Network representation of multicellular activity in pancreatic islets: Technical considerations for functional connectivity analysis.

Within the islets of Langerhans, beta cells orchestrate synchronized insulin secretion, a pivotal aspect of metabolic homeostasis. Despite the inherent heterogeneity and multimodal activity of individual cells, intercellular coupling acts as a homogenizing force, enabling coordinated responses through the propagation of intercellular waves. Disruptions in this coordination are implicated in irregular insulin secretion, a hallmark of diabetes. Recently, innovative approaches, such as integrating multicellular calcium imaging with network analysis, have emerged for a quantitative assessment of the cellular activity in islets. However, different groups use distinct experimental preparations, microscopic techniques, apply different methods to process the measured signals and use various methods to derive functional connectivity patterns. This makes comparisons between findings and their integration into a bigger picture difficult and has led to disputes in functional connectivity interpretations. To address these issues, we present here a systematic analysis of how different approaches influence the network representation of islet activity. Our findings show that the choice of methods used to construct networks is not crucial, although care is needed when combining data from different islets. Conversely, the conclusions drawn from network analysis can be heavily affected by the pre-processing of the time series, the type of the oscillatory component in the signals, and by the experimental preparation. Our tutorial-like investigation aims to resolve interpretational issues, reconcile conflicting views, advance functional implications, and encourage researchers to adopt connectivity analysis. As we conclude, we outline challenges for future research, emphasizing the broader applicability of our conclusions to other tissues exhibiting complex multicellular dynamics.

Spatially and Temporally Resolved Dynamic Response of Co-Based Composite Interface during the Oxygen Evolution Reaction.

Interfacial interaction dictates the overall catalytic performance and catalytic behavior rules of the composite catalyst. However, understanding of interfacial active sites at the microscopic scale is still limited. Importantly, identifying the dynamic action mechanism of the "real" active site at the interface necessitates nanoscale, high spatial-time-resolved complementary-operando techniques. In this work, a Co3O4 homojunction with a well-defined interface effect is developed as a model system to explore the spatial-correlation dynamic response of the interface toward oxygen evolution reaction. Quasi in situ scanning transmission electron microscopy-electron energy-loss spectroscopy with high spatial resolution visually confirms the size characteristics of the interface effect in the spatial dimension, showing that the activation of active sites originates from strong interfacial electron interactions at a scale of 3 nm. Multiple time-resolved operando spectroscopy techniques explicitly capture dynamic changes in the adsorption behavior for key reaction intermediates. Combined with density functional theory calculations, we reveal that the dynamic adjustment of multiple adsorption configurations of intermediates by highly activated active sites at the interface facilitates the O-O coupling and *OOH deprotonation processes. The dual dynamic regulation mechanism accelerates the kinetics of oxygen evolution and serves as a pivotal factor in promoting the oxygen evolution activity of the composite structure. The resulting composite catalyst (Co-B@Co3O4/Co3O4 NSs) exhibits an approximately 70-fold turnover frequency and 20-fold mass activity than the monomer structure (Co3O4 NSs) and leads to significant activity (η10 ∼257 mV). The visual complementary analysis of multimodal operando/in situ techniques provides us with a powerful platform to advance our fundamental understanding of interfacial structure-activity relationships in composite structured catalysts.

Patients with ASPSCR1-TFE3 fusion achieve better response to ICI based combination therapy among TFE3-rearranged renal cell carcinoma.

