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Background: The precise localization of stones within the submandibular duct is crucial for the successful intraoral removal in sialolithiasis. Customizing surgical approaches based on the stone's ductal location is imperative. Particularly challenging are stones beneath the lingual nerve, requiring a landmark-guided approach due to their non-palpable nature. This study aimed to comprehend stone positioning, location-specific characteristics, and develop suitable surgical approaches. We conducted a thorough analysis of numerous preoperative computed tomography (CT) scans for this purpose., Methods: We performed a retrospective review of the medical records of patients who underwent intraoral stone removal between 2006 and 2022. Two different surgical approaches were applied based on the stone location as determined by preoperative CT scans. The mediolingual approach was used for superficial stones, while the laterogingival approach was reserved for deeper stones. Patient demographics, sialolithiasis features, and postoperative complications were analyzed. T-test was performed to compare stone characteristics between different locations, and a receiver operating characteristic curve analysis was used to identify the critical size threshold for predicting stone location., Results: Medical records of 465 patients were reviewed. Out of 616 stones, 614 were successfully removed with two distinct surgical approaches guided by preoperative CT scans. Two patients reported retention, and 11 experienced postoperative tongue sensation changes. The hilum was the most common stone location, and deeper stones, approached laterolingually, were generally larger. Analysis identified a 4.25 mm width as the most sensitive and specific threshold for deep stones. Stone volume showed no statistically significant difference between smokers and non-smokers, alcohol consumers and non-consumer., Conclusion: The result of the study underscore the significance of precise stone localization and endorse the efficacy of landmark-guided surgical approaches in managing sialolithiasis., Competing Interests: Declarations. Ethics approval and consent to participate: This study and the written consent waiver were approved by the Institutional Review Board (IRB no. 2021-08-031-006). Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Salivary stones, known as sialoliths, form within the salivary ducts due to abnormal salivary composition and cause painful symptoms, for which surgical removal is the primary treatment. This study explored the role of the salivary microbial communities in the formation of sialoliths. We conducted a comparative analysis of microbial communities present in the saliva and salivary stones, and sequenced the 16S rRNA gene in samples obtained from patients with sialoliths and from healthy individuals. Although the diversity in the saliva was high, the essential features of the microbial environment in sialoliths were low diversity and evenness. The association of microbial abundance between stones and saliva revealed a positive correlation between Peptostreptococcus and Porphyromonas, and a negative correlation for Pseudomonas in saliva. The functional potential differences between saliva and stones Bacterial chemotaxis and the citrate cycle were negatively correlated with most genera found in salivary stone samples. However, the functions required for organic compound degradation did not differ between the saliva samples. Although some microbes were shared between the sialoliths and saliva, their compositions differed significantly. Our study presents a novel comparison between salivary stones and salivary microbiomes, suggesting potential preventive strategies against sialolithiasis., (© 2024. The Author(s).)

Vascular endothelial growth factor 165 (VEGF 165 ) is a prominent isoform of the VEGF-A protein that plays a crucial role in various angiogenesis-related diseases. It is homodimeric, and each of its monomers is composed of two domains connected by a flexible linker. DNA aptamers, which have emerged as potent therapeutic molecules for many proteins with high specificity and affinity, can also work for VEGF 165 . A DNA aptamer heterodimer composed of monomers of V7t1 and del5-1 connected by a flexible linker (V7t1:del5-1) exhibits a greater binding affinity with VEGF 165 compared to either of the two monomers alone. Although the structure of the complex formed between the aptamer heterodimer and VEGF 165 is unknown due to the highly flexible linkers, gaining structural information will still be valuable for future developments. Toward this end of accessing structural information, we adopt an ensemble docking approach here. We first obtain an ensemble of structures for both VEGF 165 and the aptamer heterodimer by considering both small- and large-scale motions. We then proceed through an extraction process based on ensemble docking, molecular dynamics simulations, and binding free energy calculations to predict the structures of the VEGF 165 /V7t1:del5-1 complex. Through the same procedures, we reach a new aptamer heterodimer that bears a locked nucleic acid-modified counterpart of V7t1, namely RNV66:del5-1, which also binds well with VEGF 165 . We apply the same protocol to the monomeric units V7t1, RNV66, and del5-1 to target VEGF 165 . We observe that V7t1:del5-1 and RNV66:del5-1 show higher binding affinities with VEGF 165 than any of the monomers, consistent with experiments that support the notion that aptamer heterodimers are more effective anti-VEGF 165 aptamers than monomeric aptamers. Among the five different aptamers studied here, the newly designed RNV66:del5-1 shows the highest binding affinity with VEGF 165 . We expect that our ensemble docking approach can help in de novo designs of homo/heterodimeric anti-angiogenic drugs to target the homodimeric VEGF 165 .

