Active Targeting Hyaluronan Conjugated Nanoprobe for Magnetic Particle Imaging and Near-Infrared Fluorescence Imaging of Breast Cancer and Lung Metastasis.

A major contributing cause to breast cancer related death is metastasis. Moreover, breast cancer metastasis often shows little symptoms until a large area of the organs is occupied by metastatic cancer cells. Breast cancer multimodal imaging is attractive since it integrates advantages from several modalities, enabling more accurate cancer detection. Glycoprotein CD44 is overexpressed on most breast cancer cells and is the primary cell surface receptor for hyaluronan (HA). To facilitate breast cancer diagnosis, we report an indocyanine green (ICG) and HA conjugated iron oxide nanoparticle (NP-ICG-HA), which enabled active targeting to breast cancer by HA-CD44 interaction and detected metastasis with magnetic particle imaging (MPI) and near-infrared fluorescence imaging (NIR-FI). When evaluated in a transgenic breast cancer mouse model, NP-ICG-HA enabled the detection of multiple breast tumors in MPI and NIR-FI, providing more comprehensive images and a diagnosis of breast cancer. Furthermore, NP-ICG-HAs were evaluated in a lung metastasis model. Upon NP-ICG-HA administration, MPI showed clear signals in the lungs, indicating the tumor sites. This is the first time that HA-based NPs have enabled MPI of cancer. NP-ICG-HAs are an attractive platform for noninvasive detection of primary breast cancer and lung metastasis.

The HSP40 family chaperone isoform DNAJB6b prevents neuronal cells from tau aggregation.

BACKGROUND: Alzheimer's disease (AD) is the most common neurodegenerative disorder with clinical presentations of progressive cognitive and memory deterioration. The pathologic hallmarks of AD include tau neurofibrillary tangles and amyloid plaque depositions in the hippocampus and associated neocortex. The neuronal aggregated tau observed in AD cells suggests that the protein folding problem is a major cause of AD. J-domain-containing proteins (JDPs) are the largest family of cochaperones, which play a vital role in specifying and directing HSP70 chaperone functions. JDPs bind substrates and deliver them to HSP70. The association of JDP and HSP70 opens the substrate-binding domain of HSP70 to help the loading of the clients. However, in the initial HSP70 cycle, which JDP delivers tau to the HSP70 system in neuronal cells remains unclear. RESULTS: We screened the requirement of a diverse panel of JDPs for preventing tau aggregation in the human neuroblastoma cell line SH-SY5Y by a filter retardation method. Interestingly, knockdown of DNAJB6, one of the JDPs, displayed tau aggregation and overexpression of DNAJB6b, one of the isoforms generated from the DNAJB6 gene by alternative splicing, reduced tau aggregation. Further, the tau bimolecular fluorescence complementation assay confirmed the DNAJB6b-dependent tau clearance. The co-immunoprecipitation and the proximity ligation assay demonstrated the protein-protein interaction between tau and the chaperone-cochaperone complex. The J-domain of DNAJB6b was critical for preventing tau aggregation. Moreover, reduced DNAJB6 expression and increased tau aggregation were detected in an age-dependent manner in immunohistochemical analysis of the hippocampus tissues of a mouse model of tau pathology. CONCLUSIONS: In summary, downregulation of DNAJB6b increases the insoluble form of tau, while overexpression of DNAJB6b reduces tau aggregation. Moreover, DNAJB6b associates with tau. Therefore, this study reveals that DNAJB6b is a direct sensor for its client tau in the HSP70 folding system in neuronal cells, thus helping to prevent AD.

Goldilocks principle of minimally invasive surgery for gastric subepithelial tumors.

