Prevalence and time course of postoperative nausea and vomiting and severe pain in patients under general anesthesia with patient-controlled intravenous analgesia.

Introduction: Postoperative nausea and vomiting (PONV) and pain are common and distressing complications in patients undergoing surgery. However, it remains uncertain whether timing of the postoperative course or the diel rhythm influences the occurrence of PONV or severe pain. Therefore, we aimed to explore the temporal distribution of PONV and severe pain. Material and methods: In this prospective observational study, we enrolled patients aged 18-65 years with American Society of Anesthesiologists classifications I-III, who were scheduled for surgery under general anesthesia. Patients were visited postoperatively at regular intervals (every 6 h over a 24-h period). Incidence of PONV was recorded and categorized based on real-time divisions: before dawn (00:00-05:59), morning (06:00-11:59), afternoon (12:00-17:59), and evening (18:00-23:59) and as sequential periods (i.e., 0-6, 6-12, 12-18, and 18-24 h). Severe pain and use of additional remedies were also recorded. Results: A total of 724 patients were included in the final analysis. Of these, 14.92 % experienced PONV within the first 6 h, and 8.29 % received antiemetic therapy. Occurrence of PONV and administration of remedies declined over the 24-h postoperative period. The lowest rate of PONV was observed during the pre-dawn hours (5.66 %). There was no statistically significant difference in the incidence of PONV 24-h postoperatively between surgeries with different end times. Patients underwent orthopedic surgeries had the highest incidence of PONV during 18:00-23:59, gynecological surgery patients had the highest incidence at 12:00-17:59, and 6:00-11:59 for other surgery patients. All patients had the lowest incidence during 0:00-5:59. During the initial 6-h postoperative period, 24.59 % of patients experienced severe pain, which declined in the remaining episodes. Patients who underwent orthopedic and gynecological surgeries exhibited similar temporal patterns and distribution characteristics of PONV and severe pain. Discussion: Both PONV and severe pain declined within the 24-h postoperative period, particularly within the first 6 h. Additionally, the onset patterns of PONV vary among patients undergoing different types of surgeries, all patients demonstrated decreased susceptibility to PONV between 00:00-05:59. Our findings enhance prevention and treatment strategies within an optimized timeframe during the postoperative course.

Refining the 8th edition TNM classification for EBV related nasopharyngeal carcinoma.

The AJCC/UICC TNM classification describes anatomic extent of tumor progression and guides treatment decisions. Our comprehensive analysis of 8,834 newly diagnosed patients with non-metastatic Epstein-Barr virus related nasopharyngeal carcinoma (NPC) from six Chinese centers indicates certain limitations in the current staging system. The 8th edition of the AJCC/UICC TNM classification inadequately differentiates patient outcomes, particularly between T2 and T3 categories and within the N classification. We propose reclassifying cases of T3 NPC with early skull-base invasion as T2, and elevating N1-N2 cases with grade 3 image-identified extranodal extension (ENE) to N3. Additionally, we suggest combining T2N0 with T1N0 into a single stage IA. For de novo metastatic (M1) NPC, we propose subdivisions of M1a, defined by 1-3 metastatic lesions without liver involvement, and M1b, characterized by >3 metastatic lesions or liver involvement. This proposal better reflects responses of NPC patients to the up-to-date treatments and their evolving risk profiles.

Patterns and Prognosis of Local Recurrence of Nasopharyngeal Carcinoma after Intensity-modulated Radiotherapy.