The vascular endothelial growth factor receptor 2 (VEGFR-2) is a member of receptor tyrosine kinases (RTKs) and is a dimeric membrane protein that functions as a primary regulator of angiogenesis. As is usual with RTKs, spatial alignment of its transmembrane domain (TMD) is essential toward VEGFR-2 activation. Experimentally, the helix rotations within TMD around their own helical axes are known to participate importantly toward the activation process in VEGFR-2, but the detailed dynamics of the interconversion between the active and inactive TMD forms have not been clearly elucidated at the molecular level. Here, we attempt to elucidate the process by using coarse grained (CG) molecular dynamics (MD) simulations. We observe that inactive dimeric TMD in separation is structurally stable over tens of microseconds, suggesting that TMD itself is passive and does not allow spontaneous signaling of VEGFR-2. By starting from the active conformation, we reveal the mechanism of TMD inactivation through analyzing the CG MD trajectories. We observe that interconversions between a left-handed overlay and a right-handed one are essential for the process of going from an active TMD structure to the inactive form. In addition, our simulations find that the helices can rotate properly when the overlaying structure of the helices interconverts and when the crossing angle of the two helices changes by larger than ~40 degrees. As the activation right after the ligand attachment on VEGFR-2 will take place in the reverse manner of this inactivation process, these structural aspects will also appear importantly for the activation process. The rather large change in helix configuration for activation also explains why VEGFR-2 rarely self-activate and how the activating ligand structurally drive the whole VEGFR-2. This mechanism of TMD activation / inactivation within VEGFR-2 may help in further understanding the overall activation processes of other RTKs., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Go et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Vascular endothelial growth factor 165 (VEGF 165 ), a predominant isoform of VEGF signal proteins, is an ideal target for developing drugs against various diseases. It is composed of a heparin binding domain (HBD) and a receptor binding domain (RBD), which are connected by a flexible linker. Among the two domains, RBD is utilized in binding with the signal transduction protein, the VEGF receptor (VEGFR). None the less for its pharmaceutical importance, structure-based studies for developing drugs has been severely hindered by the lack of its whole structure determination, mainly owing to the existence of the flexible linker. Fortunately, the utilization of computer simulation methods can offer a possibility to circumvent this difficult issue. Here, we employ ensemble docking in combination with the anisotropic network model analysis to examine the interactions between DNA aptamers and VEGF 165 . We model three-dimensional structures of aptamer variants based on their sequence information and perform docking calculations with the whole VEGF 165 structure. Indeed, we show that we can closely reproduce the experimental binding affinity order among different DNA aptamer variants by inclusively considering the flexible nature of VEGF. In addition, we address how DNA aptamer that binds to HBD of VEGF 165 impedes the interaction between VEGFR and VEGF 165 through RBD, even though HBD and RBD are rather distant. The present study illustrates that the flexible docking scheme employed here can be applied to tricky cases that involve flexible proteins with undetermined structures, toward effectively predicting ligand binding affinities to such proteins., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Recent studies have reported the advantages of spinal anesthesia over general anesthesia in orthopedic patients. However, little is known about the relationship between acute kidney injury (AKI) after total knee arthroplasty (TKA) and anesthetic technique. This study aimed to identify the influence of anesthetic technique on AKI in TKA patients. We also evaluated whether the choice of anesthetic technique affected other clinical outcomes. We retrospectively reviewed medical records of patients who underwent TKA between January 2008 and August 2016. Perioperative data were obtained and analyzed. To reduce the influence of potential confounding factors, propensity score (PS) analysis was performed. A total of 2809 patients and 2987 cases of TKA were included in this study. A crude analysis of the total set demonstrated a significantly lower risk of AKI in the spinal anesthesia group. After PS matching, the spinal anesthesia group showed a tendency for reduced AKI, without statistical significance. Furthermore, the spinal anesthesia group showed a lower risk of pulmonary and vascular complications, and shortened hospital stay after PS matching. In TKA patients, spinal anesthesia had a tendency to reduce AKI. Moreover, spinal anesthesia not only reduced vascular and pulmonary complications, but also shortened hospital stay., Competing Interests: The authors declare no conflicts of interest.

