Spatial Multiplexing of Fluorescent Reporters for Imaging Signaling Network Dynamics.

In order to analyze how a signal transduction network converts cellular inputs into cellular outputs, ideally one would measure the dynamics of many signals within the network simultaneously. We found that, by fusing a fluorescent reporter to a pair of self-assembling peptides, it could be stably clustered within cells at random points, distant enough to be resolved by a microscope but close enough to spatially sample the relevant biology. Because such clusters, which we call signaling reporter islands (SiRIs), can be modularly designed, they permit a set of fluorescent reporters to be efficiently adapted for simultaneous measurement of multiple nodes of a signal transduction network within single cells. We created SiRIs for indicators of second messengers and kinases and used them, in hippocampal neurons in culture and intact brain slices, to discover relationships between the speed of calcium signaling, and the amplitude of PKA signaling, upon receiving a cAMP-driving stimulus.

Olaparib enhances sensitization of BRCA-proficient breast cancer cells to x-rays and protons.

PURPOSE: This study aimed to compare the radiosensitizing effect of the PARP inhibitor, Olaparib, between proton and X-rays irradiations in BRCA-proficient breast cancer (BC) cells. METHODS: Two BRCA-proficient BC cell lines, MDA-MB-231 and T47D BC, were used. Cell proliferation was assessed using the CCK-8 assay, and radiosensitivity was determined through the clonogenic survival assay. Flow cytometry was employed to analyze cell cycle distribution and apoptosis. The kinetics of DNA damage repair were evaluated using γH2AX immunofluorescence imaging and the comet assay. Tumor spheroid assays were conducted to test radiosensitivity in a three-dimensional culture condition. RESULTS: Olaparib sensitized both MDA-MB-231 and T47D cells to proton and X-ray irradiation in the clonogenic assay. MDA-MB-231 cells exhibited a higher dose enhancement factor for Olaparib than T47D cells. Olaparib increased radiation-induced G2/M cell cycle arrest and apoptosis specifically in MDA-MB-231 cells. γH2AX immunostaining and the comet assay showed Olaparib augmented radiation-induced DNA damage and apoptosis. The enhancement effect of Olaparib was more pronounced in proton irradiation than in X-ray irradiation, particularly in MDA-MB-231 cells than T47D cells. Both radiation and Olaparib dose-dependently inhibited spheroid growth in both cell lines. The synergy scores demonstrated that Olaparib interacted more strongly with protons than X-rays. The addition of an ATR inhibitor further enhanced Olaparib-induced proton radiosensitization in MDA-MB-231 cells. CONCLUSION: This study found that Olaparib enhanced radiation efficacy in BRCA-proficient breast cancer cells, with a more pronounced effect observed with proton irradiation compared to X-ray irradiation. Combining Olaparib with an ATR inhibitor increased the radiosensitizing effect of protons.

Quantitative assessment of breast volume changes after whole-breast irradiation for breast cancer using breast auto-segmentation.

PURPOSE: This study aimed to quantitatively estimate the changes in breast volume associated with radiotherapy in patients undergoing breast-conserving surgery and whole-breast irradiation (WBI). METHODS: Pre-WBI simulation computed tomography (CT) scans and post-WBI follow-up chest CT scans from a total of 1,151 breast cancer patients were analyzed using a deep-learning-driven auto-segmentation approach. The CT-based asymmetry index (CTAI) was calculated by dividing the volume of the irradiated breast by the volume of the contralateral breast. Significant breast shrinkage was defined as a CTAI < 0.85. To quantify changes in CTAI over the follow-up period, the CTAI ratio was determined as the post-WBI CTAI divided by the pre-WBI CTAI. A multivariate logistic regression analysis was conducted to identify potential variables associated with post-WBI significant breast shrinkage. RESULTS: The median CTAI values for pre- and post-WBI CT scans were 0.973 (interquartile range: 0.887-1.069) and 0.866 (interquartile range: 0.773-0.967), respectively. The difference between them was statistically significant (p < 0.001). Following WBI, there was an increase in the rate of significant breast shrinkage from 16.3 to 44.8%. The CTAI ratio showed a negative association with the time interval (p < 0.001, Pearson r = - 0.310). In the multivariate logistic regression analysis, lower pre-WBI CTAI, younger age, and longer interval between CT scans were found to be significantly associated with a higher occurrence of post-WBI significant breast shrinkage. CONCLUSION: Breast volume decreases following WBI, and this decrease is correlated with an increased duration after WBI. These findings highlight the long-term consequences of WBI on breast asymmetry.