Objective: To investigate the patterns of local failure and prognosis in patients with locally recurrent nasopharyngeal carcinoma (rNPC) after primary intensity-modulated radiotherapy (IMRT). Methods: The data of 298 patients with locally rNPC after IMRT were retrospectively analyzed. Magnetic resonance images of the initial and recurrent tumors were reviewed and, for patients with extra-nasopharyngeal local recurrence, the gross tumor volume of local recurrence was transferred to the original IMRT plan for dosimetry analysis. Significant prognostic factors for overall survival (OS) were selected by multivariate Cox regression analysis. Results: The commonest recurrence sites were the nasopharynx (93%, 277/298) and skull base (53.7%, 160/298). Of the 21 patients with extra-nasopharyngeal recurrence (19 cases valid), 12 had in-field failures, 4 had marginal failures, and 3 had out-field failures. The ethmoid sinus (57.1%, 4/7) and nasal cavity (28.6%, 2/7) were the most frequent sites of marginal and out-field failures. After median follow-up of 37 months, the 3-year and estimated 5-year OS rates were 57.3% and 41.7%, respectively. Multivariate analysis showed that age, recurrence interval, plasma Epstein-Barr virus (EBV) DNA level, and recurrent T stage were independent prognostic factors for OS. Conclusions: Local failure after IMRT occurs most commonly in the nasopharynx and skull base. In patients with extra-nasopharyngeal recurrence, in-field failure remains the main failure pattern, and marginal and out-field failures mainly occur in the ethmoid sinus and nasal cavity. Elder age, shorter recurrence interval, detectable plasma EBV DNA, and advanced recurrent T stage are negative predictors of OS in patients with rNPC.

Effect of noise isolation using noise-cancelling headphones during laparoscopic surgery for postoperative pain reduction: A randomized clinical trial.

STUDY OBJECTIVE: Most laparoscopic surgeries under general anesthesia are performed in noisy environments, although the effect of intraoperative noise reduction on postoperative pain remains uncertain. This study aimed to explore whether postoperative pain could be reduced through the intraoperative use of noise-cancelling headphones. DESIGN: This study was conducted as a prospective parallel-group randomized clinical trial. SETTING: Operating room and surgery room. PATIENTS: Ninety patients who underwent laparoscopic surgery under general anesthesia. INTERVENTIONS: In the intervention group, noise-cancelling headphones were used to reduce noise intensity during laparoscopic surgery under general anesthesia. MEASUREMENTS: The primary outcome was the maximum movement-evoked pain intensity within 24 h post-surgery, measured using a 10-point numeric rating scale. Secondary outcomes included the maximum resting pain score and total opioid consumption during the 24-h period post-surgery. Mean intraoperative noise and the proportion of intraoperative time with noise intensity ≥70 dB were recorded. MAIN RESULTS: The maximum movement-evoked pain score was significantly lower in the intervention group than in the control group (mean score [SD], 2.7 [1.0] and 4.0[1.0], respectively; P < 0.001). The intervention group required significantly fewer opioids than the control group (mean [SD], 44.2 [12.8] and 51.3[17.5] mg, respectively; P = 0.032). In the control group, but not the intervention group, all postoperative pain scores were significantly associated with the proportion of intraoperative time with noise intensity ≥70 dB, which was an independent risk factor for postoperative pain. CONCLUSION: During laparoscopic surgery under general anesthesia, intraoperative noise isolation using noise-cancelling headphones is a safe and effective strategy for relieving postoperative pain and decreasing total opioid analgesic consumption.

Effect of intraoperative noise on postoperative pain in surgery patients under general anesthesia: evidence from a prospective study and mouse model.

BACKGROUND: Most patients are in a noisy environment during abdominal surgery under general anesthesia. This study included patients who underwent abdominal surgery under general anesthesia and established an animal model to determine whether intraoperative noise affects postoperative pain. MATERIALS AND METHODS: This prospective study included 200 patients who underwent abdominal surgery under general anesthesia. Intraoperative noise and electroencephalograms were continuously recorded, and the mean level and time proportion of noise intensity of greater than 70 dB were calculated. Maximum postoperative pain was assessed using a numerical rating scale at 0-12 h and 12-24 h after surgery, and postoperative analgesia consumption in patients receiving patient-controlled intravenous analgesia was recorded. Postoperative pain intensity and electroencephalogram amplitude were compared between patients with high-noise exposure (time proportion of noise intensity greater than 70 dB ≥40%) and low-noise exposure (<40%). Mechanical pain sensitivity was tested in two groups of mice with plantar incisions exposed to 40 dB or 70-100 dB. RESULTS: The time proportion of noise intensity greater than 70 dB was identified as an independent risk factor for postoperative pain intensity ( P <0.001). P ain numerical rating scale 0-12 h (4.5±1.5 vs. 3.7±1.3, P =0.001) and 12-24 h (3.9±1.5 vs. 3.2±1.1, P =0.004) after surgery in patients with high-noise exposure was significantly higher than in patients with low-noise exposure. The electroencephalogram amplitude of patients with high-noise exposure was significantly lower than that of patients with low-noise exposure ( P <0.05). In the mouse model, mechanical hyperalgesia in the 70-100 dB group was significantly greater than that in the 40 dB group ( P <0.001). CONCLUSION: High-level intraoperative noise exposure aggravates the degree of postoperative pain and analgesic needs of patients undergoing abdominal surgery, which may be related to the impact of noise on the neurophysiological activity of the brain and postoperative hyperalgesia.