BACKGROUND: Minimally invasive surgery had been tailored to individual cases of gastric subepithelial tumors (SETs) after comparing the clinical outcomes of endoscopic resection (ER), laparoscopic resection (LR), and hybrid methods. AIM: To study the use of Goldilocks principle to determine the best form of minimally invasive surgery for gastric SETs. METHODS: In this retrospective study, 194 patients of gastric SETs with high probability of surgical intervention were included. All patients underwent tumor resection in the operating theater between January 2013 and December 2021. The patients were divided into two groups, ER or LR, according to the tumor characteristics and the initial intent of intervention. Few patients in the ER group required further backup laparoscopic surgery after an incomplete ER. The patients who had converted open surgery were excluded. A logistic regression model was used to assess the associations between patient characteristics and the likelihood of a treatment strategy. The area under the curve was used to assess the discriminative ability of tumor size and Youden's index to determine the optimal cut-off tumor size. RESULTS: One-hundred ninety-four patients (100 in the ER group and 94 in the LR group) underwent tumor resection in the operating theater. In the ER group, 27 patients required backup laparoscopic surgery after an incomplete ER. The patients in the ER group had small tumor sizes and shorter procedure durations while the patients in the LR group had large tumor sizes, exophytic growth, malignancy, and tumors that were more often located in the middle or lower third of the stomach. Both groups had similar durations of hospital stays and a similar rate of major postoperative complications. The patients in the ER group who underwent backup surgery required longer procedures (56.4 min) and prolonged stays (2 d) compared to the patients in the LR group without the increased rate of major postoperative complications. The optimal cut-off point for the tumor size for laparoscopic surgery was 2.15 cm. CONCLUSION: Multidisciplinary teamwork leads to the adoption of different strategies to yield efficient clinical outcomes according to the tumor characteristics.

Recurrent and convolutional neural networks for sequential multispectral optoacoustic tomography (MSOT) imaging.

Multispectral optoacoustic tomography (MSOT) is a beneficial technique for diagnosing and analyzing biological samples since it provides meticulous details in anatomy and physiology. However, acquiring high through-plane resolution volumetric MSOT is time-consuming. Here, we propose a deep learning model based on hybrid recurrent and convolutional neural networks to generate sequential cross-sectional images for an MSOT system. This system provides three modalities (MSOT, ultrasound, and optoacoustic imaging of a specific exogenous contrast agent) in a single scan. This study used ICG-conjugated nanoworms particles (NWs-ICG) as the contrast agent. Instead of acquiring seven images with a step size of 0.1 mm, we can receive two images with a step size of 0.6 mm as input for the proposed deep learning model. The deep learning model can generate five other images with a step size of 0.1 mm between these two input images meaning we can reduce acquisition time by approximately 71%.

Super-resolution and segmentation deep learning for breast cancer histopathology image analysis.

Traditionally, a high-performance microscope with a large numerical aperture is required to acquire high-resolution images. However, the images' size is typically tremendous. Therefore, they are not conveniently managed and transferred across a computer network or stored in a limited computer storage system. As a result, image compression is commonly used to reduce image size resulting in poor image resolution. Here, we demonstrate custom convolution neural networks (CNNs) for both super-resolution image enhancement from low-resolution images and characterization of both cells and nuclei from hematoxylin and eosin (H&E) stained breast cancer histopathological images by using a combination of generator and discriminator networks so-called super-resolution generative adversarial network-based on aggregated residual transformation (SRGAN-ResNeXt) to facilitate cancer diagnosis in low resource settings. The results provide high enhancement in image quality where the peak signal-to-noise ratio and structural similarity of our network results are over 30 dB and 0.93, respectively. The derived performance is superior to the results obtained from both the bicubic interpolation and the well-known SRGAN deep-learning methods. In addition, another custom CNN is used to perform image segmentation from the generated high-resolution breast cancer images derived with our model with an average Intersection over Union of 0.869 and an average dice similarity coefficient of 0.893 for the H&E image segmentation results. Finally, we propose the jointly trained SRGAN-ResNeXt and Inception U-net Models, which applied the weights from the individually trained SRGAN-ResNeXt and inception U-net models as the pre-trained weights for transfer learning. The jointly trained model's results are progressively improved and promising. We anticipate these custom CNNs can help resolve the inaccessibility of advanced microscopes or whole slide imaging (WSI) systems to acquire high-resolution images from low-performance microscopes located in remote-constraint settings.

Combinatorial synthesis of a hyaluronan based polysaccharide library for enhanced CD44 binding.