Metal Cocatalyst Engineering in Metal-Semiconductor Hybrid Photocatalysts Achieves a Fivefold Enhancement of Hydrogen Evolution.

This study explores the optimal morphology of photochemical hydrogen evolution catalysts in a one-dimensional system. Systematic engineering of metal tips on precisely defined CdSe@CdS dot-in-rods is conducted to exert control over morphology, composition, and both factors. The outcome yields an optimized configuration, a Au-Pt core-shell structure with a rough Pt surface (Au@r-Pt), which exhibits a remarkable fivefold increase in quantum efficiency, reaching 86% at 455 nm and superior hydrogen evolution rates under visible and AM1.5G irradiation conditions with prolonged stability. Kinetic investigations using photoelectrochemical and time-resolved measurements demonstrate a greater extent and extended lifetime of the charge-separated state on the tips as well as rapid water reduction kinetics on high-energy surfaces. This approach sheds light on the critical role of cocatalysts in hybrid photocatalytic systems for achieving high performance.

Systemic C-peptide supplementation ameliorates retinal neurodegeneration by inhibiting VEGF-induced pathological events in diabetes.

Diabetic retinopathy (DR) is caused by retinal vascular dysfunction and neurodegeneration. Intraocular delivery of C-peptide has been shown to be beneficial against hyperglycemia-induced microvascular leakage in the retina of diabetes; however, the effect of C-peptide on diabetes-induced retinal neurodegeneration remains unknown. Moreover, extraocular C-peptide replacement therapy against DR to avoid various adverse effects caused by intravitreal injections has not been studied. Here, we demonstrate that systemic C-peptide supplementation using osmotic pumps or biopolymer-conjugated C-peptide hydrogels ameliorates neurodegeneration by inhibiting vascular endothelial growth factor-induced pathological events, but not hyperglycemia-induced vascular endothelial growth factor expression, in the retinas of diabetic mice. C-peptide inhibited hyperglycemia-induced activation of macroglial and microglial cells, downregulation of glutamate aspartate transporter 1 expression, neuronal apoptosis, and histopathological changes by a mechanism involving reactive oxygen species generation in the retinas of diabetic mice, but transglutaminase 2, which is involved in retinal vascular leakage, is not associated with these pathological events. Overall, our findings suggest that systemic C-peptide supplementation alleviates hyperglycemia-induced retinal neurodegeneration by inhibiting a pathological mechanism, involving reactive oxygen species, but not transglutaminase 2, in diabetes.

Diagnostic assessments and treatment results of well-differentiated gastric-type adenocarcinoma of the uterine cervix (Adenoma malignum): A multicenter retrospective analysis of KROG 22-03 study.

OBJECTIVE: Among cervical adenocarcinomas, well-differentiated gastric adenocarcinoma of the uterine cervix (WD-GAS), previously termed adenoma malignum (minimal deviation adenocarcinoma) is not well understood. Because of its rarity and difficulty in diagnosis, there is no standard care for WD-GAS. Thus, we conducted the first multicenter retrospective study on WD-GAS to clarify prognostic factors for long-term survival and recurrence. METHODS: Patients diagnosed with WD-GAS at eight hospitals participated in this multi-center study. Overall survival (OS) and recurrence-free survival (RFS) were calculated with the Kaplan-Meier method. Additionally, OS between the early and advanced FIGO stage groups were compared with the log-rank test. Cox regression analysis was conducted to identify significant factors associated with recurrence-free survival (RFS). RESULTS: A total of 73 patients from eight hospitals in South Korea were included in the analysis. The median follow-up period was 44.8 months, and all patients underwent curative surgical intervention as the primary treatment. Recurrence was observed in 17 patients (23.3%). Ten patients had locoregional recurrence, four patients had distant metastasis, and three patients presented with both locoregional recurrence and distant metastasis. The Cox regression analysis identified several statistically significant factors associated with RFS, including vaginal invasion (VI), parametrial invasion (PMI), resection margin (RM), and nodal and lymphovascular invasion (LVI). When considering these five factors together, patients without any of the factors exhibited recurrence-free survival (RFS) of 97.0% at three years and those with more than one of these factors had a 3-year RFS of 65.4% (P < 0.001). CONCLUSION: WD-GAS showed relatively high locoregional recurrence rate. Positive PMI, VI, RM, nodal involvement, and LVI were associated with a significant increase in recurrence or distant metastasis rates.