Characterization of tea (Camellia sinensis L.) flower extract and insights into its antifungal susceptibilities of Aspergillus flavus.

BACKGROUND: Tea (Camellia sinensis L.) flowers will compete with tea leaves in nutrition and are abandoned as an undesirable by-product. In this study, the biological efficacy of tea flowers was investigated. Further exploration of its antifungal activity was explained. METHODS: Tea flowers harvested from China were characterized in term of component, antioxidant ability, tyrosinase inhibition, and antifungal ability. Chemical compounds of tea flowers were analyzed by LC-MS. Disinfectant compounds were identified in tea flowers, and 2-ketobutyric acid exhibited antifungal activity against Aspergillus flavusCCTCC AF 2023038. The antifungal mechanism of 2-ketobutyric acid was further investigated by RNA-seq. RESULTS: Water-soluble tea flower extracts (TFEs) exhibited free radical scavenging activity against 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2, 2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid)(ABTS) as well as a high ferric-reducing ability. However, no inhibition of tyrosinase activity was observed. In the antifungal test, 6.4 mg/mL TFE reached 71.5% antifungal rate and the electrical conductivity of the culture broth increased with increasing concentration of TFE, implying that it damaged the fungal cell membrane by the TFE. Several disinfectants were identified in TFE by LC-MS, and 2-ketobutyric acid was also confirmed to be capable of fungal inhibition. Propidium iodide (PI) staining indicated that 2-ketobutyric acid caused damage to the cell membrane. RNA-seq analysis revealed that 3,808 differentially expressed genes (DEGs) were found in A. flavus CCTCC AF 2023038 treated by 2-ketobutyric acid, and more than 1,000 DEGs involved in the integral and intrinsic component of membrane were affected. Moreover, 2-ketobutyric acid downregulated aflatoxin biosynthesis genes and decreased the aflatoxin production. CONCLUSIONS: Overall, TFE exhibited excellent antioxidant ability and fungal inhibition against A. flavus CCTCC AF 2023038 due to its abundant disinfectant compounds. As a recognized food additive, 2-ketobutyric acid is safe to use in the food industry and can be utilized as the basis for the research and development of strong fungicides.

The tumor immune microenvironment of nasopharyngeal carcinoma after gemcitabine plus cisplatin treatment.

Gemcitabine plus cisplatin (GP) chemotherapy is the standard of care for nasopharyngeal carcinoma (NPC). However, the mechanisms underpinning its clinical activity are unclear. Here, using single-cell RNA sequencing and T cell and B cell receptor sequencing of matched, treatment-naive and post-GP chemotherapy NPC samples (n = 15 pairs), we show that GP chemotherapy activated an innate-like B cell (ILB)-dominant antitumor immune response. DNA fragments induced by chemotherapy activated the STING type-I-interferon-dependent pathway to increase major histocompatibility complex class I expression in cancer cells, and simultaneously induced ILB via Toll-like receptor 9 signaling. ILB further expanded follicular helper and helper type 1 T cells via the ICOSL-ICOS axis and subsequently enhanced cytotoxic T cells in tertiary lymphoid organ-like structures after chemotherapy that were deficient for germinal centers. ILB frequency was positively associated with overall and disease-free survival in a phase 3 trial of patients with NPC receiving GP chemotherapy ( NCT01872962 , n = 139). It also served as a predictor for favorable outcomes in patients with NPC treated with GP and immunotherapy combined treatment (n = 380). Collectively, our study provides a high-resolution map of the tumor immune microenvironment after GP chemotherapy and uncovers a role for B cell-centered antitumor immunity. We also identify and validate ILB as a potential biomarker for GP-based treatment in NPC, which could improve patient management.

