Comparison of Four Diagnostic Guidelines for Hepatocellular Carcinoma Using Gadoxetic Acid-enhanced Liver MRI.

Background Noninvasive diagnostic guidelines for hepatocellular carcinoma (HCC) vary across different global geographic areas, especially regarding criteria about gadoxetic acid-enhanced MRI. Purpose To compare the diagnostic performance of four different international HCC diagnosis guidelines and readers' judgment in diagnosing HCC using gadoxetic acid-enhanced MRI in patients at high risk for HCC. Materials and Methods This retrospective study included patients who had not undergone treatment, were at risk for HCC, and who underwent gadoxetic acid-enhanced MRI from January 2015 to June 2018 from 11 tertiary hospitals in South Korea. Four radiologists independently reviewed focal liver lesions (FLLs) according to four guidelines: American Association for the Study of Liver Diseases (AASLD)/Liver Imaging Reporting and Data System (LI-RADS), Korean Liver Cancer Association-National Cancer Center (KLCA-NCC), European Association for the Study of the Liver (EASL), and Asian Pacific Association for the Study of the Liver (APASL). Reader judgment (HCC or not HCC) was also recorded. Malignant FLLs were confirmed at pathology, and histologic and clinical follow-up data were used for benign FLLs. The guidelines' diagnostic performance was compared using generalized estimating equations. Additionally, the diagnostic odds ratio was assessed. Results A total of 2445 FLLs (median size, 27.4 mm) were analyzed in 2237 patients (mean age, 59 years ± 11 [SD]; 1666 male patients); 69.3% (1694 of 2445) were HCCs. KLCA-NCC showed the highest accuracy (80.0%; 95% CI: 78.7, 81.2; P = .001), with high sensitivity in Eastern guidelines (APASL, 89.1% [95% CI: 87.8, 90.3]; KLCA-NCC, 78.2% [95% CI: 76.6, 79.7]) and high specificity in Western guidelines (AASLD/LI-RADS, 89.6% [95% CI: 87.8, 91.2]; EASL, 88.1% [95% CI: 86.2, 89.9]) (P = .001). The diagnostic odds ratios were 20.7 (95% CI: 17.0, 25.3) for AASLD/LI-RADS, 18.9 (95% CI: 15.8, 22.6) for KLCA-NCC, 16.8 (95% CI: 13.8, 20.4) for EASL, and 8.9 (95% CI: 7.4, 10.7) for APASL. The readers' judgment demonstrated higher accuracy than that of the guidelines (accuracy, 86.0%; 95% CI: 84.9, 86.9; P = .001). Conclusion Among four different international HCC diagnosis guidelines, Eastern guidelines demonstrated higher sensitivity, whereas Western guidelines displayed higher specificity. KLCA-NCC achieved the highest accuracy, and AASLD/LI-RADS exhibited the highest diagnostic odds ratio. © RSNA, 2024 Supplemental material is available for this article.

Machine learning-based response assessment in patients with rectal cancer after neoadjuvant chemoradiotherapy: radiomics analysis for assessing tumor regression grade using T2-weighted magnetic resonance images.

PURPOSE: This study aimed to assess tumor regression grade (TRG) in patients with rectal cancer after neoadjuvant chemoradiotherapy (NCRT) through a machine learning-based radiomics analysis using baseline T2-weighted magnetic resonance (MR) images. MATERIALS AND METHODS: In total, 148 patients with locally advanced rectal cancer(T2-4 or N+) who underwent MR imaging at baseline and after chemoradiotherapy between January 2010 and May 2021 were included. A region of interest for each tumor mass was drawn by a radiologist on oblique axial T2-weighted images, and main features were selected using principal component analysis after dimension reduction among 116 radiomics and three clinical features. Among eight learning models that were used for prediction model development, the model showing best performance was selected. Treatment responses were classified as either good or poor based on the MR-assessed TRG (mrTRG) and pathologic TRG (pTRG). The model performance was assessed using the area under the receiver operating curve (AUROC) to classify the response group. RESULTS: Approximately 49% of the patients were in the good response (GR) group based on mrTRG (73/148) and 26.9% based on pTRG (28/104). The AUCs of clinical data, radiomics models, and combined radiomics with clinical data model for predicting mrTRG were 0.80 (95% confidence interval [CI] 0.73, 0.87), 0.74 (95% CI 0.66, 0.81), and 0.75(95% CI 0.68, 0.82), and those for predicting pTRG was 0.62 (95% CI 0.52, 0.71), 0.74 (95% CI 0.65, 0.82), and 0.79 (95% CI 0.71, 0.87). CONCLUSION: Radiomics combined with clinical data model using baseline T2-weighted MR images demonstrated feasible diagnostic performance in predicting both MR-assessed and pathologic treatment response in patients with rectal cancer after NCRT.