Weibull parametric model for survival analysis in women with endometrial cancer using clinical and T2-weighted MRI radiomic features.

BACKGROUND: Semiparametric survival analysis such as the Cox proportional hazards (CPH) regression model is commonly employed in endometrial cancer (EC) study. Although this method does not need to know the baseline hazard function, it cannot estimate event time ratio (ETR) which measures relative increase or decrease in survival time. To estimate ETR, the Weibull parametric model needs to be applied. The objective of this study is to develop and evaluate the Weibull parametric model for EC patients' survival analysis. METHODS: Training (n = 411) and testing (n = 80) datasets from EC patients were retrospectively collected to investigate this problem. To determine the optimal CPH model from the training dataset, a bi-level model selection with minimax concave penalty was applied to select clinical and radiomic features which were obtained from T2-weighted MRI images. After the CPH model was built, model diagnostic was carried out to evaluate the proportional hazard assumption with Schoenfeld test. Survival data were fitted into a Weibull model and hazard ratio (HR) and ETR were calculated from the model. Brier score and time-dependent area under the receiver operating characteristic curve (AUC) were compared between CPH and Weibull models. Goodness of the fit was measured with Kolmogorov-Smirnov (KS) statistic. RESULTS: Although the proportional hazard assumption holds for fitting EC survival data, the linearity of the model assumption is suspicious as there are trends in the age and cancer grade predictors. The result also showed that there was a significant relation between the EC survival data and the Weibull distribution. Finally, it showed that Weibull model has a larger AUC value than CPH model in general, and it also has smaller Brier score value for EC survival prediction using both training and testing datasets, suggesting that it is more accurate to use the Weibull model for EC survival analysis. CONCLUSIONS: The Weibull parametric model for EC survival analysis allows simultaneous characterization of the treatment effect in terms of the hazard ratio and the event time ratio (ETR), which is likely to be better understood. This method can be extended to study progression free survival and disease specific survival. TRIAL REGISTRATION: ClinicalTrials.gov NCT03543215, https://clinicaltrials.gov/ , date of registration: 30th June 2017.

Control of lateral root formation by rapamycin-induced dimerization of engineered RGI/BAK1 and by BIR3 chimera.

Leucine-rich repeat receptor kinases (LRR-RKs) play a pivotal role in diverse aspects of growth, development, and immunity in plants by sensing extracellular signals. Typically, LRR-RKs are activated through the ligand-induced interaction with a SOMATIC EMBRYOGENESIS RECEPTOR KINASE (SERK) coreceptor, triggering downstream signaling. ROOT MERISTEM GROWTH FACTOR1 (RGF1) INSENSITIVEs (RGIs) LRR-RLK receptors promote primary root meristem activity while inhibiting lateral root (LR) development in response to RGF peptide. In this study, we employed rapamycin-induced dimerization (RiD) and BAK1-INTERACTING RECEPTOR-LIKE KINASE3 (BIR3) chimera approaches to explore the gain-of-function of RGI1, RGI4, and RGI5. Rapamycin induced the association of cytosolic kinase domains (CKDs) of RGI1 and the BAK1 coreceptor, activating both mitogen-activated protein kinase 3 (MPK3) and MPK6. Rapamycin significantly inhibited LR formation in RiD-RGI1/RGI4/RGI5-BAK1 plants. Using transgenic Arabidopsis expressing RGI1CKD fused to the BIR3-LRR chimera under estradiol control, we observed a substantial reduction in LR density upon ß-estradiol treatment. Additionally, we identified a decrease in root gravitropism in BIR3 chimera plants. In contrast, RiD-RGI/BAK1 plants did not exhibit defects in root gravitropism, implying the importance of combinatorial interactions between RGIs and SERK coreceptors in the inhibition of root gravitropism. Constitutive activation of RGIs with BAK1 in RiD-RGI/BAK1 plants by rapamycin treatment resulted in the inhibition of primary root growth, resembling the inhibitory effects observed with high concentrations of phytohormones on primary root elongation. Our findings highlight that the interactions between CKDs of RGIs and BAK1, constitutively induced by rapamycin or BIR3 chimera, efficiently control LR development.

