Colposcopy is widely used to detect cervical cancers, but experienced physicians who are needed for an accurate diagnosis are lacking in developing countries. Artificial intelligence (AI) has been ...recently used in computer-aided diagnosis showing remarkable promise. In this study, we developed and validated deep learning models to automatically classify cervical neoplasms on colposcopic photographs. Pre-trained convolutional neural networks were fine-tuned for two grading systems: the cervical intraepithelial neoplasia (CIN) system and the lower anogenital squamous terminology (LAST) system. The multi-class classification accuracies of the networks for the CIN system in the test dataset were 48.6 ± 1.3% by Inception-Resnet-v2 and 51.7 ± 5.2% by Resnet-152. The accuracies for the LAST system were 71.8 ± 1.8% and 74.7 ± 1.8%, respectively. The area under the curve (AUC) for discriminating high-risk lesions from low-risk lesions by Resnet-152 was 0.781 ± 0.020 for the CIN system and 0.708 ± 0.024 for the LAST system. The lesions requiring biopsy were also detected efficiently (AUC, 0.947 ± 0.030 by Resnet-152), and presented meaningfully on attention maps. These results may indicate the potential of the application of AI for automated reading of colposcopic photographs.
Vaccines and therapeutics are urgently needed for the pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Here, we screen human monoclonal antibodies (mAb) targeting the ...receptor binding domain (RBD) of the viral spike protein via antibody library constructed from peripheral blood mononuclear cells of a convalescent patient. The CT-P59 mAb potently neutralizes SARS-CoV-2 isolates including the D614G variant without antibody-dependent enhancement effect. Complex crystal structure of CT-P59 Fab/RBD shows that CT-P59 blocks interaction regions of RBD for angiotensin converting enzyme 2 (ACE2) receptor with an orientation that is notably different from previously reported RBD-targeting mAbs. Furthermore, therapeutic effects of CT-P59 are evaluated in three animal models (ferret, hamster, and rhesus monkey), demonstrating a substantial reduction in viral titer along with alleviation of clinical symptoms. Therefore, CT-P59 may be a promising therapeutic candidate for COVID-19.
The survival benefit of prone positioning during mechanical ventilation for acute respiratory distress syndrome has been a matter of debate. Recent multicenter randomized controlled trials have shown ...a significant reduction of 28-day and 90-day mortality associated with prone positioning during mechanical ventilation for severe acute respiratory distress syndrome. We performed an up-to-date meta-analysis on this topic and elucidated the effect of prone positioning on overall mortality and associated complications.
PubMed, EMBASE, BioMed Central, Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, and conference proceedings through May 2013.
Randomized controlled trial comparing overall mortality of prone-versus-supine positioning in patients with acute respiratory distress syndrome.
Data were extracted for populations, interventions, outcomes, and risk of bias. The prespecified primary endpoint was overall mortality, using the longest available follow-up in each study. The odds ratio with 95% CI was the effect measure.
This analysis included 11 randomized controlled trial, 2,246 total adult patients, and 1,142 patients ventilated in the prone position. Prone positioning during ventilation significantly reduced overall mortality in the random-effect model (odds ratio, 0.77; 95% CI, 0.59-0.99; p = 0.039; I = 33.7%), and the effects were marked in the subgroup in which the duration of prone positioning was more than 10 hr/session, compared with the subgroup with a short-term duration of prone positioning (odds ratio, 0.62; 9% CI, 0.48-0.79; p = 0.039; pinteraction = 0.015). Prone positioning was significantly associated with pressure ulcers (odds ratio, 1.49; 95% CI, 1.18-1.89; p = 0.001; I = 0.0%) and major airway problems (odds ratio, 1.55; 95% CI, 1.10-2.17; p = 0.012; I = 32.7%).
Ventilation in the prone position significantly reduced overall mortality in patients with severe acute respiratory distress syndrome. Sufficient duration of prone positioning was significantly associated with a reduction in overall mortality. Prone ventilation was also significantly associated with pressure ulcers and major airway problems.