Assessing Active Bowel Inflammation in Crohn's Disease Using Intestinal Ultrasound: Correlation With Fecal Calprotectin.

AIM: To analyze the correlation between intestinal ultrasound (IUS) and serum and fecal biomarkers, and the characteristics of small bowel disease, for the assessment of active bowel inflammation. METHODS: Patients with Crohn's disease (CD) who underwent an initial IUS examination between July 2018 and November 2022 at our institution were included retrospectively. We divided small and large bowels into seven segments, and recorded the presence of active inflammation according to following criteria: bowel wall thickness ≥ mm with ≥1 of feature of active disease on IUS. The correlations between IUS-assessed activity and serum C-reactive protein (CRP, mg/dL) and fecal calprotectin (FC, µg/g) levels were analyzed. RESULTS: A total of 127 patients were included (mean age: 32.42 ± 12.07, M:F = 90:37, median disease duration 6 years [0-35]). Of them, 78 showed active bowel inflammation (61.4%), with inflammation distal to the terminal ileum being the most common disease location (n = 61, 78.2%). FC and serum CRP levels were significantly correlated with the number of segments with active inflammation (rho = 0.58, 0.48), number of segments with complications (r = 0.35, 0.31), and US activity score (r = 0.62, 0.54). With FC cutoff values of 100 and 150 µg/g, the concordance rates for patients with active small bowel disease were 78.7% (26/33) and 72.7% (24/33), respectively, which were better than those for other disease locations. CONCLUSIONS: Disease activity determined by IUS was significantly correlated with the biomarkers, with a better concordance rate in patients with active small bowel disease than in those with other disease locations with FC cut-off values of 100 and 150 µg/g.

Alignment-tolerant single-shot digital holographic microscopy based on computer-controlled telecentricity.

An alignment-tolerant telecentric digital holographic microscopy (AT-T-DHM) system based on computer-controlled telecentricity is proposed. It consists of a three-step process-optical recording, computational compensation, and retrieving processes. With a tube-lens-based two-beam interferometer, phase information of the object is recorded on the hologram, where another optical quadratic phase error (O-QPE) due to the misalignment of the tube lens happens to be added. In the computational compensation process, this phase error can be estimated, by which the O-QPE is balanced out from the recorded hologram. Then, only the phase information of the object can be retrieved from the O-QPE-compensated hologram. This computational compensation process makes the proposed system virtually operate in a telecentric imaging mode, which enables implementing a practical AT-T-DHM. Wave-optical analysis and experiments with a test object confirm the feasibility of the proposed system.

Closha: bioinformatics workflow system for the analysis of massive sequencing data.

BACKGROUND: While next-generation sequencing (NGS) costs have fallen in recent years, the cost and complexity of computation remain substantial obstacles to the use of NGS in bio-medical care and genomic research. The rapidly increasing amounts of data available from the new high-throughput methods have made data processing infeasible without automated pipelines. The integration of data and analytic resources into workflow systems provides a solution to the problem by simplifying the task of data analysis. RESULTS: To address this challenge, we developed a cloud-based workflow management system, Closha, to provide fast and cost-effective analysis of massive genomic data. We implemented complex workflows making optimal use of high-performance computing clusters. Closha allows users to create multi-step analyses using drag and drop functionality and to modify the parameters of pipeline tools. Users can also import the Galaxy pipelines into Closha. Closha is a hybrid system that enables users to use both analysis programs providing traditional tools and MapReduce-based big data analysis programs simultaneously in a single pipeline. Thus, the execution of analytics algorithms can be parallelized, speeding up the whole process. We also developed a high-speed data transmission solution, KoDS, to transmit a large amount of data at a fast rate. KoDS has a file transfer speed of up to 10 times that of normal FTP and HTTP. The computer hardware for Closha is 660 CPU cores and 800 TB of disk storage, enabling 500 jobs to run at the same time. CONCLUSIONS: Closha is a scalable, cost-effective, and publicly available web service for large-scale genomic data analysis. Closha supports the reliable and highly scalable execution of sequencing analysis workflows in a fully automated manner. Closha provides a user-friendly interface to all genomic scientists to try to derive accurate results from NGS platform data. The Closha cloud server is freely available for use from http://closha.kobic.re.kr/ .