BACKGROUND: TFE3-rearranged renal cell carcinoma (TFE3-rRCC) is a rare but highly heterogeneous renal cell carcinoma (RCC) entity, of which the clinical treatment landscape is largely undefined. This study aims to evaluate and compare the efficacy of different systemic treatments and further explore the molecular correlates. METHODS: Thirty-eight patients with metastatic TFE3-rRCC were enrolled. Main outcomes included progression-free survival (PFS), overall survival, objective response rate (ORR) and disease control rate. RNA sequencing was performed on 32 tumors. RESULTS: Patients receiving first-line immune checkpoint inhibitor (ICI) based combination therapy achieved longer PFS than those treated without ICI (median PFS: 11.5 vs. 5.1 months, P = 0.098). After stratification of fusion partners, the superior efficacy of first-line ICI based combination therapy was predominantly observed in ASPSCR1-TFE3 rRCC (median PFS: not reached vs. 6.5 months, P = 0.01; ORR: 67.5% vs. 10.0%, P = 0.019), but almost not in non-ASPSCR1-TFE3 rRCC. Transcriptomic data revealed enrichment of ECM and collagen-related signaling in ASPSCR1-TFE3 rRCC, which might interfere with the potential efficacy of anti-angiogenic monotherapy. Whereas angiogenesis and immune activities were exclusively enriched in ASPSCR1-TFE3 rRCC and promised the better clinical outcomes with ICI plus tyrosine kinase inhibitor combination therapy. CONCLUSIONS: The current study represents the largest cohort comparing treatment outcomes and investigating molecular correlates of metastatic TFE3-rRCC based on fusion partner stratification. ICI based combination therapy could serve as an effective first-line treatment option for metastatic ASPSCR1-TFE3 rRCC patients. Regarding with other fusion subtypes, further investigations should be performed to explore the molecular mechanisms to propose pointed therapeutic strategy accordingly.

Metal-Organic Framework-Based Nanomaterials for Regulation of the Osteogenic Microenvironment.

As the global population ages, bone diseases have become increasingly prevalent in clinical settings. These conditions often involve detrimental factors such as infection, inflammation, and oxidative stress that disrupt bone homeostasis. Addressing these disorders requires exogenous strategies to regulate the osteogenic microenvironment (OME). The exogenous regulation of OME can be divided into four processes: induction, modulation, protection, and support, each serving a specific purpose. To this end, metal-organic frameworks (MOFs) are an emerging focus in nanomedicine, which show tremendous potential due to their superior delivery capability. MOFs play numerous roles in OME regulation such as metal ion donors, drug carriers, nanozymes, and photosensitizers, which have been extensively explored in recent studies. This review presents a comprehensive introduction to the exogenous regulation of OME by MOF-based nanomaterials. By discussing various functional MOF composites, this work aims to inspire and guide the creation of sophisticated and efficient nanomaterials for bone disease management.

Magnetic Activation: A Novel Approach to Enhance Hydrogen Evolution Activity of Co0.85Se@CNTs Heterostructured Catalyst.

The heterostructure strategy is currently an effective method for enhancing the catalytic activity of materials. However, the challenge that is how to further improve their catalytic performance, based on the principles of material modification is must addressed. Herein, a strategy is introduced for magnetically regulating the catalytic activity to further enhance the hydrogen evolution reaction (HER) activity for Co0.85Se@CNTs heterostructured catalyst. Building on heterostructure modulation, an external alternating magnetic field (AMF) is introduced to enhance the electronic localization at the active sites, which significantly boosts catalytic performance (71 to 43 mV at 10 mA cm-2). To elucidate the catalytic mechanism, especially under the influence of the AMF, in situ Raman spectroscopy is innovatively applied to monitor the HER process of Co0.85Se@CNTs, comparing conditions with and without the AMF. This study demonstrates that introducing the AMF does not induce a change in the true active site. Importantly, it shows that the Lorentz force generated by the AMF enhances HER activity by promoting water molecule adsorption and O─H bond cleavage, with the Stark tuning rate indicating increased water interaction and bond cleavage efficiency. Theoretical calculations further support that the AMF optimizes energy barriers for key reaction intermediates (steps of *H2O-TS and *H+*1/2H2).

Electron Accumulation Induced by Electron Injection-Incomplete Discharge on NiFe LDH for Enhanced Oxygen Evolution Reaction.