Radiotherapy using high linear energy transfer (LET) radiation results in effectively killing tumor cells while minimizing dose (biological effective) to normal tissues to block toxicity. It is well ...known that high LET radiation leads to lower cell survival per absorbed dose than low LET radiation. High-linear energy transfer (LET) neutron treatment induces autophagy in tumor cells, but its precise mechanisms in osteosarcoma are unknown. Here, we investigated this mechanism and the underlying signaling pathways. Autophagy induction was examined in gamma-ray-treated KHOS/NP and MG63 osteosarcoma cells along with exposure to high-LET neutrons. The relationship between radiosensitivity and autophagy was assessed by plotting the cell surviving fractions against autophagy levels. Neutron treatment increased autophagy rates in irradiated KHOS/NP and MG63 cells; neutrons with high-LETs showed more effective inhibition than those with lower LET gamma-rays. To determine whether the unfolded protein response and Akt-mTOR pathways triggered autophagy, phosphorylated eIF2α and JNK levels, and phospho-Akt, phosphor-mTOR, and phospho-p70S6 levels were, respectively, investigated. High-LET neutron exposure inhibited Akt phosphorylation and increased Beclin 1 expression during the unfolded protein response, thereby enhancing autophagy. The therapeutic efficacy of high-LET neutron radiation was also assessed in vivo using an orthotopic mouse model. Neutron-irradiated mice showed reduced tumor growth without toxicity relative to gamma-ray-treated mice. The effect of high-LET neutron exposure on the expression of signaling proteins LC3, p-elF2a, and p-JNK was investigated by immunohistochemistry. Tumors in high-LET-neutron radiation-treated mice showed higher apoptosis rates, and neutron exposure significantly elevated LC3 expression, and increased p-elF2a and p-JNK expression levels. Overall, these results demonstrate that autophagy is important in radiosensitivity, cell survival, and cellular resistance against high-LET neutron radiation. This correlation between cellular radiosensitivity and autophagy may be used to predict radiosensitivity in osteosarcoma.
Milk is a nutrient-rich food source, and among the various milks, breast milk is a nutrient source provided by mothers to newborns in many mammals. Exosomes are nano-sized membranous extracellular ...vesicles that play important roles in cell-to-cell communication. Exosomes originate from endogenous synthesis and dietary sources such as milk. Discovered through electron microscopy as floating vesicles, the existence of exosomes in human milk was confirmed owing to a density between 1.10 and 1.18 g/mL in a sucrose gradient corresponding to the known density of exosomes and detection of MHC classes I and II, CD63, CD81, and CD86 on the vesicles. To date, milk exosomes have been used for treating many diseases, including cancers, and are widely proposed as promising carriers for the delivery of chemotherapeutic agents. However, few studies on milk exosomes focus on geriatric health, especially sarcopenia and osteoporosis related to bone and muscle. Therefore, the present study focused on milk exosomes and their cargoes, which are potential candidates for dietary supplements, and when combined with drugs, they can be effective in treating musculoskeletal diseases. In this review, we introduce the basic concepts, including the definition, various sources, and cargoes of milk exosomes, and exosome isolation and characterization methods. Additionally, we review recent literature on the musculoskeletal system and milk exosomes. Since inflammation and oxidative stress underly musculoskeletal disorders, studies reporting the antioxidant and anti-inflammatory properties of milk exosomes are also summarized. Finally, the therapeutic potential of milk exosomes in targeting muscle and bone health is proposed.
Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) entry is mediated by the interaction of the viral spike (S) protein with angiotensin‐converting enzyme 2 (ACE2) on the host cell surface. ...Although a clinical trial testing soluble ACE2 (sACE2) for COVID‐19 is currently ongoing, our understanding of the delivery of sACE2 via small extracellular vesicles (sEVs) is still rudimentary. With excellent biocompatibility allowing for the effective delivery of molecular cargos, sEVs are broadly studied as nanoscale protein carriers. In order to exploit the potential of sEVs, we design truncated CD9 scaffolds to display sACE2 on the sEV surface as a decoy receptor for the S protein of SARS‐CoV‐2. Moreover, to enhance the sACE2‐S binding interaction, we employ sACE2 variants. sACE2‐loaded sEVs exhibit typical sEVs characteristics and bind to the S protein. Furthermore, engineered sEVs inhibit the entry of wild‐type (WT), the globally dominant D614G variant, Beta (K417N‐E484K‐N501Y) variant, and Delta (L452R‐T478K‐D614G) variant SARS‐CoV‐2 pseudovirus, and protect against authentic SARS‐CoV‐2 and Delta variant infection. Of note, sACE2 variants harbouring sEVs show superior antiviral efficacy than WT sACE2 loaded sEVs. Therapeutic efficacy of the engineered sEVs against SARS‐CoV‐2 challenge was confirmed using K18‐hACE2 mice. The current findings provide opportunities for the development of new sEVs‐based antiviral therapeutics.
Pentraxin-3 (PTX3) is recognized as a modulator of inflammation and a mediator of tissue repair. In this study, we characterized the role of PTX3 on some biological functions of human dental pulp ...stem cells (HDPSCs). The expression level of PTX3 significantly increased during osteogenic/odontogenic differentiation of HDPSCs, whereas the knockdown of PTX3 decreased this differentiation. Silencing of PTX3 in HDPSCs inhibited their migration and C-X-C chemokine receptor type 4 (CXCR4) expression. Our present study indicates that PTX3 is involved in osteogenic/odontogenic differentiation and migration of HDPSCs, and may contribute to the therapeutic potential of HDPSCs for regeneration and repair.