Risk Factors Affecting Clinical Outcomes of Low-risk Early-stage Human Papillomavirus-Associated Endocervical Adenocarcinoma Treated by Surgery Alone: Application of Silva Pattern.

This study aimed to report the clinical outcomes and risk factors for survival of patients with low-risk early-stage human papillomavirus-associated (HPVA) endocervical adenocarcinoma (EAC) treated with surgery alone. This retrospective study obtained the clinicopathological data of patients with early-stage HPVA EAC who underwent surgery between 2012 and 2018. The Silva pattern of invasion was determined by reviewing pathology slides. Locoregional recurrence-free survival (RFS), RFS, and overall survival were calculated, and the risk factors for survival were analyzed. One hundred seventeen patients with a median follow-up of 5.2 years (0.5-9.7 yr) were included. The most common histologic type was usual (94/117, 80.3%). The Silva pattern was A in 79 patients (67.5%), B in 30 (25.6%), and C in 8 (6.8%). The 5-year locoregional RFS, RFS, and overall survival rates were 92.4%, 87.8%, and 97.2%, respectively. The presence of intermediate-risk factors and Silva pattern C were significantly associated with worse survival. Based on these findings, patients were categorized into 2 groups: Group 1 (Silva pattern A or Silva pattern B without intermediate-risk factors) and Group 2 (Silva pattern B with intermediate-risk factors or Silva pattern C ). Group 2 showed significantly worse outcomes than Group 1, including the 5-year locoregional RFS (98.6% vs 68.0%), RFS (96.4% vs 54.6%), and overall survival (100.0% vs 86.5%). In conclusion, surgery alone for early-stage HPVA EAC resulted in favorable outcomes. Consideration of the Silva pattern, in addition to well-known risk factors, could help in precise risk group stratification of low-risk, early-stage HPVA EAC.

Coronary Artery Calcification on Low-Dose Lung Cancer Screening CT in South Korea: Visual and Artificial Intelligence-Based Assessment and Association With Cardiovascular Events.

BACKGROUND. Coronary artery calcification (CAC) on lung cancer screening low-dose chest CT (LDCT) is a cardiovascular risk marker. South Korea was the first Asian country to initiate a national LDCT lung cancer screening program, although CAC-related outcomes are poorly explored. OBJECTIVE. The purpose of this article is to evaluate CAC prevalence and severity using visual analysis and artificial intelligence (AI) methods and to characterize CAC's association with major adverse cardiovascular events (MACEs) in patients undergoing LDCT in Korea's national lung cancer screening program. METHODS. This retrospective study included 1002 patients (mean age, 62.4 ± 5.4 [SD] years; 994 men, eight women) who underwent LDCT at two Korean medical centers between April 2017 and May 2023 as part of Korea's national lung cancer screening program. Two radiologists independently assessed CAC presence and severity using visual analysis, consulting a third radiologist to resolve differences. Two AI software applications were also used to assess CAC presence and severity. MACE occurrences were identified by EMR review. RESULTS. Interreader agreement for CAC presence and severity, expressed as kappa, was 0.793 and 0.671, respectively. CAC prevalence was 53.4% by consensus visual assessment, 60.1% by AI software I, and 56.6% by AI software II. CAC severity was mild, moderate, and severe by consensus visual analysis in 28.0%, 10.3%, and 15.1%; by AI software I in 39.9%, 14.0%, and 6.2%; and by AI software II in 34.9%, 14.3%, and 7.3%. MACEs occurred in 36 of 625 (5.6%) patients with follow-up after LDCT (median, 1108 days). MACE incidence in patients with no, mild, moderate, and severe CAC for consensus visual analysis was 1.1%, 5.0%, 2.9%, and 8.6%, respectively (p < .001); for AI software I, it was 1.3%, 3.0%, 7.9%, and 11.3% (p < .001); and for AI software II, it was 1.2%, 3.4%, 7.7%, and 9.6% (p < .001). CONCLUSION. For Korea's national lung cancer screening program, MACE occurrence increased significantly with increasing CAC severity, whether assessed by visual analysis or AI software. The study is limited by the large sex imbalance for Korea's national lung cancer screening program. CLINICAL IMPACT. The findings provide reference data for health care practitioners engaged in developing and overseeing national lung cancer screening programs, highlighting the importance of routine CAC evaluation.

