siRNA treatment targeting integrin α11 overexpressed via EZH2-driven axis inhibits drug-resistant breast cancer progression.

BACKGROUND: Breast cancer, the most prevalent cancer in women worldwide, faces treatment challenges due to drug resistance, posing a serious threat to patient survival. The present study aimed to identify the key molecules that drive drug resistance and aggressiveness in breast cancer cells and validate them as therapeutic targets. METHODS: Transcriptome microarray and analysis using PANTHER pathway and StemChecker were performed to identify the most significantly expressed genes in tamoxifen-resistant and adriamycin-resistant MCF-7 breast cancer cells. Clinical relevance of the key genes was determined using Kaplan-Meier survival analyses on The Cancer Genome Atlas dataset of breast cancer patients. Gene overexpression/knockdown, spheroid formation, flow cytometric analysis, chromatin immunoprecipitation, immunocytochemistry, wound healing/transwell migration assays, and cancer stem cell transcription factor activation profiling array were used to elucidate the regulatory mechanism of integrin α11 expression. Tumour-bearing xenograft models were used to demonstrate integrin α11 is a potential therapeutic target. RESULTS: Integrin α11 was consistently upregulated in drug-resistant breast cancer cells, and its silencing inhibited cancer stem cells (CSCs) and epithelial-mesenchymal transition (EMT) while restoring sensitivity to anticancer drugs. HIF1α, GLI-1, and EZH2 contributed the most to the regulation of integrin α11 and EZH2 expression, with EZH2 being more necessary for EZH2 autoinduction than HIF1α and GLI-1. Additionally, unlike HIF1α or EZH2, GLI-1 was the sole transcription factor activated by integrin-linked focal adhesion kinase, indicating GLI-1 as a key driver of the EZH2-integrin α11 axis operating for cancer stem cell survival and EMT. Kaplan-Meier survival analysis using The Cancer Genome Atlas (TCGA) dataset also revealed both EZH2 and integrin α11 could be strong prognostic factors of relapse-free and overall survival in breast cancer patients. However, the superior efficacy of integrin α11 siRNA therapy over EZH2 siRNA treatment was demonstrated by enhanced inhibition of tumour growth and prolonged survival in murine models bearing tumours. CONCLUSION: Our findings elucidate that integrin α11 is upregulated by EZH2, forming a positive feedback circuit involving FAK-GLI-1 and contributing to drug resistance, cancer stem cell survival and EMT. Taken together, the results suggest integrin α11 as a promising prognostic marker and a powerful therapeutic target for drug-resistant breast cancer.

The verification of delta SCF and Slater's transition state theory for the calculation of core ionization energy.

The core ionization energies of second- and third-period elements of the molecules C2 H5 NO2 , SiF4 , Si(CH3 )4 , PF3 , POF3 , PSF3 , CS2 , OCS, SO2 , SO2 F2 , CH3 Cl, CFCl3 , SF5 Cl, and Cl3 PS are calculated by using Hartree-Fock (HF), and Kohn-Sham (KS) with BH&HLYP, B3LYP, and LC-BOP functionals. We used ΔSCF, Slater's transition state (STS), and two previously proposed shifted STS (1) and shifted STS (2) methods, which have been developed. The errors of ΔSCF and STS come mainly from the self-interaction errors (SIE) and can be corrected with a shifting scheme. In this study, we used the shifting parameters determined for each atom. The shifted STS (1) reproduces ΔSCF almost perfectly with mean absolute deviations (MAD) of 0.02 eV. While ΔSCF and STS vary significantly depending on the functional used, the variation of shifted STS (2) is small, and all shifted STS (2) values are close to the observed ones. The deviations of the shifted STS (2) from the experiment are 0.24 eV (BH&HLYP), 0.19 eV (B3LYP), and 0.23 eV (LC-BOP). These results further support the use of shifted STS methods for predicting the core ionization energies.

Synthesis, Properties, and Application of Ultrathin and Flexible Tellurium Nanorope Films: Beyond Conventional 2D Materials.