Optimizing the local electronic structure of electrocatalysts can effectively lower the energy barrier of electrochemical reactions, thus enhancing the electrocatalytic activity. However, the intrinsic contribution of the electronic effect is still experimentally unclear. In this work, the electron injection-incomplete discharge approach to achieve the electron accumulation (EA) degree on the nickel-iron layered double hydroxide (NiFe LDH) is proposed, to reveal the intrinsic contribution of EA toward oxygen evolution reaction (OER). Such NiFe LDH with EA effect results in only 262 mV overpotential to reach 50 mA cm-2, which is 51 mV-lower compared with pristine NiFe LDH (313 mV), and reduced Tafel slope of 54.8 mV dec-1 than NiFe LDH (107.5 mV dec-1). Spectroscopy characterizations combined with theoretical calculations confirm that the EA near concomitant Vo can induce a narrower energy gap and lower thermodynamic barrier to enhance OER performance. This study clarifies the mechanism of the EA effect on OER activity, providing a direct electronic structure modulation guideline for effective electrocatalyst design.

A Comparison of Clinicopathologic Outcomes and Patterns of Lymphatic Spread Across Neoadjuvant Chemotherapy, Neoadjuvant Chemoradiotherapy, and Neoadjuvant Immunochemotherapy in Locally Advanced Esophageal Squamous Cell Carcinoma.

BACKGROUND: Neoadjuvant chemoradiotherapy (NCRT) is recommended as the treatment standard for locally advanced esophageal squamous cell carcinoma (ESCC). The use of immunotherapy in the neoadjuvant setting has gained attention. Multiple, clinical trials have explored the efficacy and safety of neoadjuvant immunochemotherapy (NICT). We evaluated the differences in clinicopathologic outcomes and the patterns of lymphatic spread among patients receiving neoadjuvant chemotherapy (NCT), NCRT, and NICT before esophagectomy for locally advanced ESCC. METHODS: A total of 702 patients with ESCC who completed transthoracic esophagectomy followed neoadjuvant therapy were included. Pathological characteristics, including pathologic complete response (pCR), tumor regression grade (TRG) score and patterns of lymphatic spread, were evaluated. RESULTS: Compared with the NCT group, the NCRT group and NICT group had an advantage in pathological response (P < 0.05). The pCR rate was 8.1% in the NCT group, 29.9% in the NCRT group, and 23.6% in the NICT group. The TRG score (P < 0.05) and pathologic T stage (P < 0.05) in the NCT group were significantly higher. Compared with NICT, NCRT can significantly reduce the rate of lymph node metastasis rate in station 1R (0 vs. 3.4%, P < 0.05) and 2R (1.1% vs. 6.8%, P < 0.05). Subgroup analysis according to the tumor location distribution showed that NICT group had higher lymph node metastasis rate in station 2R (9.1%) in middle thoracic cases (P < 0.05) and in station 18 (7.5%) (P < 0.05) in lower thoracic cases. CONCLUSIONS: NCRT or NICT followed by surgery may result in a promising pCR rate and show a better performance in therapeutic response of primary lesion. For patients with lymph node metastasis in station 1R and 2R, NCRT should be the optimal preoperative treatment strategy.

Controllable non-uniformly distributed spiking cluster generation in broadband optoelectronic oscillator.

An approach to achieve controllable non-uniformly distributed spiking cluster generation is proposed and demonstrated based on an externally-triggered broadband optoelectronic oscillator (OEO). The theory of controlling the distribution of the spiking pulses in a spiking cluster is established. Based on the theory, the dynamic and the distribution characteristics are analyzed and revealed in the stable spiking oscillation state under different externally-injected trigger signal voltages. The peak-voltage envelop of the cluster and the interval of the spiking pulses are demonstrated to have an approximate negative linearity relationship with the externally-injected trigger signal voltage in both the numerical simulation and the experiment, where a square waveform, a trapezoidal waveform, a parabola waveform, and a half-sinusoidal waveform are used as the externally-injected trigger signals. The results indicate that the spiking pulse distribution in the generated spiking cluster can be well controlled through tuning the externally-injected trigger signal voltage. The proposed scheme can be utilized in spiking encoding and reservoir computing.

Phase-locked dual-frequency microwave signal generation in an optoelectronic oscillator based on frequency mixing mutual injection.