The Hammersmith Score Optimises Patient Selection and Predicts for Overall Survival in Early-Phase Cancer Trial Participants Independent of Tumour Burden.

INTRODUCTION: As tumour response rates are increasingly demonstrated in early-phase cancer trials (EPCT), optimal patient selection and accurate prognostication are paramount. Hammersmith Score (HS), a simple prognostic index derived on routine biochemical measures (albumin <35 g/L, lactate dehydrogenase >450 IU/L, sodium <135 mmol/L), is a validated predictor of response and survival in EPCT participants. HS has not been validated in the cancer immunotherapy era. METHODS: We retrospectively analysed characteristics and outcomes of unselected referrals to our early-phase unit (12/2019-12/2022). Independent predictors for overall survival (OS) were identified from univariable and multivariable models. HS was calculated for 66 eligible trial participants and compared with the Royal Marsden Score (RMS) to predict OS. Multivariable logistic regression and C-index was used to compare predictive ability of prognostic models. RESULTS: Of 212 referrals, 147 patients were screened and 82 patients treated in EPCT. Prognostic stratification by HS identifies significant difference in median OS, and HS was confirmed as a multivariable predictor for OS (HR: HS 1 vs. 0 2.51, 95% CI: 1.01-6.24, p = 0.049; HS 2/3 vs. 0: 10.32, 95% CI: 2.15-49.62, p = 0.004; C-index 0.771) with superior multivariable predictive ability than RMS (HR: RMS 2 vs. 0/1 5.46, 95% CI: 1.12-26.57, p = 0.036; RMS 3 vs. 0/1 6.83, 95% CI: 1.15-40.53, p < 0.001; C-index 0.743). CONCLUSIONS: HS is a validated prognostic index for patients with advanced cancer treated in the context of modern EPCTs, independent of tumour burden. HS is a simple, inexpensive prognostic tool to optimise referral for EPCT.

Inhibition of voltage-dependent K+ channels in rabbit coronary arterial smooth muscle cells by the atypical antipsychotic agent sertindole.

The regulation of membrane potential and the contractility of vascular smooth muscle cells (VSMCs) by voltage-dependent K+ (Kv) potassium channels are well-established. In this study, native VSMCs from rabbit coronary arteries were used to investigate the inhibitory effect of sertindole, an atypical antipsychotic agent, on Kv channels. Sertindole induced dose-dependent inhibition of Kv channels, with an IC50 of 3.13 ± 0.72 µM. Although sertindole did not cause a change in the steady-state activation curve, it did lead to a negative shift in the steady-state inactivation curve. The application of 1- or 2-Hz train pulses failed to alter the sertindole-induced inhibition of Kv channels, suggesting use-independent effects of the drug. The inhibitory response to sertindole was significantly diminished by pretreatment with a Kv1.5 inhibitor but not by Kv2.1 and Kv7 subtype inhibitors. These findings demonstrate the sertindole dose-dependent and use-independent inhibition of vascular Kv channels (mainly the Kv1.5 subtype) through a mechanism that involves altering steady-state inactivation curves. Therefore, the use of sertindole as an antipsychotic drug may have adverse effects on the cardiovascular system.