Nanomaterials that can be easily processed into thin films are highly desirable for their wide range of applicability in electrical and optical devices. Currently, Te-based 2D materials are of interest because of their superior electrical properties compared to transition metal dichalcogenide materials. However, the large-scale manufacturing of these materials is challenging, impeding their commercialization. This paper reports on ultrathin, large-scale, and highly flexible Te and Te-metal nanorope films grown via low-power radiofrequency sputtering for a short period at 25 °C. Additionally, the feasibility of such films as transistor channels and flexible transparent conductive electrodes is discussed. A 20 nm thick Te-Ni-nanorope-channel-based transistor exhibits a high mobility (≈450 cm2 V-1 s-1 ) and on/off ratio (105 ), while 7 nm thick Te-W nanorope electrodes exhibit an extremely low haze (1.7%) and sheet resistance (30 Ω sq-1 ), and high transmittance (86.4%), work function (≈4.9 eV), and flexibility. Blue organic light-emitting diodes with 7 nm Te-W anodes exhibit significantly higher external quantum efficiencies (15.7%), lower turn-on voltages (3.2 V), and higher and more uniform viewing angles than indium-tin-oxide-based devices. The excellent mechanical flexibility and easy coating capability offered by Te nanoropes demonstrate their superiority over conventional nanomaterials and provide an effective outlet for multifunctional devices.

Bio-Inspired Photosensory Artificial Synapse Based on Functionalized Tellurium Multiropes for Neuromorphic Computing.

Nanomaterials like graphene and transition metal dichalcogenides are being explored for developing artificial photosensory synapses with low-power optical plasticity and high retention time for practical nervous system implementation. However, few studies are conducted on Tellurium (Te)-based nanomaterials due to their direct and small bandgaps. This paper reports the superior photo-synaptic properties of covalently bonded Tellurium sulfur oxide (TeSOx ) and Tellurium selenium oxide (TeSeOx )nanomaterials, which are fabricated by incorporating S and Se atoms on the surface of Te multiropes using vapor deposition. Unlike pure Te multiropes, the TeSOx and TeSeOx multiropes exhibit controllable temporal dynamics under optical stimulation. For example, the TeSOx multirope-based transistor displays a photosensory synaptic response to UV light (λ = 365 nm). Furthermore, the TeSeOx multirope-based transistor exhibits photosensory synaptic responses to UV-vis light (λ = 365, 565, and 660 nm), reliable electrical performance, and a combination of both photodetector and optical artificial synaptic properties with a maximum responsivity of 1500 AW-1 to 365 nm UV light. This result is among the highest reported for Te-heterostructure-based devices, enabling optical artificial synaptic applications with low voltage spikes (1 V) and low light intensity (21 µW cm-2 ), potentially useful for optical neuromorphic computing.

Phase Change Heterostructure Memory with Oxygen-Doped Sb2Te3 Layers for Improved Durability and Reliability through Nano crystalline Island Formation.

Phase-change random access memory represents a notable advancement in nonvolatile memory technology; however, it faces challenges in terms of thermal stability and reliability, hindering its broader application. To mitigate these issues, doping and structural modification techniques such as phase-change heterostructures (PCH) are widely studied. Although doping typically enhances thermal stability, it can adversely affect the switching speed. Structural modifications such as PCH have struggled to sustain stable performance under high atmospheric conditions. In this study, these challenges are addressed by synergizing oxygen-doped Sb2Te3 (OST) with PCH technology. This study presents a novel approach in which OST significantly improves the crystallization temperature, power efficiency, and cyclability. Subsequently, the integration of the PCH technology bolsters the switching speed and further amplifies the device's reliability and endurance by refining the grain size (≈7 nm). The resultant OST-PCH devices exhibit exceptional performance metrics, including a drift coefficient of 0.003 in the RESET state, endurance of ≈4 × 108 cycles, an switching speed of 300 ns, and 67.6 pJ of RESET energy. These findings suggest that the OST-PCH devices show promise for integration into embedded systems, such as those found in automotive applications and Internet of Things devices.

Preoperative COVID-19 and Postoperative Mortality in Cancer Surgery: A South Korean Nationwide Study.