Hepatitis C virus (HCV) utilizes autophagy to promote its propagation. Here we show the autophagy-mediated suppression of HCV replication via the endoplasmic reticulum (ER) protein SCOTIN. SCOTIN ...overexpression inhibits HCV replication and infectious virion production in cells infected with cell culture-derived HCV. HCV nonstructural 5A (NS5A) protein, which is a critical factor for HCV RNA replication, interacts with the IFN-β-inducible protein SCOTIN, which transports NS5A to autophagosomes for degradation. Furthermore, the suppressive effect of SCOTIN on HCV replication is impaired in both ATG7-silenced cells and cells treated with autophagy or lysosomal inhibitors. SCOTIN does not affect the overall flow of autophagy; however, it is a substrate for autophagic degradation. The physical association between the transmembrane/proline-rich domain (TMPRD) of SCOTIN and Domain-II of NS5A is essential for autophagosomal trafficking and NS5A degradation. Altogether, our findings suggest that IFN-β-induced SCOTIN recruits the HCV NS5A protein to autophagosomes for degradation, thereby restricting HCV replication.
Background & Aims Despite increasing use of various imaging examinations for non-invasive assessment of hepatic steatosis (HS), their relative accuracy is unknown. The objective of this study is to ...prospectively compare the accuracy of computed tomography (CT), dual gradient echo magnetic resonance imaging (DGE-MRI), proton magnetic resonance spectroscopy (1 H-MRS), and ultrasonography (US) for the diagnosis and quantitative estimation of HS. Methods A total of 161 consecutive potential living liver donors underwent US (performed by two independent radiologists, US1 and US2), CT, DGE-MRI,1 H-MRS, and liver biopsy on the same day. Using the histologic degree of HS as the reference standard, we compared the diagnostic performance of US1, US2, CT, DGE-MRI, and1 H-MRS for diagnosing HS ⩾ 5% and HS ⩾ 30% and compared the accuracy of CT, DGE-MRI, and1 H-MRS in the quantitative estimation of HS. Results DGE-MRI and1 H-MRS significantly outperformed CT and US for the diagnosis of HS ⩾ 5%. DGE-MRI showed a tendency of higher accuracy than the other examinations for diagnosing HS ⩾ 30%. The cross-validated sensitivity and specificity of DGE-MRI at the optimal cut-off were 76.7% and 87.1%, respectively, for diagnosing HS ⩾ 5% and 90.9% and 94%, respectively, for diagnosing HS ⩾ 30%. The cross-validated Bland–Altman 95% limits of agreement between the estimated degree of HS on imaging examinations and the histologic degree of HS, were the narrowest with DGE-MRI, yielding −12.7% to 12.7%. Conclusions Among CT, DGE-MRI,1 H-MRS, and US, DGE-MRI is the most accurate method for the diagnosis and quantitative estimation of HS. Therefore, DGE-MRI may be the preferred imaging examination for the non-invasive assessment of HS.
Three-dimensional (3D) printing using hydrogel has made great strides when it comes to mimicking 3D artificial tissue in the medical field. However, most structures do not mimic the dynamic movement ...of the tissues. Without imitating dynamic movements, there are limitations on the extent to which the proper implementation of the tissue's own functions can be achieved.
In this study, we intend to present an approach to solving this problem using hydroxybutyl methacrylated chitosan (HBC-MA), a photo-crosslinkable/temperature reversible chitosan polymer. In addition, stereolithography-3D (SLA-3D) printing technology was used, which is more likely to mimic the complex microstructure. As a control, a 3D structure made with pristine poly(ethylene glycol) dimethacrylate (PEG-DMA) was created, and a 4D structure was prepared by adding HBC-MA to poly(ethylene glycol) dimethacrylate (PEG-DMAP) resin.
HBC-MA caused the expansion of water into the polymer matrix at low temperature, and the 4D structure resulted in expansion of the polymer volume, generating dynamic movement due to the expansion of water. Conversely, as the temperature rose, deswelling occurred, followed by a decrease in the volume, showing a shape memory property of returning to the existing structure. Morphological, swelling, and mechanical analysis further confirmed the principle of dynamic movement. In addition, parameters were provided through calculation of the bending ratio angle (θ).
Through this, it is suggested that HBC-MA can be applied as a core polymer for SLA-4D printing, and has high potential for realizing the dynamic movement of tissue.
PDF