Second-generation antipsychotic quetiapine blocks voltage-dependent potassium channels in coronary arterial smooth muscle cells.

Voltage-dependent K+ (Kv) channels play an important role in restoring the membrane potential to its resting state, thereby maintaining vascular tone. In this study, native smooth muscle cells from rabbit coronary arteries were used to investigate the inhibitory effect of quetiapine, an atypical antipsychotic agent, on Kv channels. Quetiapine showed a concentration-dependent inhibition of Kv channels, with an IC50 of 47.98 ± 9.46 µM. Although quetiapine (50 µM) did not alter the steady-state activation curve, it caused a negative shift in the steady-state inactivation curve. The application of 1 and 2 Hz train steps in the presence of quetiapine significantly increased the inhibition of Kv current. Moreover, the recovery time constants from inactivation were prolonged in the presence of quetiapine, suggesting that its inhibitory action on Kv channels is use (state)-dependent. The inhibitory effects of quetiapine were not significantly affected by pretreatment with Kv1.5, Kv2.1, and Kv7 subtype inhibitors. Based on these findings, we conclude that quetiapine inhibits Kv channels in both a concentration- and use (state)-dependent manner. Given the physiological significance of Kv channels, caution is advised in the use of quetiapine as an antipsychotic due to its potential side effects on cardiovascular Kv channels.

Current Status and Associated Factors of Post-Hemorrhagic Hydrocephalus in Infants of 22 to 28 Weeks Gestation With Severe Intraventricular Hemorrhage in Korea: A Nationwide Cohort Study.

BACKGROUND: Post-hemorrhagic hydrocephalus (PHH), a common complication of severe intraventricular hemorrhage (IVH) in very low birth weight (BW) infants, is associated with significant morbidity and poor neurological outcomes. The objective of this study was to assess the current status of PHH and analyze the risk factors associated with the necessity of treatment for PHH in infants born between 22 and 28 weeks of gestation, specifically those with severe IVH (grade 3 or 4). METHODS: The analysis was conducted on 1,097 infants who were born between 22-28 gestational weeks and diagnosed with severe IVH, using data from the Korean Neonatal Network. We observed that the prevalence of PHH requiring treatment was 46.3% in infants with severe IVH. RESULTS: Higher rates of mortality, transfer during admission, cerebral palsy, and ventriculoperitoneal shunt after discharge were higher in infants with PHH than in those without PHH. PHH in severe IVH was associated with a higher rate of pulmonary hemorrhage, seizures, and IVH grade 4 in the entire cohort. In addition, it was associated with a lower rate of small for gestational age and chorioamnionitis. In the subgroup analysis, high BW, outborn status, pulmonary hemorrhage, seizure, sepsis, and IVH grade 4 were associated with a higher incidence of PHH between 22 and 25 gestational weeks (GW). In infants born between 26 and 28 GW, a higher incidence of PHH was associated with seizures and IVH grade 4. CONCLUSION: It is necessary to maintain meticulous monitoring and neurological intervention for infants with PHH not only during admission but also after discharge. In addition, identifying the clinical factors that increase the likelihood of developing PHH from severe IVH is crucial.

Three-Dimensional Analysis of Bone Remodeling After Closed Treatment for Mandibular Condylar Head Fracture.