BACKGROUND: We evaluated the impact of preoperative COVID-19 on early postoperative mortality in patients undergoing time-sensitive cancer surgery. METHODS: This retrospective, nationwide cohort study included adult patients who underwent various cancer (thyroid, breast, stomach, colorectal, hepatobiliary, genitourinary, lung, and multiple cancer) surgeries under general anesthesia in South Korea in 2022. Patients were grouped according to the duration from the date of COVID-19 confirmation to the date of surgery (0-2 weeks, 3-4 weeks, 5-6 weeks, and ≥7 weeks). Patients without preoperative COVID-19 also were included. Multivariable logistic regression analysis with Firth correction was performed to investigate the association between preoperative COVID-19 and 30-day and 90-day postoperative mortality. The covariates encompassed sociodemographic factors, the type of surgery, and vaccination status in addition to the aforementioned groups. RESULTS: Of the 99,555 patients analyzed, 30,933 (31.1%) were preoperatively diagnosed with COVID-19. Thirty-day mortality was increased in those who underwent surgery within 0-2 weeks after diagnosis of COVID-19 (adjusted odds ratio [OR], 1.47; 95% confidence interval [CI], 1.02-2.12; P = 0.038); beyond 2 weeks, there was no significant increase in mortality. A similar pattern was observed for 90-day mortality. Full vaccination against COVID-19 was associated with reduced 30-day (OR 0.38; 95% CI 0.29-0.50; P < 0.001) and 90-day (OR 0.39; 95% CI 0.33-0.46; P < 0.001) mortality. CONCLUSIONS: Cancer surgery within 2 weeks of COVID-19 diagnosis was associated with increased early postoperative mortality. These findings support current guidelines that recommend postponing elective surgery for at least 2 weeks after the diagnosis of COVID-19.

Effect of an intravenous acetaminophen/ibuprofen fixed-dose combination on postoperative opioid consumption and pain after video-assisted thoracic surgery: a double-blind randomized controlled trial.

BACKGROUND: Video-assisted thoracoscopic surgery (VATS) often induces significant postoperative pain, potentially leading to chronic pain and decreased quality of life. This study aimed to evaluate the acetaminophen/ibuprofen combination effectiveness in reducing analgesic requirements and pain intensity in patients undergoing VATS. STUDY DESIGN: This is a double-blinded randomized controlled trial. METHODS: Adult patients scheduled for elective VATS for lung resection were randomized to receive either intravenous acetaminophen and ibuprofen (intervention group) or 100 mL normal saline (control group). Treatments were administered post-anesthesia induction and every 6 h for three cycles. The primary outcome was total analgesic consumption at 24 h postoperatively. Secondary outcomes were cumulative analgesic consumption at 2 and 48 h; analgesic-related side effects at 2, 24, and 48 h; quality of recovery at 24 h and 48 h postoperatively; pain intensity at rest and during coughing; and rescue analgesics use. Chronic postsurgical pain (CPSP) was assessed through telephone interviews 3 months postoperatively. RESULTS: The study included 96 participants. The intervention group showed significantly lower analgesic consumption at 24 h and 48 h postoperatively (24 h: median difference: - 100 µg equivalent intravenous fentanyl [95% confidence interval (CI) - 200 to - 5 µg], P = 0.037; 48 h: median difference: - 140 µg [95% CI - 320 to - 20 µg], P = 0.035). Compared to the controls, the intervention group exhibited a significantly lower quality of recovery 24 h post-surgery, with no significant difference at 48 h. All pain scores except for coughing at 48 h post-surgery were significantly lower in the intervention group compared to the controls. No significant differences were observed between the groups in postoperative nausea and vomiting occurrence, hospital stay length, and CPSP. CONCLUSION: Perioperative administration of acetaminophen/ibuprofen significantly decreased analgesic needs in patients undergoing VATS, providing an effective postoperative pain management strategy, and potentially minimizing the need for stronger analgesics.

Volatile Anesthetic Use Versus Total Intravenous Anesthesia for Patients Undergoing Heart Valve Surgery: A Nationwide Population-Based Study.

