experiments based on datasets of different PET tracers, i.e., 18F-FDG, 18F-ACBC, 18F-DCFPyL, and 68Ga-DOTATATE, were conducted to evaluate the proposed framework. Quantitative results show that the proposed Spach Transformer framework outperforms state-of-the-art deep learning architectures.

Correction: Kim et al. Mito-TIPTP Increases Mitochondrial Function by Repressing the Rubicon-p22phox Interaction in Colitis-Induced Mice. Antioxidants 2021, 10, 1954.

In the original publication [...].

Identification of ulcerative colitis-specific immune cell signatures from public single-cell RNA-seq data.

BACKGROUND: Single-cell RNA-seq enabled microscopic studies on tissue microenvironment of many diseases. Inflammatory bowel disease, an autoimmune disease, is involved with various dysfunction of immune cells, for which single-cell RNA-seq may provide us a deeper insight into the causes and mechanism of this complex disease. OBJECTIVE: In this work, we used public single-cell RNA-seq data to study tissue microenvironment around ulcerative colitis, an inflammatory bowel disease causing chronic inflammation and ulcers in large intestine. METHODS: Since not all the datasets provide cell-type annotations, we first identified cell identities to select cell populations of our interest. Differentially expressed genes and gene set enrichment analysis was then performed to infer the polarization/activation state of macrophages and T cells. Cell-to-cell interaction analysis was also performed to discover distinct interactions in ulcerative colitis. RESULTS: Differentially expressed genes analysis of the two datasets confirmed the regulation of CTLA4, IL2RA, and CCL5 genes in the T cell subset and regulation of S100A8/A9, CLEC10A genes in macrophages. Cell-to-cell interaction analysis showed CD4+ T cells and macrophages interact actively to each other. We also identified IL-18 pathway activation in inflammatory macrophages, evidence that CD4+ T cells induce Th1 and Th2 differentiation, and also found that macrophages regulate T cell activation through different ligand-receptor pairs, viz. CD86-CTL4, LGALS9-CD47, SIRPA-CD47, and GRN-TNFRSF1B. CONCLUSION: Analysis of these immune cell subsets may suggest novel strategies for the treatment of inflammatory bowel disease.

Inhibition of CD82 improves colitis by increasing NLRP3 deubiquitination by BRCC3.

CD82 is a transmembrane protein that is involved in cancer suppression and activates immune cells; however, information on the NLRP3 inflammasome is limited. Herein, we show that although CD82 suppressed the activation of the NLRP3 inflammasome in vivo and in vitro, CD82 deficiency decreased the severity of colitis in mice. Furthermore, two binding partners of CD82, NLRP3 and BRCC3, were identified. CD82 binding to these partners increased the degradation of NLRP3 by blocking BRCC3-dependent K63-specific deubiquitination. Previous studies have shown that CD82-specific bacteria in the colon microbiota called Bacteroides vulgatus (B. vulgatus) regulated the expression of CD82 and promoted the activation of the NLRP3 inflammasome. Accordingly, we observed that B. vulgatus administration increased mouse survival by mediating CD82 expression and activating NLRP3 in mice with colitis. Overall, this study showed that CD82 suppression reduced the pathogenesis of colitis by elevating the activation of the NLRP3 inflammasome through BRCC3-dependent K63 deubiquitination. Based on our findings, we propose that B. vulgatus is a novel therapeutic candidate for colitis.

Colon-Targeted eNAMPT-Specific Peptide Systems for Treatment of DSS-Induced Acute and Chronic Colitis in Mouse.

Nicotinamide phosphoribosyl transferase (NAMPT) is required to maintain the NAD+ pool, among which extracellular (e) NAMPT is associated with inflammation, mainly mediated by macrophages. However, the role of (e) NAMPT in inflammatory macrophages in ulcerative colitis is insufficiently understood. Here our analyses of single-cell RNA-seq data revealed that the levels of NAMPT and CYBB/NOX2 in macrophages were elevated in patients with colitis and in mouse models of acute and chronic colitis. These findings indicate the clinical significance of NAMPT and CYBB in colitis. Further, we found that eNAMPT directly binds the extracellular domains of CYBB and TLR4 in activated NLRP3 inflammasomes. Moreover, we developed a recombinant 12-residue TK peptide designated colon-targeted (CT)-conjugated multifunctional NAMPT (rCT-NAMPT), comprising CT as the colon-targeting moiety, which harbors the minimal essential residues required for CYBB/TLR4 binding. rCT-NAMPT effectively suppressed the severity of disease in DSS-induced acute and chronic colitis models through targeting the colon and inhibiting the interaction of NAMPT with CYBB or TLR4. Together, our data show that rCT-NAMPT may serve as an effective novel candidate therapeutic for colitis by modulating the NLRP3 inflammasome-mediated immune signaling system.