An approach to generating stable phase-locked dual-frequency microwave signals is proposed and demonstrated based on a dual-passband optoelectronic oscillator (OEO). Mode gain competition is broken by employing frequency mixing mutual injection effect to realize phase locking between the two oscillation signals, which is achieved by applying a single-tone signal to a microwave mixer in the OEO cavity. In addition, a dual-loop configuration with balanced detection is utilized to ensure a high side mode suppression ratio (SMSR) and ultra-low phase noise, which also enhances the stability of the generated signal. In the experiment, a phase-locked dual-frequency microwave signal at 9.9982 GHz and 10.1155 GHz is generated by using the proposed OEO scheme. The SMSR and the phase noise are 75 dB and -141 dBc/Hz@10 kHz, respectively. Additionally, the Allan deviation of the generated signal is in the order of 10-11@1 s. These parameters are superior to those based on the same OEO but with a single-loop configuration, which are also compared in detail.

Suppression of Brillouin scattering-induced noise in long-haul high-power RoF links via non-uniformly distributed four-tone phase modulation.

An approach to suppressing Brillouin scattering-induced noise in long-haul high-power radio-over-fiber (RoF) links is proposed via non-uniformly distributed four-tone phase modulation. Four single-tone signals with uneven frequency intervals are utilized to phase modulate the optical signal before transmission. The power transferring from the optical carrier to the non-uniformly distributed modulation sidebands largely suppresses the Brillouin scattering-induced relative intensity noise (RIN). In the experiment, transmission of a 64-QAM wireless communication signal centered at 10 GHz and with a bandwidth of 100 MHz is demonstrated. The threshold of the stimulated Brillouin scattering (SBS) in a high-power RoF link involving a spool of a single-mode fiber (SMF) with a length of 20.5 km is increased by 11 dB based on this scheme, compared with that without phase modulation. Under an input optical power of 19 dBm, the error vector magnitude (EVM) and the adjacent channel leakage ratio (ACLR) are optimized from 34.39% to 1.32% and from -20.73 dBc to -35.32 dBc, without and with phase modulation, respectively. This scheme paves a way to realizing long-haul high-power RoF links for efficiently transmitting broadband wireless communication signals in cloud radio access networks (C-RANs).

Neoadjuvant radiation target volume definition in esophageal squamous cell cancer: a multicenter recommendations from Chinese experts.

BACKGROUND: This study aimed to establish a consensus on the delineation of target volumes for neoadjuvant radiation therapy (nRT) in esophageal squamous cell carcinoma (ESCC) within China. METHODS: From February 2020 to June 2021, nine ESCC patients who received nRT were retrospectively selected from Sun Yat-sen University Cancer Center and Shandong Cancer Hospital. A panel from eight cancer radiotherapy centers performed two rounds of nRT target volume delineation for these patients: the first round for cases 1-6 and the second for cases 7-9. Online meetings were held after each delineation round to discuss findings. The consistency of delineations across centers was compared using mean undirected Hausdorff distances (Hmean), dice similarity coefficients (DSC), and total volumes, analyzed with the Mann-Whitney U test. RESULTS: The second round of delineations showed improved consistency across centers (total clinical target volume (CTVtotal): mean DSC = 0.76-0.81; mean Hmean = 2.11-3.14 cm) compared to the first round (CTVtotal: mean DSC = 0.63-0.64; mean Hmean = 5.66-7.34 cm; DSC and Hmean: P < 0.050 between rounds), leading to the formation of a consensus and an atlas for ESCC nRT target volume delineation. A proposal was reached through evaluating target volume delineations, analyzing questionnaire survey outcomes, and reviewing pertinent literature. CONCLUSIONS: We have developed guidelines and an atlas for target volume delineation in nRT therapy for ESCC in China. These resources are designed to facilitate more consistent delineation of target volumes in both clinical practice and clinical trials.

Consolidation chemotherapy after definitive concurrent chemoradiotherapy in patients with inoperable esophageal squamous cell carcinoma: a multicenter non-inferiority phase III randomized clinical trial.