Hyaluronan (HA) plays important roles in a wide range of biological events. The principal receptor of HA in the human body is the Cluster of Differentiation 44 (CD44). To enhance the binding between HA and CD44, a new approach was designed to take advantage of the four-component Ugi reaction. By modifying the carboxyl group on HA with various amine, aldehyde, and isocyanide moieties through the Ugi reaction, 36 HA like polysaccharides were generated. Two lead compounds were identified with enhanced CD44 binding compared to unmodified HA, which was confirmed by surface plasmon resonance (SPR), cellular studies and an in vivo mouse tumor model. Ski-learn as a machine learning tool was applied to analyze library data and yield predictions with an accuracy over 80 %. In conclusion, modification of HA via the Ugi reaction can be a promising strategy to develop novel binders toward HA receptors such as CD44.

Indocyanine Green-Conjugated Superparamagnetic Iron Oxide Nanoworm for Multimodality Breast Cancer Imaging.

Breast cancer is the leading cause of cancer-associated deaths among women. Techniques for non-invasive breast cancer detection and imaging are urgently needed. Multimodality breast cancer imaging is attractive since it can integrate advantages from several modalities, enabling more accurate cancer detection. In order to accomplish this, indocyanine green (ICG)-conjugated superparamagnetic iron oxide nanoworm (NW-ICG) has been synthesized as a contrast agent. When evaluated in a spontaneous mouse breast cancer model, NW-ICG gave a large tumor to normal tissue contrasts in multiple imaging modalities including magnetic particle imaging, near-infrared fluorescence imaging, and photoacoustic imaging, providing more comprehensive detection and imaging of breast cancer. Thus, NW-ICGs are an attractive platform for non-invasive breast cancer diagnosis.

Comparison Between Same-Day and Split-Dose Preparations with Sodium Picosulfate/Magnesium Citrate: A Randomized Noninferiority Study.

BACKGROUND: Sodium picosulfate/magnesium citrate (SPMC) is a small-volume bowel cleansing agent with similar efficacy to and better tolerability than polyethylene glycol. However, we found no data on which SPMC preparation (same-day vs. split-dose) provides better bowel cleansing efficacy for afternoon colonoscopy. AIMS: To compare bowel cleansing efficacy of different timing of the regimen. METHODS: This randomized, single-center, endoscopist-blinded, noninferior study compared same-day and split-dose SPMC preparations for afternoon colonoscopy in 101 and 96 patients, respectively. We also included a prospective observation group of 100 patients receiving morning colonoscopy to compare bowel preparation between morning and afternoon colonoscopies. Bowel cleansing efficacy was then evaluated by the Aronchick Scale, Ottawa Bowel Preparation Scale (OBPS), Boston Bowel Preparation Scale (BBPS), and the Bubble Scale. RESULTS: Same-day and split-dose preparations were similar in efficacy in all four scales. In the Aronchick Scale, the success rate (excellent and good cleanliness) was higher in same-day preparation than in split-dose preparation (100% vs. 92.8%). The same-day preparation also obtained a better OBPS score (1.4 vs. 2.1), but BBPS showed no difference between such groups (7.7 vs. 7.4). CONCLUSION: Same-day preparation with SPMC is not inferior to split-dose preparation for afternoon colonoscopy.

Upper endoscopy photodocumentation quality evaluation with novel deep learning system.