BACKGROUND: Many studies have suggested that volatile anesthetic use may improve postoperative outcomes after cardiac surgery compared to total intravenous anesthesia (TIVA) owing to its potential cardioprotective effect. However, the results were inconclusive, and few studies have included patients undergoing heart valve surgery. METHODS: This nationwide population-based study included all adult patients who underwent heart valve surgery between 2010 and 2019 in Korea based on data from a health insurance claim database. Patients were divided based on the use of volatile anesthetics: the volatile anesthetics or TIVA groups. After stabilized inverse probability of treatment weighting (IPTW), the association between the use of volatile anesthetics and the risk of cumulative 1-year all-cause mortality (the primary outcome) and cumulative long-term (beyond 1 year) mortality were assessed using Cox regression analysis. RESULTS: Of the 30,755 patients included in this study, the overall incidence of 1-year mortality was 8.5%. After stabilized IPTW, the risk of cumulative 1-year mortality did not differ in the volatile anesthetics group compared to the TIVA group (hazard ratio, 0.98; 95% confidence interval, 0.90-1.07; P = .602), nor did the risk of cumulative long-term mortality (hazard ratio, 0.98; 95% confidence interval, 0.93-1.04; P = .579) at a median (interquartile range) follow-up duration of 4.8 (2.6-7.6) years. CONCLUSIONS: Compared with TIVA, volatile anesthetic use was not associated with reduced postoperative mortality risk in patients undergoing heart valve surgery. Our findings indicate that the use of volatile anesthetics does not have a significant impact on mortality after heart valve surgery. Therefore, the choice of anesthesia type can be based on the anesthesiologists' or institutional preference and experience.

Effect of Transition Metal Dichalcogenide Based Confinement Layers on the Performance of Phase-Change Heterostructure Memory.

Phase-change random-access memory is a promising non-volatile memory technology. However repeated phase-change operations can cause durability issues owing to defects formed by long-distance atom diffusion. To mitigate these issues, phase-change heterostructure (PCH) devices with confinement material (CM) layers based on transition metal dichalcogenides (TMDs) such as TiTe2 have been proposed. This study implements PCH devices with additional TMDs, including NiTe2 and MoTe2 , alongside TiTe2 , and analyzes their characteristics by examining the differences in the CM layers. The results show that the NiTe2 -based PCH device demonstrates a RESET current of 1.4 mA, 38% lower than that of the TiTe2 -based device, enabling low-power operation. Furthermore, the MoTe2 -based PCH device exhibits a cycling endurance exceeding 107 cycles, a five-fold improvement in durability compare with the TiTe2 -based device. The performance differences observe in each PCH device can be attributed to the variation in the material properties, such as the cohesive energy and electrical conductivity, of the TMDs used as the CM layer. These results provide critical clues to improve the performance and reliability of conventional PCH memory devices.

Effect of a repeated verbal reminder of orientation on emergence agitation after general anaesthesia for minimally invasive abdominal surgery: a randomised controlled trial.

BACKGROUND: An orientation strategy providing repeated verbal reminders of time, place, and person has been widely used for the non-pharmacological management of delirium. We hypothesised that using this strategy could reduce emergence agitation and improve recovery profiles. METHODS: This prospective observer-blinded RCT included male and female patients aged 18-70 yr undergoing minimally invasive abdominal surgery. During emergence from general anaesthesia, subjects in the orientation group (n=57) were provided a repeated reminder, including orientation: '(Patient's name), you are now recovering from general anaesthesia after surgery at Seoul National University Hospital, open your eyes!' via noise-cancelling headphones, whereas those in the control group (n=57) only heard their name: '(Patient's name), open your eyes!'. The primary outcome was the incidence of emergence agitation (Riker sedation agitation scale [SAS] ≥5). The incidence of dangerous agitation (SAS=7), maximal SAS score in the operating room, and recovery profile until 24 h postoperatively were evaluated as secondary outcomes. RESULTS: The incidence of emergence agitation in the operating room was significantly lower in the orientation group than in the control group (16/57 [28.1%] vs 38/57 [66.7%]; relative risk [95% confidence interval], 0.5 [0.3-0.7]; P<0.001). The incidence of dangerous agitation (0 [0.0%] vs 10 [17.5%], P=0.001) and the median maximal SAS score (4 [4-5] vs 5 [4-6], P<0.001) were also lower in the orientation group. Secondary outcomes, other than agitation-related variables, were comparable between the two groups. CONCLUSIONS: Repeated verbal stimulation of orientation may serve as a simple and easily applicable strategy to reduce emergence agitation after general anaesthesia. CLINICAL TRIAL REGISTRATION: NCT05105178.

The core ionization energies calculated by delta SCF and Slater's transition state theory.