Single-shot digital holographic microscopy with a modified lateral-shearing interferometer based on computational telecentricity.

Single-shot digital holographic microscopy (SS-DHM) with a modified lateral-shearing interferometer (MLSI) based on computational telecentricity is proposed. The proposed system is composed of three-step processes such as optical recording, digital compensation and numerical reconstruction processes. In the 1st step, the object beam is optically recorded with the MLSI, where a tube lens is set to be located at the slightly shorter distance than its focal length from the objective lens. Then, another phase factor due to the deviated locating of the tube lens from its focal length is additionally generated, which is called an additional quadratic phase factor (AQPF). However, in the 2nd step, this AQPF can be balanced out with the computer-generated version of the AQPF. In the 3rd step, the three-dimensional (3-D) object can be finally reconstructed from this AQPF-compensated hologram. Thus, by combined use of the optical recording and digital compensation processes of the AQPF, the proposed system can be made virtually operate in a so-called computational telecentricity, which enables us to implement a MLSI-based SS-DHM system. Wave-optical analysis and successful experiments with actual 3-D objects confirm the feasibility of the proposed system in the practical application fields.

Ultraviolet photodetector using pn junction formed by transferrable hollow n-TiO2 nano-spheres monolayer.

We report an ultraviolet (UV) photodetector with a universally transferable monolayer film with ordered hollow TiO2 spheres on p-GaN. After forming a TiO2 monolayer film by unidirectional rubbing of hollow TiO2 spheres on a polydimethylsiloxane (PDMS) supporting plate, we used a 5% polyvinyl alcohol (PVA) aqueous solution to transfer the film onto the target substrate. The PVA/TiO2 monolayer film was detached from the PDMS film and transferred to the p-GaN/Al2O3 substrate. To investigate the effects of crystallized phases of the TiO2 hollow spheres, anatase and rutile TiO2 sphere monolayers prepared by combining template synthesis and thermal treatment. The responsiveness of the UV photodetectors using anatase and rutile hollow n-TiO2 monolayer/p-GaN was 0.203 A/W at 312 nm and 0.093 A/W at 327 nm, respectively.

An Algorithm for Management After Transjugular Intrahepatic Portosystemic Shunt Placement According to Clinical Manifestations.

We propose an algorithm for management after transjugular intrahepatic portosystemic shunt (TIPS) placement according to clinical manifestations. For patients with an initial good clinical response, surveillance Doppler ultrasound is recommended to detect stenosis or occlusion. A TIPS revision can be performed using basic or advanced techniques to treat stenosis or occlusion. In patients with an initial poor clinical response, a TIPS venogram with pressure measurements should be performed to assess shunt patency. The creation of a parallel TIPS may also be required if the patient is symptomatic and the portal pressure remains high after TIPS revision. Additional procedures may also be necessary, such as peritoneovenous shunt (Denver shunt) placement for refractory ascites, tunneled pleural catheter for hepatic hydrothorax, and balloon-occluded retrograde transvenous obliteration procedure for gastric variceal bleeding. A TIPS reduction procedure can also be performed in patients with uncontrolled hepatic encephalopathy or hepatic failure.

Slim-structured electro-floating display system based on the polarization-controlled optical path.