OBJECTIVES: Visualization and photodocumentation during endoscopy procedures are suggested to be one indicator for endoscopy performance quality. However, this indicator is difficult to measure and audit manually in clinical practice. Artificial intelligence (AI) is an emerging technology that may solve this problem. METHODS: A deep learning model with an accuracy of 96.64% was developed from 15,305 images for upper endoscopy anatomy classification in the unit. Endoscopy images for asymptomatic patients receiving screening endoscopy were evaluated with this model to assess the completeness of photodocumentation rate. RESULTS: A total of 15,723 images from 472 upper endoscopies performed by 12 endoscopists were enrolled. The complete photodocumentation rate from the pharynx to the duodenum was 53.8% and from the esophagus to the duodenum was 78.0% in this study. Endoscopists with a higher adenoma detection rate had a higher complete examination rate from the pharynx to duodenum (60.0% vs. 38.7%, P < 0.0001) and from esophagus to duodenum (83.0% vs. 65.7%, P < 0.0001) compared with endoscopists with lower adenoma detection rate. The pharynx, gastric angle, gastric retroflex view, gastric antrum, and the first portion of duodenum are likely to be missed by endoscopists with lower adenoma detection rates. CONCLUSIONS: We report the use of a deep learning model to audit endoscopy photodocumentation quality in our unit. Endoscopists with better performance in colonoscopy had a better performance for this quality indicator. The use of such an AI system may help the endoscopy unit audit endoscopy performance.

A Nomogram for Predicting Laparoscopic and Endoscopic Cooperative Surgery during the Endoscopic Resection of Subepithelial Tumors of the Upper Gastrointestinal Tract.

BACKGROUND: Considering the widespread use of esophagogastroduodenoscopy, the prevalence of upper gastrointestinal (GI) subepithelial tumors (SET) increases. For relatively safer removal of upper GI SETs, endoscopic submucosal dissection (ESD) has been developed as an alternative to surgery. This study aimed to analyze the outcome of endoscopic resection for SETs and develop a prediction model for the need for laparoscopic and endoscopic cooperative surgery (LECS) during the procedure. METHOD: We retrospectively analyzed 123 patients who underwent endoscopic resection for upper GI SETs between January 2012 and December 2020 at our institution. Intraoperatively, they underwent ESD or submucosal tunneling endoscopic resection (STER). RESULTS: ESD and STER were performed in 107 and 16 patients, respectively. The median age was 55 years, and the average tumor size was 1.5 cm. En bloc resection was achieved in 114 patients (92.7%). The median follow-up duration was 242 days without recurrence. Perforation occurred in 47 patients (38.2%), and 30 patients (24.4%) underwent LECS. Most perforations occurred in the fundus. Through multivariable analysis, we built a nomogram that can predict LECS requirement according to tumor location, size, patient age, and sex. The prediction model exhibited good discrimination ability, with an area under the curve (AUC) of 0.893. CONCLUSIONS: Endoscopic resection is a noninvasive procedure for small upper-GI SETs. Most perforations can be successfully managed endoscopically. The prediction model for LECS requirement is useful in treatment planning.

Endoscopic Resection for Gastric Subepithelial Tumor with Backup Laparoscopic Surgery: Description of a Single-Center Experience.

The aim of this study was to analyze patients who underwent endoscopic resection (ER) for gastric subepithelial tumors (SETs) with a high probability of surgical intervention. Between January 2013 and January 2021, 83 patients underwent ER at the operation theater and 27 patients (32.5%) required backup surgery mainly due to incidental perforation or uncontrolled bleeding despite endoscopic repairing. The tumor was predominantly located in the upper-third stomach (81%) with a size ≤ 2 cm (69.9%) and deep to the muscularis propria (MP) layer (92.8%) but there were no significant differences between two groups except tumor exophytic growth as a risk factor in the surgery group (37% vs. 0%, p < 0.0001). Patients in the ER-only group had shorter durations of procedure times (60 min vs. 185 min, p < 0.0001) and lengths of stay (5 days vs. 7 days, p < 0.0001) but with a higher percentage of overall morbidity graded III (0% vs. 7.1%, p = 0.1571). After ER, five patients (6%) had delayed perforation and two (2.4%) required emergent laparoscopic surgery. Neither recurrence nor gastric stenosis was reported during long-term surveillance. Here, we provide a minimally invasive strategy of endoscopic resection with backup laparoscopic surgery for gastric SETs.

Formation and Near-Infrared Emission of CsPbI3 Nanoparticles Embedded in Cs4PbI6 Crystals.