Closed treatment of mandibular condylar fractures has been used for its indications based on the fracture site, fracture status, and patient age. Posttreatment mandibular condyle size is associated with mandibular function; however, a few studies have reported bone remodeling patterns and volume changes in the condyle and glenoid fossa after mandibular condylar head fractures (CHFs). Therefore, volumetric changes in the mandibular condyle and glenoid fossa were analyzed in the present study, and bone remodeling patterns were evaluated after mandibular CHFs. The present study included 16 condyles from 12 patients who received closed treatment for CHF. After reconstruction of a 3-dimensional skull model, including the mandible, using computed tomography data taken immediately after injury and 6 months after treatment, volume changes in the mandibular condyle and glenoid fossa were analyzed. The condylar volume increased by 0.32±0.66 cm3 during the 6-month healing period without statistical significance (P=0.093). Regarding the glenoid fossa, the fossa showed a statistically significant volume increase of 0.41±0.59 cm3 (P=0.021), and 12 glenoid fossae (75%) showed downward bone apposition; however, no change or only mild bone resorption was observed in 4 glenoid fossae (25%). The results of this study indicated that the volume changes in the mandibular condyle after closed treatment of a mandibular CHF are not significant, and the glenoid fossa adapts to the displaced mandibular condyle through downward growth accompanied by volume increase.

Tailoring Two-Dimensional Matter Using Strong Light-Matter Interactions.

The shaping of matter into desired nanometric structures with on-demand functionalities can enhance the miniaturization of devices in nanotechnology. Herein, strong light-matter interaction was used as an optical lithographic tool to tailor two-dimensional (2D) matter into nanoscale architectures. We transformed 2D black phosphorus (BP) into ultrafine, well-defined, beyond-diffraction-limit nanostructures of ten times smaller size and a hundred times smaller spacing than the incident, femtosecond-pulsed light wavelength. Consequently, nanoribbons and nanocubes/cuboids scaling tens of nanometers were formed by the structured ablation along the extremely confined periodic light fields originating from modulation instability, the tailoring process of which was visualized in real time via light-coupled in situ transmission electron microscopy. The current findings on the controllable nanoscale shaping of BP will enable exotic physical phenomena and further advance the optical lithographic techniques for 2D materials.

Drug Repositioning via Graph Neural Networks: Identifying Novel JAK2 Inhibitors from FDA-Approved Drugs through Molecular Docking and Biological Validation.

The increasing utilization of artificial intelligence algorithms in drug development has proven to be highly efficient and effective. One area where deep learning-based approaches have made significant contributions is in drug repositioning, enabling the identification of new therapeutic applications for existing drugs. In the present study, a trained deep-learning model was employed to screen a library of FDA-approved drugs to discover novel inhibitors targeting JAK2. To accomplish this, reference datasets containing active and decoy compounds specific to JAK2 were obtained from the DUD-E database. RDKit, a cheminformatic toolkit, was utilized to extract molecular features from the compounds. The DeepChem framework's GraphConvMol, based on graph convolutional network models, was applied to build a predictive model using the DUD-E datasets. Subsequently, the trained deep-learning model was used to predict the JAK2 inhibitory potential of FDA-approved drugs. Based on these predictions, ribociclib, topiroxostat, amodiaquine, and gefitinib were identified as potential JAK2 inhibitors. Notably, several known JAK2 inhibitors demonstrated high potential according to the prediction results, validating the reliability of our prediction model. To further validate these findings and confirm their JAK2 inhibitory activity, molecular docking experiments were conducted using tofacitinib-an FDA-approved drug for JAK2 inhibition. Experimental validation successfully confirmed our computational analysis results by demonstrating that these novel drugs exhibited comparable inhibitory activity against JAK2 compared to tofacitinib. In conclusion, our study highlights how deep learning models can significantly enhance virtual screening efforts in drug discovery by efficiently identifying potential candidates for specific targets such as JAK2. These newly discovered drugs hold promises as novel JAK2 inhibitors deserving further exploration and investigation.

Surgical Drainage and Simultaneous Sinus Floor Augmentation in Patients with Chronic Maxillary Sinusitis.