BACKGROUND: Definitive concurrent chemoradiotherapy (dCCRT) is the gold standard for the treatment of locally advanced esophageal squamous cell carcinoma (ESCC). However, the potential benefits of consolidation chemotherapy after dCCRT in patients with esophageal cancer remain debatable. Prospective randomized controlled trials comparing the outcomes of dCCRT with or without consolidation chemotherapy in patients with ESCC are lacking. In this study, we aim to generate evidence regarding consolidation chemotherapy efficacy in patients with locally advanced, inoperable ESCC. METHODS: This is a multicenter, prospective, open-label, phase-III randomized controlled trial comparing non-inferiority of dCCRT alone to consolidation chemotherapy following dCCRT. In total, 600 patients will be enrolled and randomly assigned in a 1:1 ratio to receive either consolidation chemotherapy after dCCRT (Arm A) or dCCRT alone (Arm B). Overall survival will be the primary endpoint, whereas progression-free survival, locoregional progression-free survival, distant metastasis-free survival, and treatment-related toxicity will be the secondary endpoints. DISCUSSION: This study aid in further understanding the effects of consolidation chemotherapy after dCCRT in patients with locally advanced, inoperable ESCC. TRIAL REGISTRATION: ChiCTR1800017646.

Targeted inhibition of autophagy in hepatic stellate cells by hydroxychloroquine: An effective therapeutic approach for the treatment of liver fibrosis.

BACKGROUND AND PURPOSE: Liver fibrosis is a wound-healing reaction which is the main cause of chronic liver diseases worldwide. The activated hepatic stellate cell (aHSC) is the main driving factor in the development of liver fibrosis. Inhibiting autophagy of aHSC can prevent the progression of liver fibrosis, but inhibiting autophagy of other liver cells has opposite effects. Hence, targeted inhibition of autophagy in aHSC is quite necessary for the treatment of liver fibrosis, which prompts us to explore the targeted delivery system of small molecule autophagy inhibitor hydroxychloroquine (HCQ) that can target aHSC and alleviate the liver fibrosis. METHODS: The delivery system of HCQ@retinol-liposome nanoparticles (HCQ@ROL-LNPs) targeting aHSC was constructed by the film dispersion and pH-gradient method. TGF-ß-induced HSC activation and thioacetamide (TAA)-induced liver fibrosis mice model were established, and the targeting ability and therapeutic effect of HCQ@ROL-LNPs in liver fibrosis were studied subsequently in vitro and in vivo. RESULTS: HCQ@ROL-LNPs have good homogeneity and stability. They inhibited the autophagy of aHSC selectively by HCQ and reduced the deposition of extracellular matrix (ECM) and the damage to other liver cells. Compared with the free HCQ and HCQ@LNPs, HCQ@ROL-LNPs had good targeting ability, showing enhanced therapeutic effect and low toxicity to other organs. CONCLUSION: Construction of HCQ@ROL-LNPs delivery system lays a theoretical and experimental foundation for the treatment of liver fibrosis and promotes the development of clinical therapeutic drugs for liver diseases.

The survival benefit of metastasectomy for metastatic non-clear cell renal cell carcinoma: a retrospective cohort study.

PURPOSE: The aim of this study was to explore the benefit the metastasectomy for patients with metastatic non-clear cell carcinoma (non-ccRCC). METHODS: This study enrolled 120 patients with confirmed metastatic non-ccRCC from the RCC database of our center from 2008 to 2021. Patients without metastasectomy were grouped as radical nephrectomy without metastasectomy patients. The clinical outcomes included overall survival (OS) and progression-free survival (PFS). Cox regression and Kaplan-Meier analyses were used to assess potential factors that predict clinical benefits from metastasectomy. RESULTS: A total of 100 patients received radical nephrectomy alone, while the remaining 20 patients underwent both radical nephrectomy and metastasectomy. There was no significant difference in age between the two groups. Out of 100 patients who underwent radical nephrectomy, 60 were male, and out of 20 patients who had both radical nephrectomy and metastasectomy, 12 were male. Patients who underwent systemic therapy plus radical nephrectomy and metastasectomy had significantly better PFS (27.1 vs. 14.0, p = 0.032) and OS (67.3 vs. 24.0, p = 0.043) than those who underwent systemic therapy plus radical nephrectomy alone. Furthermore, for patients without liver metastasis (n = 54), systemic therapy plus radical nephrectomy and metastasectomy improved both PFS (p = 0.028) and OS (p = 0.043). Similarly, for patients with metachronous metastasis, systemic therapy plus radical nephrectomy and metastasectomy improved both PFS (p = 0.043) and OS (p = 0.032). None of the patients experienced serious perioperative complications (Clavien-Dindo Classification ≥ III grade). CONCLUSION: Metastasectomy in patients with metastatic non-ccRCC may provide clinical benefits in terms of improved PFS and OS, especially in patients without liver metastasis and those with metachronous metastasis.