A new slim-type electro-floating display system based on the polarization-controlled optical path is proposed. In the proposed system, the optical path between the input plane and Fresnel lens can be made recursive by repetitive transmission and reflection of the input beam by employing a new polarization-based optical path controller (P-OPC), which is composed of two quaterwave plates, a half mirror and a reflective polarizer. Based on this P-OPC, the absolute optical path between the input plane and Fresnel lens, virtually representing the physical depth of the display system, can be reduced down to one third of its original path, which results in the same rate of decrease in the volume size of the display system. The operational principle of the proposed system is analyzed with the Jones matrix. In addition, to confirm the feasibility of the proposed system, experiments with test prototypes are carried out, and the results are comparatively discussed with those of the conventional system.

Sonography of Abdominal Wall Masses and Masslike Lesions: Correlation With Computed Tomography and Magnetic Resonance Imaging.

Sonography is usually regarded as a first-line imaging modality for masses and masslike lesions in the abdominal wall. A dynamic study focusing on a painful area or palpable mass and the possibility of ultrasound-guided aspiration or biopsy are the major advantages of sonography. On the other hand, cross-sectional imaging clearly shows anatomy of the abdominal wall; thereby, it is valuable for diagnosing and evaluating the extent of diseases. Cross-sectional imaging can help differentiate neoplastic lesions from non-neoplastic lesions. This pictorial essay focuses on sonographic findings of abdominal wall lesions compared with computed tomographic and magnetic resonance imaging findings.

Sonography of Gastrointestinal Tract Diseases: Correlation With Computed Tomographic Findings and Endoscopy.

Sonographic evaluation of the gastrointestinal (GI) tract may be difficult because of overlying intraluminal bowel gas and gas-related artifacts. However, in the absence of these factors and with the development of high-resolution scanners and the technical experience of radiologists, sonography can become a powerful tool for GI tract assessment. This pictorial essay focuses on sonographic findings of GI tract lesions compared with endoscopic, computed tomographic, and magnetic resonance imaging findings. Neoplastic and non-neoplastic diseases and postoperative complications are illustrated, and the distinctive sonographic characteristics of these entities are highlighted.

Distribution of Epididymal Involvement in Mumps Epididymo-orchitis.

OBJECTIVES: To evaluate characteristic sonographic findings for mumps orchitis with epididymal involvement. METHODS: This study included 18 patients (aged 12-18 years) with mumps orchitis. We assessed the volume, echogenicity, and vascularity of the testes and the transverse diameter, echogenicity, and vascularity of the epididymal head, body, and tail. We classified 4 types of epididymal involvement: 1A, focal swelling of the epididymal head with hypervascularity only on the swollen head; 1B, focal swelling of the epididymal head with hypervascularity on the entire epididymis; 1C, diffuse swelling of the entire epididymis with hypervascularity; and 2, no epididymal involvement. The Student t test was used to evaluate the significance of the size of each part of the epididymis and the epididymal head-to-tail diameter ratio. RESULTS: Orchitis was unilateral in 13 patients and bilateral in 5. Of 23 affected hemiscrotums, 7 (30.4%) were type 1A, 4 (17.4%) type 1B, 2 (8.7%) type 1C, and 10 (43.5%) type 2. In 11 patients with unilateral epididymal involvement, the mean diameters ± SDs of the epididymal heads on the affected and contralateral sides were 1.11 ± 0.19 (range, 0.7-1.7) and 0.65 ± 0.14 (0.3-0.9) cm (significantly different, P <.001). The diameters of the epididymal tails on the affected and contralateral sides were 0.51 ± 0.41 (0.2-0.8) and 0.46 ± 0.21 (0.3-0.6) cm (not statistically different, P = .106). The mean head-to-tail ratios on the affected and contralateral sides were 2.28 ± 0.49 (1.29-3.00) and 1.41 ± 0.22 (1.00-1.75; significantly different, P < .001). In all types 1A and 1B, the ratio was higher than 2.00; in 22 of 23 unaffected epididymides, the ratio was lower than 2.00. CONCLUSIONS: Focal swelling of epididymal heads was a characteristic sonographic finding of mumps epididymo-orchitis, and a head-to-tail ratio higher than 2.00 can be a useful diagnostic finding.

Gastrointestinal tract perforation: evaluation of MDCT according to perforation site and elapsed time.