Cs4PbI6, as a rarely investigated member of the Cs4PbX6 (X is a halogen element) family, has been successfully synthesized at low temperatures, and the synthetic conditions have been optimized. Metal iodides such as LiI, KI, NiI2, CoI2, and ZnI2, as additives, play an important role in enhancing the formation of the Cs4PbI6 microcrystals. ZnI2 with the lowest dissociation energy is the most efficient additive to supply iodide ions, and its amount of addition has also been optimized. Strong red to near-infrared (NIR) emission properties have been detected, and its optical emission centers have been identified to be numerous embedded perovskite-type α-CsPbI3 nanocrystallites (∼5 nm in diameter) based on investigations of temperature- and pressure-dependent photoluminescent properties. High-resolution transmission electron microscopy was used to detect these hidden nanoparticles, although the material was highly beam-sensitive and confirmed a "raisin bread"-like structure of the Cs4PbI6 crystals. A NIR mini-LED for the biological application has been successfully fabricated using as-synthesized Cs4PbI6 crystals. This work provides information for the future development of infrared fluorescent nanoscale perovskite materials.

Nuclear envelope tethering inhibits the formation of ALT-associated PML bodies in ALT cells.

Telomere length homeostasis is essential for maintaining genomic stability and cancer proliferation. Telomerase-negative cancer cells undergo recombination-mediated alternative lengthening of telomeres. Telomeres associate with the nuclear envelope through the shelterin RAP1 and nuclear envelope SUN1 proteins. However, how the associations between telomeres and the nuclear envelope affect the progression of telomere recombination is not understood. Here, we show that telomere anchorage might inhibit telomere-telomere recombination. SUN1 depletion stimulates the formation of alternative lengthening of telomeres-associated promyelocytic leukemia bodies in ALT cells. In contrast, overexpression of a telomere-nuclear envelope-tethering chimera protein, RAP1-SUN1, suppresses APB formation. Moreover, inhibition of this nuclear envelope attachment alleviates the requirement of TOP3α for resolving the supercoiling pressure during telomere recombination. A coimmunoprecipitation assay revealed that the SUN1 N-terminal nucleoplasmic domain interacts with the RAP1 middle coil domain, and phosphorylation-mimetic mutations in RAP1 inhibit this interaction. However, abolishing the RAP1-SUN1 interaction does not hinder APB formation, which hints at the existence of another SUN1-dependent telomere anchorage pathway. In summary, our results reveal an inhibitory role of telomere-nuclear envelope association in telomere-telomere recombination and imply the presence of redundant pathways for the telomere-nuclear envelope association in ALT cells.

Intercostal Nerve Block Using an Innovative Intraneedle Ultrasound Transducer: A Proof-of-Concept study.

Intercostal nerve block is a widely used and effective approach to providing regional anesthesia in the thoracic region for pain relief. However, during ultrasound-guided intercostal nerve block, inaccurate identification of the anatomic structures or suboptimal positioning of the needle tip may result in complications and blockade failure. In this study, we designed an intraneedle ultrasound (INUS) system and validated its efficacy in identifying anatomic structures relevant to thoracic region anesthesia. The 20-MHz INUS transducer comprised a single lead magnesium niobate-lead titanate crystal, and gain was set to 20 dB. It fit into a regular 18G needle and emitted radiofrequency-mode ultrasound signals at 1 mm from the needle tip. One hundred intercostal punctures were performed in 10 piglets. Intercostal spaces were identified by surface ultrasound or palpation and located by inserting and advancing the INUS transducer needle until the appropriate anatomy was identified. Blockade success was defined by ideal saline and dye spreading and confirmed by dissection. The pleura had a distinctive ultrasound signal, and successful detection of the intercostal muscles, endothoracic fascia and double-layered parietal and visceral pleura was achieved in all 100 puncture attempts. INUS allows real-time identification of intercostal structures and facilitates successful intercostal nerve blocks.

Direct-acting antiviral treatment for Hepatitis C Virus in geriatric patients: a real-world retrospective comparison between early and late elderly patients.