Safety, tolerability, pharmacokinetic, pharmacodynamic and immunogenicity profiles of Exendin-4-IgG4-Fc in healthy subjects: A phase 1, single-centre, randomized, double-blind, dose escalation study.

AIM: Novel long-acting drugs for type 2 diabetes mellitus may optimize patient compliance and glycaemic control. Exendin-4-IgG4-Fc (E4F4) is a long-acting glucagon-like peptide-1 receptor agonist. This first-in-human study investigated the safety, tolerability, pharmacokinetic, pharmacodynamic and immunogenicity profiles of a single subcutaneous injection of E4F4 in healthy subjects. METHODS: This single-centre, randomized, double-blind, placebo-controlled phase 1 clinical trial included 96 subjects in 10 sequential cohorts that were provided successively higher doses of E4F4 (0.45, 0.9, 1.8, 3.15, 4.5, 6.3, 8.1, 10.35, 12.6 and 14.85 mg) or placebo (ChinaDrugTrials.org.cn: ChiCTR2100049732). The primary endpoint was safety and tolerability of E4F4. Secondary endpoints were pharmacokinetic, pharmacodynamic and immunogenicity profiles of E4F4. Safety data to day 15 after the final subject in a cohort had been dosed were reviewed before commencing the next dose level. RESULTS: E4F4 was safe and well tolerated among healthy Chinese participants in this study. There was no obvious dose-dependent relationship between frequency, severity or causality of treatment-emergent adverse events. Cmax and area under the curve of E4F4 were dose proportional over the 0.45-14.85 mg dose range. Median Tmax and t1/2 ranged from 146 to 210 h and 199 to 252 h, respectively, across E4F4 doses, with no dose-dependent trends. For the intravenous glucose tolerance test, area under the curve of glucose in plasma from time 0 to 180 min showed a dose-response relationship in the 1.8-10.35 mg dose range, with an increased response at the higher doses. CONCLUSION: E4F4 exhibited an acceptable safety profile and linear pharmacokinetics in healthy subjects. The recommended phase 2 dose is 4.5-10.35 mg once every 2 weeks.

Fabricating Porous Alkali-Resistant Resin for Segregation of Perrhenate/Pertechnetate Anions from Wastewater.

The elimination of the ß-emitting pertechnetate ion (99TcO4-) from highly alkaline tank waste poses a daunting challenge that is of great significance for nuclear safety and environmental protection. Herein, we report a strategy to fabricate an alkaline-stable porous resin (PANPEI-MeCl) that features hyperbranched quaternary amine groups grafted on the surface and confined within the pores of a superhydrophobic polymer matrix synthesized by a one-pot method, exhibiting a clear superiority both in adsorption kinetics and efficiency compared with available commercial anion-exchange resins applying to 99TcO4- capture. Notably, the alkaline stability of the resin can be improved by manipulating the length of side chain alkyl groups, and it shows ultrahigh structural integrity and prominent performance toward acid/alkaline soaking, high-temperature calcination procedures, and high doses of ionizing radiation. Encouraged by its excellent peculiarity, PANPEI-MeCl can continuously capture most of the ReO4- from the simulated radioactive waste by using a sequential injection automatic separation system.

Characteristics of Tongue Pressure Measured by Novel Multisite Flexible Sensors in Nasopharyngeal Carcinoma Patients With Dysphagia.