OBJECTIVES: To evaluate multidetector computed tomography (MDCT) for the prediction of perforation site according to each gastrointestinal (GI) tract site and elapsed time. METHODS: One hundred and sixty-eight patients who underwent MDCT before laparotomy for GI tract perforation were enrolled and allocated to an early or late lapse group based on an elapsed time of 7 h. Two reviewers independently evaluated the perforation site and assessed the following CT findings: free air location, mottled extraluminal air bubbles, focal bowel wall discontinuity, segmental bowel wall thickening, perivisceral fat stranding and localised fluid collection. RESULTS: The overall diagnostic accuracy was 91.07 % and 91.67 % for reviewers 1 and 2, respectively, with excellent agreement (kappa 0.86). Accuracies (98.97 % and 97.94 %) and agreements (kappa 0.894) for stomach and duodenum perforation were higher than for other perforation sites. Strong predictors of perforation at each site were: focal bowel wall discontinuity for stomach, duodenal bulb and left colon, mottled extraluminal air bubbles for retroperitoneal duodenum and right colon, and segmental bowel wall thickening for small bowel. The diagnostic accuracy was not different between the early- and late-lapse groups. CONCLUSIONS: MDCT can accurately predict upper GI tract perforation with high reliability. Elapsed time did not affect the accuracy of perforation site prediction. KEY POINTS: Perforation of the stomach and duodenum can be accurately predicted with MDCT. Knowledge of CT findings predicting perforation site can improve diagnostic accuracy. Elapsed time does not significantly affect accuracy in predicting perforation sites.

Diagnostic effectiveness of dynamic colpocystoproctography in women planning for combined surgery with urinary incontinence and pelvic organ prolapse.

OBJECTIVE: To evaluate the advantage of performing the dynamic cystoproctography (DCP) in patients planning for combined surgery due to urinary incontinence and pelvic organ prolapse (POP). MATERIALS AND METHODS: We performed DCP on a total of 113 consecutive women with POP and compared the findings of the physical examination with POP quantification against those of DCP including squeezing, straining and evacuation phases, and analyzed the changes to the rates of surgical planning. For statistical analysis, sensitivity, specificity, and positive predictive value of each test were performed. RESULTS: DCP identified an additional 10 cases of cystocele, 32 cases of rectocele, 2 cases of enterocele, 4 cases of sigmoidocele, and 8 cases of rectal intussusception compared to those cases who were only included for a physical examination. The initial surgical plan was changed in a total of 24 cases (22.1%). The prevalence of bowel symptoms in the group in which the surgical plan changed was higher than in the group with no changes to the surgical plan (p = 0.023). CONCLUSIONS: DCP may be a more sensitive test for diagnosing POP compared to physical examination alone, and it is useful to patients with bowel symptoms by making surgical planning for combined surgery with stress urinary incontinence and POP.

Net global warming potential index rather than soil carbon stock change could provide better understanding of the carbon balance in soil systems.

This study was conducted to determine the soil organic carbon (SOC) stock change factor for green manure crops that was developed by the Intergovernmental Panel on Climate Change (IPCC) Tier 2 method and compare this with the net global warming potential (GWP) index that is used to evaluate the contribution of green manuring to global warming. Four treatments were barley (Hordeum vulgare L.; B), hairy vetch (Vicia villosa R.; HV), a barley/hairy vetch mixture (BHV) and a conventional treatment (C). The aboveground biomass of green manure crops was incorporated into the soil on 25 May 2018, 26 April 2019, 29 April 2020, 30 April 2021 and 2 May 2022. Maize (Zea mays L.) was transplanted as the subsequent crop after the incorporation of green manures. SOC stock decreased with green manures, even though carbon input with green manures, including B, HV and BHV, was greater than that with C. The mean value of the SOC stock change factor for green manure crops, including B, HV and BHV was 0.627 and was significantly lower than that of the C. However, the net GWP also decreased with the incorporation of green manure crops, and the mean value of the relative net GWP index across B, HV and BHV was 0.853. These conflicting results were caused by different estimation methods between annual SOC change (△SOC) and net GWP. The estimation of SOC stock change using △SOC suggested by the IPCC method may overestimate the contribution of green manure crops to global warming. The net GWP method with comprehensive input and output of carbon in the soil system could provide a better understanding of the carbon balance in soil systems. In the current study, the comparison of △SOC and net GWP was conducted for at one site of upland soil for 5 years. Therefore, further research on estimating the effect of green manure crops on net GWP in various types of soil for longer years should be conducted.