The core ionization energies of the second-period and third-period elements are studied by ΔSCF and Slater's transition state (STS) theory by using Hartree-Fock (HF) and Kohn-Sham (KS) approximations. Electron correlation increases the estimated core ionization energies, while the self-interaction error (SIE) decreases them, especially for the third-period elements and is a more significant factor. As a result, while HF lacks electron correlation, it is free of SIE and reasonably predicts the core ionization energies. The core ionization energies calculated by HF STS are very close to those calculated by HF ΔSCF, showing that STS reasonably describes the relaxation of the core hole. The core ionization energies calculated by KS are particularly sensitive to the SIE of the functional used, with functionals having less SIE yielding more accurate ΔSCF core ionization energies. Consequently, BH&HLYP gives better results than B3LYP and LC-BOP since BH&HLYP is the hybrid functional with high proportion of the exact HF exchange. Although the core ionization energies are underestimated by ΔSCF due to SIE, STS gives larger core ionization energies than ΔSCF due to a concave behavior of the error curves of STS, which is also related to SIE. The mean absolute deviations of STS relative to ΔSCF, and relative to the experiment, are almost constant regardless of the nuclei among the element in the second period, and likewise among those in the third period. The systematic nature suggests that shifting the STS core ionization energies may be useful. We propose the shifted STS (1) for reproducing ΔSCF values, and the shifted STS (2) to reproduce the observed ones for KS calculations. Both schemes work quite well. The calculated results of KS ΔSCF and STS vary depending on the functional. However, the variation of each species' shifted STS (2) is very small, and all shifted STS (2) values are close to the observed ones. As the shifted STS require only one SCF calculation, they are simple and practical for predicting the core ionization energies.

Comparison of the recovery profile of remimazolam with flumazenil and propofol anesthesia for open thyroidectomy.

BACKGROUND: Previous studies have consistently reported a slower recovery of consciousness following remimazolam-based total intravenous anesthesia without flumazenil than with propofol. This study aimed to compare the reversal effect of flumazenil on the recovery of consciousness after remimazolam-based total intravenous anesthesia with the propofol recovery profile. METHODS: This prospective, single-blinded, randomized trial included 57 patients undergoing elective open thyroidectomy at a tertiary university hospital. Patients were randomly allocated to receive either remimazolam- or propofol-based total intravenous anesthesia (remimazolam group: 28 patients, propofol group: 29 patients). The primary outcome was the time from the end of general anesthesia to first eye opening (min). The secondary outcomes were the time from the end of the general anesthesia to extubation (min), initial modified Aldrete score measured at the post-anesthesia care unit, length of stay at the post-anesthesia care unit (min), occurrence of postoperative nausea and vomiting during the first 24 h postoperatively, and Korean version of Quality of Recovery-15 score at 24 h postoperatively. RESULTS: The remimazolam group showed significantly faster first eye opening time (2.3 [interquartile range, IQR: 1.8-3.3] min vs. 5.0 [IQR: 3.5-7.8] min, median difference:-2.7 [95% confidence interval, CI: -3.7 to -1.5] min, P < 0.001) and extubation time (3.2 [IQR: 2.4-4.2] min vs. 5.7 [IQR: 4.7-8.3] min, median difference: -2.7 [97.5% CI: -5.0 to -1.6] min, P < 0.001). There were no significant differences in other postoperative outcomes. CONCLUSIONS: The planned incorporation of flumazenil with remimazolam-based total intravenous anesthesia provided rapid and reliable recovery of consciousness.

Comparison of invasive and non-invasive measurements of cardiac index and systemic vascular resistance in living-donor liver transplantation: a prospective, observational study.

BACKGROUND: Based on the controversy surrounding pulmonary artery catheterization (PAC) in surgical patients, we investigated the interchangeability of cardiac index (CI) and systemic vascular resistance (SVR) measurements between ClearSight™ and PAC during living-donor liver transplantation (LDLT). METHODS: This prospective study included consecutively selected LDLT patients. ClearSight™-based CI and SVR measurements were compared with those from PAC at seven LDLT-stage time points. ClearSight™-based systolic (SAP), mean (MAP), and diastolic (DAP) arterial pressures were also compared with those from femoral arterial catheterization (FAC). For the comparison and analysis of ClearSight™ and the reference method, Bland-Altman analysis was used to analyze accuracy while polar and four-quadrant plots were used to analyze the trending ability. RESULTS: From 27 patients, 189 pairs of ClearSight™ and reference values were analyzed. The CI and SVR performance errors (PEs) exhibited poor accuracy between the two methods (51.52 and 51.73%, respectively) in the Bland-Altman analysis. CI and SVR also exhibited unacceptable trending abilities in both the polar and four-quadrant plot analyses. SAP, MAP, and DAP PEs between the two methods displayed favorable accuracy (24.28, 21.18, and 26.26%, respectively). SAP and MAP exhibited acceptable trending ability in the four-quadrant plot between the two methods, but not in the polar plot analyses. CONCLUSIONS: During LDLT, CI and SVR demonstrated poor interchangeability, while SAP and MAP exhibited acceptable interchangeability between ClearSight™ and FAC.