OBJECTIVE: To explore characteristics of tongue pressure changes in nasopharyngeal carcinoma (NPC) patients with dysphagia after radiotherapy using a novel system with multisite flexible sensors. DESIGN: Prospective observational study. SETTING: Inpatient rehabilitation centers and community dwellings. PARTICIPANTS: Nineteen patients with dysphagia after radiotherapy for NPC and 19 healthy participants were recruited for this study (N=38). INTERVENTION: Not applicable. MAIN OUTCOME MEASURES: A new 9-site (3 × 3) flexible tongue pressure sensor was used to measure tongue-to-palate pressure across different parts of the tongue. The oral tongue was divided into 3 parts: anterior tongue region (TAR), central tongue region (TCR), and posterior tongue region (TPR); 3 sensors were placed on each part. The mean tongue pressure and endurance time at the 3 sites in the TAR, TCR, and TPR were analyzed. The ratios of the mean TAR, TCR, and TPR values were calculated. RESULTS: Pressures of TAR, TCR, and TPR in NPC patients with dysphagia were significantly lower than those in healthy participants (P<.05). The pressure in TPR decreased most significantly, followed by that in TCR. The endurance times of TAR and TCR were longer than those of healthy participants (P<.05). The endurance time of TPR was not significantly different between the patients and healthy participants (P>.05). Ratios of pressure between TAR and TCR and TAR and TPR in patients were lower than that in healthy participants (P<.05). There was no significant difference in the TCR to TPR pressure ratio between patients and healthy participants (P>.05). CONCLUSIONS: Tongue pressure significantly decreased in NPC patients with dysphagia, and the drop in pressure was most pronounced in the TPR area. The results of our study indicate that we should pay attention to the pressure training of the TPR during treatments. The endurance time of the TAR and TCR increased significantly, which may be due to bolus transport compensation. Therefore, clinical rehabilitation strategies should aim to increase the endurance time training in NPC patients after radiotherapy to help increase the effectiveness of the swallowing process in patients.

GPX3-Mediated Oxidative Stress Affects Pyrimidine Metabolism Levels in Stomach Adenocarcinoma via the AMPK/mTOR Pathway.

Background: Amino acid metabolism, including ATP production, nucleotide synthesis, and redox homeostatic processes, are associated with proliferation and differentiation of tumor cells. This study aimed to identify novel prognostic biomarkers and potential therapeutic targets of amino acid metabolism-related genes for stomach adenocarcinoma (STAD). Methods: RNA sequencing transcriptome data in the TCGA-STAD (training set) and GTEx datasets (validation set) were used. The LIMMA R program enabled the differentially expressed amino acid metabolism-related genes (AAMRGs) to be found. A prognostic risk score model based on clinical phenotypic features was built using LASSO regression and step multi-Cox analyses. Gene set enrichment analysis (GSEA) was used to find potential molecular pathways associated with STAD. Hierarchical cluster analysis was used to evaluate pyrimidine metabolism. Cultured STAD cells assessed the proliferation of STAD and upregulation of GPX3 expression by CCK8 and flow cytometry. Transwell and wound healing assays assessed the impact of GPX3 on invasion and migration of STAD cells. Western blot and qRT-PCR were used to measure changes in pyrimidine metabolism-related markers and active molecules involved in the AMPK/mTOR signaling pathway. Results: Three AAMRGs, DNMT1, F2R, and GPX3, could independently predict the course of STAD. Pyrimidine metabolism appeared to be significantly associated with these by GSEA and clustering analyses. Pyrimidine metabolism was negatively correlated with GPX3. Functional studies using an overexpressed GPX3 plasmid showed an enhanced migration and invasion of STAD cells as well as the expression of genes associated with pyrimidine metabolism and the AMPK/mTOR signaling pathway. By using a CAD siRNA, it was found that that GPX3 affected 5-fluorouracil resistance during de novo synthesis of pyrimidine through the CAD-UMPS signaling axis. Conclusions: GPX3 which regulates the level of pyrimidine metabolism through the AMPK/mTOR pathway was found to be closely associated with STAD. Our findings demonstrate GPX3 is a reliable biomarker for the prognosis of amino acid metabolism and a probable target for STAD therapy.

The impact of postoperative adjuvant therapy on EGFR-mutated stage IA lung adenocarcinoma with micropapillary pathological subtypes.