Chronic maxillary sinusitis accompanied by severe thickening of the sinus mucosa, blockage of the ostium, and patient-reported symptoms requires preoperative assessment and treatment by an otolaryngologist before maxillary sinus floor augmentation (MSFA). Prescription of antibiotics and nasal saline irrigation are the first choice of treatment; however, endoscopic sinus surgery is considered when the treatment's effect is limited and drug resistance is observed. Nevertheless, MSFA performed in the presence of sinus pathologies have been reported to have favorable results when the lesions are managed properly. This report presents cases of two patients who required MSFA but were diagnosed with chronic maxillary sinusitis (case 1 with nasal sinusitis and case 2 with dental sinusitis). After 2 weeks of antibiotic therapy, endoscopic surgery was recommended due to minimal changes in the size of the sinus lesion; however, the patients refused because of improved self-reported symptoms. Therefore, intraoral surgical drainage was planned as an alternative treatment. A large bony window was prepared at the lateral wall of the maxillary sinus, and a long intentional incision was made to improve access for the suction tip in various directions and depths into the sinus cavity. Thorough suction of the purulent exudate and saline irrigation were performed through this access. The size of the perforated area was reduced along with the elevation of the Schneiderian membrane from the sinus floor, and simultaneous bone grafting with implant placement was performed. Prosthesis was delivered after 6-8 months. At 1-year follow-up after loading, favorable outcomes of implant survival and maintenance of augmented bone height were observed, with no recurrence of postoperative sinusitis. Within the limitations of the present case report, thorough sinus drainage and saline irrigation during maxillary sinus floor augmentation resolved sinus infection in patients with chronic maxillary sinusitis with short-term clinical outcomes.

Periodontal Phenotype Modification of Peri-Implant Soft Tissue Deficiency Using Subepithelial Connective Tissue Grafts and Bone Grafts in the Esthetic Region.

Peri-implant soft tissue deficiency (PSTD) is a significant factor impacting aesthetics, particularly in the anterior zone, where labial bone resorption and thin peri-implant phenotypes are common. The occurrence of a gray color around the implant fixture due to PSTD can be aesthetically concerning in the esthetic zone. In cases involving natural teeth, autogenous soft tissue grafts such as subepithelial connective tissue grafts (SCTGs), free gingival grafts (FGGs), and coronally advanced flaps (CAFs) are commonly utilized. However, there are limited reports of using bone grafts in conjunction with these techniques for modifying the gingival phenotype around both teeth and implants. In the presented cases where PSTD resulted in visible gray coloration of the implant fixture in the esthetic zone, mechanical and chemical decontamination of the exposed implant surface was performed using a titanium brush and tetracycline (Tc) HCl. Subsequently, to enhance peri-implant mucosa thickness and mask the titanium color, simultaneous SCTG and bone grafting procedures were conducted. Within the limitations of these case reports, successful esthetic outcomes were achieved and maintained without recurrence for 3-6 years following the simultaneous subepithelial connective tissue graft and bone graft procedures. These findings suggest the potential efficacy of this combined approach in addressing PSTD and enhancing aesthetic results around dental implants, though further studies are needed to validate these outcomes.

Large Peripheral Osteomas and Dental Implants: A Case Report.

Peripheral osteoma of the jaw is a rare, benign, slow-growing lesion, which usually appears as a unilateral, pedunculated, radiopaque mass protruding from the periphery and is generally solitary. Multiple osteomas without any syndromic involvement are rare. In the present case, a 75-year-old male patient underwent implant placement in the edentulous posterior ridges of the maxilla and mandible. Over 7 years, multiple masses gradually proliferated in the buccal bone of the implant in three different sextants of the posterior region, reaching a size of 2.0 cm. Clinically and radiologically, these lesions were presumed to be peripheral osteomas and were surgically removed because the large mass made self-performed oral hygiene and maintenance of peri-implant health difficult. The histopathological evaluation confirmed that peripheral osteomas were both compact and cancellous. The patient did not exhibit any other clinical manifestations of Gardner syndrome. Whether dental implant placement and loading are involved in the occurrence of peripheral osteomas is unclear, but they might have affected the consistent growth of the mass as a reactive mechanism. After resection, the functional abilities of chewing and self-cleansing significantly improved. No recurrence of peripheral osteoma was observed after 1 year of follow-up, and peri-implant health was well maintained. Within the limitations of the present case report, multiple peripheral osteomas can occur adjacent to dental implants without any syndromic issues, and a large mass of PO can harm peri-implant health which requires surgical removal. It is speculated that dental implants may be associated with the slow and consistent growth of PO.