Computational Investigation of Conformational Properties of Short Azapeptides: Insights from DFT Study and NBO Analysis.

Azapeptides have gained much attention due to their ability to enhance the stability and bioavailability of peptide drugs. Their structural preferences, essential to understanding their function and potential application in the peptide drug design, remain largely unknown. In this work, we systematically investigated the conformational preferences of three azaamino acid residues in tripeptide models, Ac-azaXaa-Pro-NHMe [Xaa = Asn (4), Asp (5), Ala (6)], using the popular DFT functionals, B3LYP and B3LYP-D3. A solvation model density (SMD) was used to mimic the solvation effect on the conformational behaviors of azapeptides in water. During the calculation, we considered the impact of the amide bond in the azapeptide models on the conformational preferences of models 4-6. We analyzed the effect of the HB between the side-chain main chain and main-chain main-chain on the conformational behaviors of azapeptides 4-6. We found that the predicted lowest energy conformation for the three models differs depending on the calculation methods. In the gas phase, B3LYP functional indicates that the conformers tttANP-1 and tttADP-1 of azapeptides 4 and 5 correspond to the type I of ß-turn, the lowest energy conformation with all-trans amide bonds. Considering the dispersion correction, B3LYP-D3 functional predicts the conformers tctANP-2 and tctADP-3 of azapeptide 4 and 5, which contain the cis amide bond preceding the Pro residue, as the lowest energy conformation in the gas phase. The results imply that azaAsx and Pro residues may involve cis-trans isomerization in the gas phase. In water, the predicted lowest energy conformer of azapeptides 4 and 5 differs from the gas phase results and depends on the calculational method. For azapeptide 6, regardless of calculation methods and phases, tttAAP-1 (ß-I turn) is predicted as the lowest energy conformer. The results imply that the effect of the side chain that can form HBs on the conformational preferences of azapeptides 4 and 5 may not be negligible. We compared the theoretical results of azaXaa-Pro models with those of Pro-azaXaa models, showing that incorporating azaamino acid residue in peptides at different positions can significantly impact the folding patterns and stability of azapeptides.

Targeting epidermal growth factor receptor in paclitaxel-resistant human breast and lung cancer cells with upregulated glucose-6-phosphate dehydrogenase.

BACKGROUND: Chemoresistance is a major obstacle to the successful treatment of triple-negative breast cancer (TNBC) and non-small-cell lung cancer (NSCLC). Therapeutic strategies to overcome chemoresistance are necessary to improve the prognosis of patients with these cancers. METHODS: Paclitaxel-resistant TNBC and NSCLC sublines were generated through continuous paclitaxel treatment over 6 months. The mechanistic investigation was conducted using MTT assay, LC/MS-based metabolite analysis, flow cytometry, western blot analysis, real-time PCR and tumour xenograft experiments. RESULTS: Glucose-6-phosphate dehydrogenase (G6PD) expression along with an increase in 3-phosphoglycerates and ribulose-5-phosphate production was upregulated in paclitaxel-resistant cells. Blockade of G6PD decreased viability of paclitaxel-resistant cells in vitro and the growth of paclitaxel-resistant MDA/R xenograft tumours in vivo. Mechanistically, activation of the epidermal growth factor receptor (EGFR)/Akt pathway mediates G6PD expression and G6PD-induced cell survival. Blockade of the EGFR pathway inhibited G6PD expression and sensitised those paclitaxel-resistant cells to paclitaxel treatment in vitro and in vivo. Analysis of publicly available datasets revealed an association between G6PD and unfavourable clinical outcomes in patients with breast or lung cancer. CONCLUSIONS: EGFR signaling-mediated G6PD expression plays a pivotal role in paclitaxel resistance, highlighting the potential of targeting EGFR to overcome paclitaxel resistance in TNBC and NSCLC cells overexpressing G6PD.