BACKGROUND: Micropapillary (MPP) adenocarcinoma is considered one of the most aggressive pathological types of lung adenocarcinoma (LADC). This retrospective study aimed to evaluate the prognostic significance and benefit of postoperative adjuvant therapy (PAT) in stage IA LADC patients with different proportions of MPP components. MATERIALS AND METHODS: We retrospectively examined clinical stage IA LADC patients who underwent surgical resection between August 2012 and December 2019. In terms of the proportion of MPP components (TPM), the tumors were reclassified into three categories: MPP patterns absent (TPMN); low proportions of MPP components (TPML); and high proportions of MPP components (TPMH). The dates of recurrence and metastasis were identified based on physical examinations and were confirmed by histopathological examination. RESULTS: Overall, 505 (TPMN, n = 375; TPML, n = 92; TPMH, n = 38) patients harboring EGFR mutations were enrolled in the study. Male sex (P = 0.044), high pathological stage (P < 0.001), and MPP pathological subtype (P < 0.001) were more frequent in the TPM-positive (TPMP) group than in the TPM-negative (TPMN) group. Five-year disease-free survival (DFS) rates were significantly lower in the TPMP group than in the TPMN group (84.5% vs. 93.4%, P = 0.006). In addition, patients with high proportions (greater than 10%) of MPP components had worse overall survival (OS) (91.0% vs. 98.9%, P = 0.025) than those with low proportions (5%≤ TPM ≤ 10%). However, postoperative EGFR tyrosine kinase inhibitors (TKIs) or adjuvant chemotherapy (ACT) cannot improve DFS and OS between EGFR-mutated patients with different proportions of MPP components. CONCLUSION: MPP was related to earlier recurrence and shortened survival time, even in stage IA. Further research needs a larger sample size to clarify that EGFR-mutated stage IA patients with MPP components obtain survival benefits from adjuvant therapy.

Associations between Alzheimer's disease biomarkers and postoperative delirium or cognitive dysfunction: A meta-analysis and trial sequential analysis of prospective clinical trials.

BACKGROUND: The relationship between Alzheimer's disease biomarkers and postoperative complications, such as postoperative delirium (POD) and postoperative cognitive dysfunction (POCD), remains a subject of ongoing debate. OBJECTIVE: This meta-analysis aimed to determine whether there is an association between perioperative Alzheimer's disease biomarkers and postoperative complications. DESIGN: We conducted a meta-analysis of observational clinical studies that explored the correlation between Alzheimer's disease biomarkers and POD or POCD in patients who have undergone surgery, following PRISMA guidelines. The protocol was previously published (INPLASY: INPLASY202350001). DATA SOURCES: A comprehensive search was conducted across PubMed, Embase, Web of Science, and Cochrane databases until March 2023. ELIGIBILITY CRITERIA: Surgical patients aged at least 18 years, studies focusing on POD or POCD, research involving Alzheimer's disease biomarkers, including Aß or tau in blood or cerebrospinal fluid (CSF), and availability of the full text. RESULTS: Our meta-analysis included 15 studies: six focusing on POD and nine on POCD. The findings revealed a negative correlation between preoperative CSF ß-amyloid 42 (Aß42) levels and the onset of POD [mean difference -86.1, 95% confidence interval (CI), -114.15 to -58.05, I2 : 47%]; this association was strongly supported by trial sequential analysis (TSA). A similar negative correlation was discerned between preoperative CSF Aß42 levels and the incidence of POCD (-165.01, 95% CI, -261.48 to -68.53, I2 : 95%). The TSA also provided robust evidence for this finding; however, the evidence remains insufficient to confirm a relationship between other Alzheimer's disease biomarkers [ß-amyloid 40 (Aß40), total tau (T-tau), phosphorylated tau (P-tau), and Aß42/T-tau ratio] and POD or POCD. CONCLUSION: The study results indicate a negative correlation between preoperative CSF Aß42 levels and the occurrence of both POD and POCD. Future investigations are warranted to identify the predictive cutoff value of preoperative CSF Aß42 for POD and POCD.