One-pot bifunctionalization of silica nanoparticles conjugated with bioorthogonal linkers: application in dual-modal imaging.

Covalent surface modification of silica nanoparticles (SNPs) offers great potential for the development of multimodal nanomaterials for biomedical applications. Herein, we report the synthesis of covalently conjugated bifunctional SNPs and their application to in vivo multimodal imaging. Bis(methallyl)silane 15 with cyclopropene and maleimide, designed as a stable bifunctional linker, was efficiently synthesized by traceless Staudiger ligation, and subsequently introduced onto the surface of monodispersed SNPs via Sc(OTf)3-catalyzed siloxane formation. The bifunctional linker-grafted SNP 20 underwent both thiol-conjugated addition and tetrazine cycloaddition in one pot. Finally, positron emission tomography/computed tomography and fluorescence imaging study of dual functional SNP [125I]28 labeled with NIR dye and 125I isotope showed a prolonged circulation in mice, which is conducive to the systemic delivery of therapeutics.

PE_PGRS38 Interaction With HAUSP Downregulates Antimycobacterial Host Defense via TRAF6.

Mycobacterium tuberculosis (Mtb) is the causative pathogen of tuberculosis (TB), which manipulates the host immunity to ensure survival and colonization in the host. Mtb possess a unique family of proteins, named PE_PGRS, associated with Mtb pathogenesis. Thus, elucidation of the functions of PE_PGRS proteins is necessary to understand TB pathogenesis. Here, we investigated the role of PE_PGRS38 binding to herpesvirus-associated ubiquitin-specific protease (HAUSP, USP7) in regulating the activity of various substrate proteins by modulating their state of ubiquitination. We constructed the recombinant PE_PGRS38 expressed in M. smegmatis (Ms_PE_PGRS38) to investigate the role of PE_PGRS38. We found that Ms_PE_PGRS38 regulated the cytokine levels in murine bone marrow-derived macrophages by inhibiting the deubiquitination of tumor necrosis factor receptor-associated factor (TRAF) 6 by HAUSP. Furthermore, the PE domain in PE_PGRS38 was identified as essential for mediating TRAF6 deubiquitination. Ms_PE_PGRS38 increased the intracellular burden of bacteria by manipulating cytokine levels in vitro and in vivo. Overall, we revealed that the interplay between HAUSP and PE_PGRS38 regulated the inflammatory response to increase the survival of mycobacteria.

Discovery of Mycobacterium tuberculosis Rv3364c-Derived Small Molecules as Potential Therapeutic Agents to Target SNX9 for Sepsis.

The serine protease inhibitor Rv3364c of Mycobacterium tuberculosis (MTB) is highly expressed in cells during MTB exposure. In this study, we showed that the 12WLVSKF17 motif of Rv3364c interacts with the BAR domain of SNX9 and inhibits endosome trafficking to interact with p47phox, thereby suppressing TLR4 inflammatory signaling in macrophages. Derived from the structure of this Rv3364c peptide motif, 2,4-diamino-6-(4-tert-butylphenyl)-1,3,5-trazine, DATPT as a 12WLVSKF17 peptide-mimetic small molecule has been identified. DATPT can block the SNX9-p47phox interaction in the endosome and suppress reactive oxygen species and inflammatory cytokine production; it demonstrated significant therapeutic effects in a mouse model of cecal ligation and puncture-induced sepsis. DATPT has considerably improved potency, with an IC50 500-fold (in vitro) or 2000-fold (in vivo) lower than that of the 12WLVSKF17 peptide. Furthermore, DATPT shows potent antibacterial activities by reduction in ATP production and leakage of intracellular ATP out of bacteria. These results provide evidence for peptide-derived small molecule DATPT with anti-inflammatory and antibacterial functions for the treatment of sepsis.