Ultrasound-guided bilateral subcostal transversus abdominis plane block in gastric cancer patients undergoing laparoscopic gastrectomy: a randomised-controlled double-blinded study.

BACKGROUND: The effectiveness of subcostal transversus abdominis plane block (TAPB) in laparoscopic gastric cancer surgery is unknown. We aimed to investigate its opioid-sparing and pain-relief effects in laparoscopic gastrectomy for gastric cancer. METHOD: One hundred and twelve patients undergoing elective laparoscopic gastrectomy were randomised to the TAPB or control group. The TAPB group received ultrasound-guided bilateral subcostal TAPB at the end of surgery, while the control group did not. We investigated fentanyl consumption administered via intravenous patient-controlled analgesia and as a rescue analgesic, the numeric rating scale (NRS) pain scores at rest and during coughing, and the opioid-related side effects at 6, 12, 24, and 48 h postoperatively. The primary outcome was cumulative fentanyl consumption at 24 h postoperatively. RESULTS: The study included 53 patients in each group. The cumulative fentanyl consumption 24 h postoperatively was significantly lower in the TAPB group than in the control group (median difference -170 mcg, P = 0.03, 95% CI -360 to -15 mcg). Subcostal TAPB also significantly reduced the resting NRS score at 48 h postoperatively (median difference -1, 95% CI -1 to 0, P = 0.01) and coughing NRS score at all time points (all median difference -1, 95% CI -2 to 0, P < 0.01, P  = 0.02, 0.01, and 0.01, respectively). However, it did not reduce the occurrence of opioid-related side effects, except the use of antiemetics during the first 6 h postoperatively (TAPB, 1.9% vs. Control, 15.1%, P = 0.03). CONCLUSION: Ultrasound-guided bilateral subcostal TAPB provides efficient postoperative analgesia with an opioid-sparing effect after laparoscopic gastrectomy.

Can the Rhomboid Major Muscle Be Used to Identify the Thoracic Spinal Segment on Ultrasonography? A Prospective Observational Study.

OBJECTIVE: We investigated the thoracic segment corresponding to the inferior margin of the rhomboid major muscle (RMM) using ultrasound (US) to evaluate its potential as a reliable anatomic landmark for segment identification. DESIGN: A prospective observational study. SETTING: An operating room. SUBJECTS: Patients who underwent procedures around the thoracic spine. METHODS: Four hundred segments corresponding to the RMM's inferior margin were identified through the use of paravertebral sagittal US and confirmed by fluoroscopy in 100 participants in the prone position with upward and downward shoulder rotation, comprising four datasets (up-right, up-left, down-right, and down-left). The US identification of the RMM's inferior margin was dichotomously scored (clear vs ambiguous). Each dataset was divided into two groups (dominant segment group vs remaining segments group), which were compared. Factors relevant to the dominant segment associated with the RMM's inferior border were determined through univariable analyses. RESULTS: The T6 segment was observed most commonly (59.5%) along the RMM's inferior border on paravertebral sagittal US acquired in the prone position, followed by T5 (25.0%), T7 (12.8%), and T4 (2.7%). The segments corresponding to the RMM remained unchanged by shoulder posture in most participants (n = 74, 74%). The RMM's inferior border was clearly distinguishable in 330 cases (82.5%). When the RMM's inferior border was clearly identified, the corresponding segment was likely to match T6 in all datasets, with odds ratios ranging from 3.24 to 6.2. CONCLUSIONS: The RMM's inferior border over the transverse process corresponded to T6 most frequently on paravertebral sagittal US, and its deep fascia was clearly visible in most cases.

Development of PD3 and PD3-B for PDEδ inhibition to modulate KRAS activity.