Coordinated ASBT and EGFR Mechanisms for Optimized Liraglutide Nanoformulation Absorption in the GI Tract.

Background: For maintenance therapy in type 2 diabetes, glucagon-like peptide-1 agonist (GLP-1A), which exhibits low cardiovascular risk and high efficacy, is a promising peptide therapeutic. However, developing an oral GLP-1A presents challenges due to the analog's poor cellular permeability and gastrointestinal (GI) stability. Methods: To mitigate such limitations, an oral nanoformulation of liraglutide (LG) was designed and achieved by combining LG with bile acid derivatives using the nanoprecipitation method. This strategy allowed the bile acid moieties to localize at the nanoparticle surface, enhancing the binding affinity for apical sodium-dependent bile acid transporter (ASBT) and improving GI stability. The in vitro characteristics, cellular permeability, and absorption mechanisms of the LG nanoformulation (LG/TD-NF) were thoroughly investigated. Furthermore, the in vivo oral absorption in rats and the glucose-lowering effects in a diabetic (db/db) mouse model were evaluated. Results: The LG/TD-NF produced neutral nanoparticles with a diameter of 58.7 ± 4.3 nm and a zeta potential of 4.9 ± 0.4 mV. Notably, when exposed to simulated gastric fluid, 65.7 ± 3.6% of the LG/TD-NF remained stable over 120 min, while free LG was fully degraded. Relative to unformulated LG, the Caco-2 cellular permeability of the nanoformulation improved, measuring 10.9 ± 2.1 (× 10-6 cm/s). The absorption mechanism prominently featured endocytosis simultaneously mediated by both ASBT and epidermal growth factor receptor (EGFR). The oral bioavailability of the LG/TD-NF was determined to be 3.62% at a dosage of 10 mg/kg, which is 45.3 times greater than that of free LG. In a diabetes model, LG/TD-NF at 10 mg/kg/day exhibited commendable glucose sensitivity and reduced HbA1c levels by 4.13% within 28 days, similar to that of subcutaneously administered LG at a dosage of 0.1 mg/kg/day. Conclusion: The oral LG/TD-NF promotes ASBT/EGFR-mediated transcytosis and assures cellular permeability within the GI tract. This method holds promise for the development of oral GLP-1A peptides as an alternative to injections, potentially enhancing patient adherence to maintenance therapy.

Immune modulation of the liver metastatic colorectal cancer microenvironment via the oral CAPOX-mediated cGAS-STING pathway.

We evaluated modulation of the immunosuppressive tumor microenvironment in both local and liver metastatic colorectal cancer (LMCC), focusing on tumor-associated macrophages, which are the predominant immunosuppressive cells in LMCC. We developed an orally administered metronomic chemotherapy regimen, oral CAPOX. This regimen combines capecitabine and a nano-micelle encapsulated, lysine-linked deoxycholate and oxaliplatin complex (OPt/LDC-NM). The treatment effectively modulated immune cells within the tumor microenvironment by activating the cGAS-STING pathway and inducing immunogenic cell death. This therapy modulated immune cells more effectively than did capecitabine monotherapy, the current standard maintenance chemotherapy for colorectal cancer. The macrophage-modifying effect of oral CAPOX was mediated via the cGAS-STING pathway. This is a newly identified mode of immune cell activation induced by metronomic chemotherapy. Moreover, oral CAPOX synergized with anti-PD-1 antibody (αPD-1) to enhance the T-cell-mediated antitumor immune response. In the CT26. CL25 subcutaneous model, combination therapy achieved a 91 % complete response rate with a confirmed memory effect against the tumor. This combination also altered the immunosuppressive tumor microenvironment in LMCC, which αPD-1 monotherapy could not achieve. Oral CAPOX and αPD-1 combination therapy outperformed the maximum tolerated dose for treating LMCC, suggesting metronomic therapy as a promising strategy.