Mito-TIPTP Increases Mitochondrial Function by Repressing the Rubicon-p22phox Interaction in Colitis-Induced Mice.

The run/cysteine-rich-domain-containing Beclin1-interacting autophagy protein (Rubicon) is essential for the regulation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase by interacting with p22phox to trigger the production of reactive oxygen species (ROS) in immune cells. In a previous study, we demonstrated that the interaction of Rubicon with p22phox increases cellular ROS levels. The correlation between Rubicon and mitochondrial ROS (mtROS) is poorly understood. Here, we report that Rubicon interacts with p22phox in the outer mitochondrial membrane in macrophages and patients with human ulcerative colitis. Upon lipopolysaccharide (LPS) activation, the binding of Rubicon to p22phox was elevated, and increased not only cellular ROS levels but also mtROS, with an impairment of mitochondrial complex III and mitochondrial biogenesis in macrophages. Furthermore, increased Rubicon decreases mitochondrial metabolic flux in macrophages. Mito-TIPTP, which is a p22phox inhibitor containing a mitochondrial translocation signal, enhances mitochondrial function by inhibiting the association between Rubicon and p22phox in LPS-primed bone-marrow-derived macrophages (BMDMs) treated with adenosine triphosphate (ATP) or dextran sulfate sodium (DSS). Remarkably, Mito-TIPTP exhibited a therapeutic effect by decreasing mtROS in DSS-induced acute or chronic colitis mouse models. Thus, our findings suggest that Mito-TIPTP is a potential therapeutic agent for colitis by inhibiting the interaction between Rubicon and p22phox to recover mitochondrial function.

Multi-Functional MPT Protein as a Therapeutic Agent against Mycobacterium tuberculosis.

Mycobacterium tuberculosis (MTB), the causative agent of tuberculosis (TB), avoids the host immune system through its virulence factors. MPT63 and MPT64 are the virulence factors secreted by MTB which regulate host proteins for the survival and proliferation of MTB in the host. Here, we found that MPT63 bound directly with TBK1 and p47phox, whereas MPT64 interacted with TBK1 and HK2. We constructed a MPT63/64-derived multifunctional recombinant protein (rMPT) that was able to interact with TBK1, p47phox, or HK2. rMPT was shown to regulate IFN-ß levels and increase inflammation and concentration of reactive oxygen species (ROS), while targeting macrophages and killing MTB, both in vitro and in vivo. Furthermore, the identification of the role of rMPT against MTB was achieved via vaccination in a mouse model. Taken together, we here present rMPT, which, by regulating important immune signaling systems, can be considered an effective vaccine or therapeutic agent against MTB.

Electroacupuncture and Manual Acupuncture Increase Joint Flexibility but Reduce Muscle Strength.

The objective of this study was to investigate the immediate effects of electroacupuncture and manual acupuncture on hip flexion range of motion (ROM), knee joint (flexion replication at 15° and 45°) and quadriceps (strength and activation) function. Forty-five neurologically healthy adults participated in this randomized controlled laboratory study. Straight leg raise test, modified Thomas test, and hip abductors strength test were performed to determine acupoints. Afterwards, one of three 15-min treatments (control-no treatment, electroacupuncture, or manual acupuncture) was randomly applied using determined acupoints. Measurements (hip flexion ROM, and knee joint and quadriceps function) were recorded at baseline, and at 0, 20, and 40 min post treatment. Both electroacupuncture (4.0°, ES = 0.41) and manual acupuncture (5.4°, ES = 0.95) treatment immediately increased hip flexion ROM, and the increased values persisted for 40-min (p = 0.01). Knee flexion replication (at 15°: p = 0.17; 45°: p = 0.19) and quadriceps activation (p = 0.71) did not change at any of the time points. Post-treatment, both electroacupuncture and manual acupuncture decreased quadriceps strength at 0-min (electroacupuncture: 9.2%, p < 0.0001, ES = 0.60) and 40-min (electroacupuncture: 7.3%, p = 0.005, ES = 0.55; manual acupuncture: 8.7%, p = 0.01, ES = 0.54). A single session of either electroacupuncture or manual acupuncture treatment (selected acupoints based on physical examination) may immediately improve joint flexibility but reduce muscle strength.