Although remote ischemic preconditioning (RIPC) has been shown to have renoprotective effects, few studies have assessed the effects of RIPC on renal function in living kidney donors. This study investigated whether RIPC performed in living kidney donors could improve residual renal function in donors and outcomes in recipients following kidney transplantation. The donors were randomized into a control group ( n = 85) and a RIPC group ( n = 85). The recipients were included according to the matched donors. Serum creatinine (sCr) concentrations and estimated glomerular filtration rate (eGFR) were compared between control and RIPC groups in donors and recipients. Delayed graft function, acute rejection, and graft failure within one year after transplantation were evaluated in recipients. sCr was significantly increased in the control group (mean, 1.13; 95% confidence interval (CI), 1.07-1.18) than the RIPC group (1.01; 95% CI, 0.95-1.07) ( p = 0.003) at discharge. Donors with serum creatinine >1.4 mg/dL at discharge had higher prevalence of chronic kidney disease ( n = 6, 26.1%) than donors with a normal serum creatinine level ( n = 8, 5.4%) ( p = 0.003) after one year. sCr concentrations and eGFR were similar in the RIPC and control groups of recipients over the one-year follow-up period. Among recipients, no outcome variables differed significantly in the RIPC and control groups. RIPC was effective in improving early renal function in kidney donors but did not improve renal function in recipients.

Purpose: This phase II study examined whether the addition of simvastatin to afatinib provides a clinical benefit compared with afatinib monotherapy in previously treated patients with nonadenocarcinomatous non-small cell lung cancer (NA-NSCLC)., Materials and Methods: Patients with advanced NA-NSCLC who progressed after one or two chemotherapy regimens were randomly assigned to a simvastatin (40 mg/day) plus afatinib (40 mg/day) (AS) arm or to an afatinib (A) arm. The primary endpoint was response rate (RR)., Results: Sixty-eight patients were enrolled (36 in the AS arm and 32 in the A arm). The RR was 5.7% (95% confidence interval [CI], 0.7 to 19.2) for AS and 9.4% (95% CI, 2.0 to 25.0) for A (p=0.440). In arms AS and A, the median progression-free survival (PFS) was 1.0 versus 3.6 months (p=0.240) and the overall survival was 10.0 months versus 7.0 months (p=0.930), respectively. Skin rash, stomatitis, and diarrhea were the most common adverse events in both arms. More grade 3 or 4 diarrhea was observed in arm A (18.8% vs. 5.6% in arm AS). In all patients, the median PFS for treatment including afatinib was not correlated with the status of epidermal growth factor receptor (EGFR) mutation (p=0.122), EGFR fluorescence in situ hybridization (p=0.944), or EGFR immunohistochemistry (p=0.976). However, skin rash severity was significantly related to the risk of progression for afatinib (hazard ratio for skin rash grade ≥ 2 vs. grade < 2, 0.44; 95% CI, 0.25 to 0.78; p=0.005)., Conclusion: There were no significant differences in the efficacy between AS and A arms in patients with NA-NSCLC.

General anesthesia is the main strategy for almost all thoracic surgeries. However, a growing body of literature has reported successful cases of non-intubated thoracic surgery with regional anesthesia. This alternative strategy not only prevents complications related to general anesthesia, such as lung injury, incomplete re-expansion and intubation related problems, but also accords with trends of shorter hospital stay and lower overall costs. We experienced a successful case of non-intubated thoracoscopic decortication for a 68-year-old man who was diagnosed as empyema while the patient kept spontaneously breathing with moderate sedation under thoracic epidural anesthesia. The patient showed a fast recovery without concerns of general anesthesia related complications and effective postoperative analgesia through thoracic epidural patient-controlled analgesia device. This is the first report of non-intubated thoracoscopic surgery under thoracic epidural anesthesia in Korea, and we expect that various well designed prospective studies will warrant the improvement of outcomes in non-intubated thoracoscopic surgery.