Stimulating macropinocytosis of peptide-drug conjugates through DNA-dependent protein kinase inhibition for treating KRAS-mutant cancer.

KRAS-mutant cancers, due to their protein targeting complexity, present significant therapeutic hurdles. The identification of the macropinocytic phenotype in these cancers has emerged as a promising alternative therapeutic target. Our study introduces MPD1, an macropinocytosis-targeting peptide-drug conjugates (PDC), which is developed to treat KRAS mutant cancers. This PDC is specifically designed to trigger a positive feedback loop through its caspase-3 cleavable characteristic. However, we observe that this loop is hindered by DNA-PK mediated DNA damage repair processes in cancer cells. To counter this impediment, we employ AZD7648, a DNA-PK inhibitor. Interestingly, the combined treatment of MPD1 and AZD7648 resulted in a 100% complete response rate in KRAS-mutant xenograft model. We focus on the synergic mechanism of it. We discover that AZD7648 specifically enhances macropinocytosis in KRAS-mutant cancer cells. Further analysis uncovers a significant correlation between the increase in macropinocytosis and PI3K signaling, driven by AMPK pathways. Also, AZD7648 reinforces the positive feedback loop, leading to escalated apoptosis and enhanced payload accumulation within tumors. AZD7648 possesses broad applications in augmenting nano-sized drug delivery and preventing DNA repair resistance. The promising efficacy and evident synergy underscore the potential of combining MPD1 with AZD7648 as a strategy for treating KRAS-mutant cancers.

A new method of fabricating robust freeform 3D ceramic scaffolds for bone tissue regeneration.

Fabrication of three-dimensional (3D) scaffolds with appropriate mechanical properties and desired architecture for promoting cell growth and new tissue formation is one of the most important efforts in tissue engineering field. Scaffolds fabricated from bioactive ceramic materials such as hydroxyapatite and tricalcium phosphate show promise because of their biological ability to support bone tissue regeneration. However, the use of ceramics as scaffold materials is limited because of their inherent brittleness and difficult processability. The aim of this study was to create robust ceramic scaffolds, which have a desired architecture. Such scaffolds were successfully fabricated by projection-based microstereolithography, and dilatometric analysis was conducted to study the sintering behavior of the ceramic materials. The mechanical properties of the scaffolds were improved by infiltrating them with a polycaprolactone solution. The toughness and compressive strength of these ceramic/polymer scaffolds were about twice those of ceramic scaffolds. Furthermore, the osteogenic gene expression on ceramic/polymer scaffolds was better than that on ceramic scaffolds. Through this study, we overcame the limitations of previous research on fabricating ceramic scaffolds and these new robust ceramic scaffolds may provide a much improved 3D substrate for bone tissue regeneration.

VnD: a structure-centric database of disease-related SNPs and drugs.

Numerous genetic variations have been found to be related to human diseases. Significant portion of those affect the drug response as well by changing the protein structure and function. Therefore, it is crucial to understand the trilateral relationship among genomic variations, diseases and drugs. We present the variations and drugs (VnD), a consolidated database containing information on diseases, related genes and genetic variations, protein structures and drug information. VnD was built in three steps. First, we integrated various resources systematically to deduce catalogs of disease-related genes, single nucleotide polymorphisms (SNPs), protein mutations and relevant drugs. VnD contains 137,195 disease-related gene records (13,940 distinct genes) and 16,586 genetic variation records (1790 distinct variations). Next, we carried out structure modeling and docking simulation for wild-type and mutant proteins to examine the structural and functional consequences of non-synonymous SNPs in the drug-related genes. Conformational changes in 590 wild-type and 4437 mutant proteins from drug-related genes were included in our database. Finally, we investigated the structural and biochemical properties relevant to drug binding such as the distribution of SNPs in proximal protein pockets, thermo-chemical stability, interactions with drugs and physico-chemical properties. The VnD database, available at http://vnd.kobic.re.kr:8080/VnD/ or vandd.org, would be a useful platform for researchers studying the underlying mechanism for association among genetic variations, diseases and drugs.