INTRODUCTION: Chronic hepatitis C virus (HCV) infection rates are high in the geriatric population considering that interferon-based therapy is usually intolerable. With the introduction of oral antiviral therapy for HCV, increased treatment tolerability and good treatment responses have been observed. However, treatment data regarding the geriatric population have been limited. Therefore, this retrospective study aimed to evaluate the efficacy and safety of direct-acting antiviral therapy for HCV in the geriatric population. MATERIALS AND METHODS: The primary end point was sustained virologic response (SVR) 12 weeks after treatment completion, whereas the secondary end points were treatment-related side effects and short-term survival rate following treatment. RESULTS: In total, 492 patients (median age, 73 years; 43.9% males), including 278 early elderly patients, were enrolled. Among the included patients, 45% had cirrhosis. HCV genotypes 1 (72.4%) and 2 (25.4%) were the most common. The overall SVR rate was 96.7%, with no difference in SVR rates observed between early and late elderly groups (96.8% vs. 96.7%; p = 0.983). Both groups showed similar side effects, including dizziness (11.4%), and fatigue (8.7%), with three patients discontinuing therapy owing to side effects. Both groups had a similar 3-year survival rate. Significant factors associated with post-treatment survival included cirrhosis, albumin, and creatinine level. CONCLUSIONS: Our real-world data showed that both early and late elderly patients could undergo direct-acting antiviral treatment for HCV with excellent treatment outcomes.

Long-Range Stereodirecting Participation across a Glycosidic Linkage in Glycosylation Reactions.

The formation of an unprecedented 12-membered macrocyclic ketal through the long-range participation of a levulinoyl group across a glycosidic linkage was observed in glycosylation reactions. This finding indicated that stereodirecting participation is not limited to groups within the glycan ring being activated, thus broadening the scope of remote group participation in glycosylation.

Glecaprevir-pibrentasvir for chronic hepatitis C: Comparing treatment effect in patients with and without end-stage renal disease in a real-world setting.

INTRODUCTION: Chronic hepatitis C virus (HCV) infection is increasingly observed in patients with renal disease. With the introduction of glecaprevir/pibrentasvir (GLE/PIB) as a pan-genotype therapy for HCV, treatment efficacy is expected to rise. MATERIALS AND METHODS: This retrospective study evaluated the efficacy and safety of GLE/PIB treatment in adults with HCV infection and end-stage renal disease (ESRD). The primary end point was sustained virological response (SVR) observed 12 weeks after completed treatment. RESULTS: We enrolled 235 patients, including 44 patients with ESRD. Median age was 60 years, and 48% were males. Twenty-two percent had cirrhosis. HCV genotypes 1 (43%) and 2 (41%) were the most common. The overall SVR rate was 96.6%. Patients with ESRD were older than those without (67.6 years vs 58.3 years, p < 0.001) and trended toward having a higher prevalence of cirrhosis (32% vs 19%, p = 0.071). A significant proportion of patients with ESRD complained of skin itching during treatment (61% vs 26%, p < 0.001), and the SVR rate were similar between these two groups (95.45% vs 96.86%, p = 0.644). CONCLUSIONS: Despite a higher rate of pruritus among patients with ESRD, GLE/PIB-based therapy achieved similarly high SVR rates among patients with and without ESRD.

Broadband Cr3+ , Sn4+ -Doped Oxide Nanophosphors for Infrared Mini Light-Emitting Diodes.

Light-emitting diodes break barriers of size and performance for displays. With devices becoming smaller, the materials also need to get smaller. Chromium(III)-doped oxide phosphors, which emit near-infrared (NIR) light, have recently been used in small electronic devices. In this work, mesoporous silica nanoparticles were used as nanocarriers. The nanophosphor ZnGa2 O4 :Cr3+ ,Sn4+ formed in the mesopore after sintering. Good dispersity and morphology were performed with average diameters of 71±7 nm. It emitted light at 600-850 nm; the intensity was optimized by tuning the doping ratio of Cr3+ and Sn4+ . Meanwhile, the light conversion efficiency increased from 7.8 % to 37 % and the molar concentration increased from 0.125 m to 0.5 m. The higher radiant flux of 3.3 mW was obtained by operating an input current of 45 mA. However, the NIR nanophosphor showed good performance on mini light-emitting diode chips.