Despite extensive efforts over 40 years, few effective KRAS inhibitors have been developed to date, mainly due to the undruggable features of KRAS proteins. In addition to the direct approach to KRAS via covalent inhibition, modulation of the prenyl-binding protein PDEδ that binds with farnesylated KRAS has emerged as an alternative strategy to abrogate KRAS activity. For the verification of new therapeutic strategies, chemical probes with the dual functions of visualisation and pharmacological inhibition against oncogenic proteins are enormously valuable to understand cellular events related to cancer. Here, we report indolizino[3,2-c]quinoline (IQ)-based fluorescent probes (PD3 and PD3-B) for PDEδ inhibition. By using the unique fluorescent characteristics of the IQ scaffold, a fluorescence polarisation (FP)-based binding assay identified PD3 as the most effective PDEδ probe among the tested PD analogues, with a low Kd value of 0.491 µM and long retention time in the binding site of PDEδ. In particular, a FP-based competition assay using deltarasin verified that PD3 occupies the farnesylation binding site of PDEδ, excluding the possibility that the FP signals resulted from non-specific hydrophobic interactions between the ligand and protein in the assay. We also designed and synthesised PD3-B (5), an affinity-based probe (ABP) from the PD3 structure, which enabled us to pull down PDEδ from bacterial lysates containing a large number of intrinsic bacterial proteins. Finally, KRAS relocalization was verified in PANC-1 cells by treatment with PD3, suggesting its potential as an effective probe to target PDEδ.

Hounsfield unit measurement method and related factors that most appropriately reflect bone mineral density on cervical spine computed tomography.

OBJECTIVE: Our study's purpose was to determine the most reliable Hounsfield unit (HU) measurement method to reflect bone mineral density (BMD) on cervical spine computed tomography (CT) and to identify any factors that influence these results. MATERIALS AND METHODS: We retrospectively analyzed 439 consecutive patients with mild head and neck injuries. Mean HU values of the C2-C7 vertebra were determined on each sagittal, coronal, and axial CT image. Correlation patterns were analyzed between the HU value and corresponding dual-energy X-ray absorptiometry (DXA) in the lumbar vertebra (T-score) and femoral neck (T-score). A sub-group analysis was performed according to patient age, sex, and degree of spinal degeneration. RESULTS: The correlation coefficients for HU and DXA ranged from 0.52 to 0.65 in all cervical segments. A simple linear regression analysis revealed the following formula: T-score = 0.01 × (HU) - 4.55. The mean HU values for osteopenia and osteoporosis were 284.0 ± 63.3 and 231.5 ± 52.8, respectively. The ROC curve indicated that the HU method has a sensitivity of 89.2% and specificity of 88.7% to diagnose osteoporosis. The HU measurement showed a high correlation value (range: r = 0.64-0.70) with spine DXA score regardless of the degree of degeneration or patient age or sex. CONCLUSION: HU values using the upper two cervical vertebrae (C2 and C3) reflected a more reliable BMD level than other segments. Additionally, the HU of cervical CT provided reliable information regardless of measurement plane, age or sex, and degree of degeneration.

Significant Therapeutic Effects of Adult Human Neural Stem Cells for Spinal Cord Injury Are Mediated by Monocyte Chemoattractant Protein-1 (MCP-1).

The limited capability of regeneration in the human central nervous system leads to severe and permanent disabilities following spinal cord injury (SCI) while patients suffer from no viable treatment option. Adult human neural stem cells (ahNSCs) are unique cells derived from the adult human brain, which have the essential characteristics of NSCs. The objective of this study was to characterize the therapeutic effects of ahNSCs isolated from the temporal lobes of focal cortical dysplasia type IIIa for SCI and to elucidate their treatment mechanisms. Results showed that the recovery of motor functions was significantly improved in groups transplanted with ahNSCs, where, in damaged regions of spinal cords, the numbers of both spread and regenerated nerve fibers were observed to be higher than the vehicle group. In addition, the distance between neuronal nuclei in damaged spinal cord tissue was significantly closer in treatment groups than the vehicle group. Based on an immunohistochemistry analysis, those neuroprotective effects of ahNSCs in SCI were found to be mediated by inhibiting apoptosis of spinal cord neurons. Moreover, the analysis of the conditioned medium (CM) of ahNSCs revealed that such neuroprotective effects were mediated by paracrine effects with various types of cytokines released from ahNSCs, where monocyte chemoattractant protein-1 (MCP-1, also known as CCL2) was identified as a key paracrine mediator. These results of ahNSCs could be utilized further in the preclinical and clinical development of effective and safe cell therapeutics for SCI, with no available therapeutic options at present.