Characterization and expression of fungal defensin in Escherichia coli and its antifungal mechanism by RNA-seq analysis.

Introduction: Invasive fungal infections (IFIs) are fatally threatening to critical patients. The fungal defensin as an antifungal protein can widely inhibit fungi. Methods: In this study, eight antifungal genes from different filamentous fungi were optimized by synonymous codon bias and heterologously expressed in Escherichia coli. Results and discussion: Only the antifungal protein (AFP) from Aspergillus giganteus was produced, whereas the AFP from its mutation of the chitin-binding domain could not be expressed, thereby suggesting the importance of the motif for protein folding. In addition, the recombinant AFP (rAFP, 100 µg/mL) pre-heated at 50°C for 1 h effectively inhibited Paecilomyces variotii CICC40716 of IFIs by 55%, and no cell cytotoxicity was observed in RAW264.7 cells. After being pre-heated at 50°C for 8 h, the fluorescence emission intensity of the rAFP decreased and shifted from 343 nm to 335 nm. Moreover, the helix and ß-turn of the rAFP gradually decreased with the pre-heated treatment temperature of 50°C via circular dichroism spectroscopy. Propidium iodide staining revealed that the rAFP could cause damage to the cell membrane. Moreover, the corresponding differentially expressed genes (DEGs) for downregulation such as amino sugar and nucleotide sugar metabolism, as well as mitogen-activated protein kinase (MAPK) signaling pathway involved in the cell wall integrity were found via the RNA-seq of rAFP treatment. By contrast, the upregulated DEGs were enriched in response to the oxidative stress of Biological Process by the Gene Ontology (GO) database. The encoding proteins of laccase, multicopper oxidase, and nitroreductase that contributed to reactive oxygen species (ROS) scavenging could be recognized. These results suggested that the rAFP may affect the integrity of the cell wall and cell membrane, and promote the increase in ROS, thereby resulting in fungal death. Consequently, drug development could be based on the inhibitory effect of the rAFP on IFIs.

Concurrent chemotherapy using taxane plus cisplatin versus cisplatin alone in high-risk nasopharyngeal carcinoma patients with suboptimal response to induction chemotherapy.

Background: Detectable Epstein-Barr virus (EBV) DNA levels and unsatisfactory tumor response to induction chemotherapy (IC) could be used to guide the risk-adapted treatment strategy of locoregionally advanced nasopharyngeal carcinoma (LANPC) before concurrent chemoradiotherapy. We aim to compare the efficacy and safety of concurrent chemotherapy using taxane plus cisplatin [double-agent concurrent chemotherapy (DACC) group] with those of cisplatin alone [single-agent concurrent chemotherapy (SACC) group] in high-risk LANPC. Methods: Overall, 197 LANPC patients with detectable EBV DNA or stable disease (SD) after IC were retrospectively included. Potential confounders between the DACC and SACC groups were adjusted by propensity score matching. Short-term efficacy and long-term survival were assessed in the two groups. Results: Although the objective response rate of the DACC group was marginally higher than that of the SACC group, the difference was not significant (92.7% versus 85.3%, p = 0.38). Concerning long-term survival, DACC did not show superiority to SACC after patient matching: 3-year progression-free survival: 87.8% versus 81.7%, p = 0.80; overall survival: 97.6% versus 97.3%, p = 0.48; distant metastasis-free survival: 87.8% versus 90.5%, p = 0.64, and; locoregional relapse-free survival: 92.3% versus 86.9%, p = 0.77. The incidence of grade 1-4 hematological toxicities was significantly higher in the DACC group. Conclusion: Due to the small sample size, we do not have sufficient evidence that concurrent chemotherapy using taxane plus cisplatin provides additional survival benefits in LANPC patients with an unfavorable response (detectable EBV DNA levels or SD) after IC. But concurrent taxane and cisplatin chemotherapy is associated with a higher rate of hematologic adverse events. Further clinical trials will be required to establish evidence and identify more effective treatment modalities for high-risk LANPC patients.

Ethanol Extract of Rosa laevigata Michx. Fruit Inhibits Inflammatory Responses through NF-κB/MAPK Signaling Pathways via AMPK Activation in RAW 264.7 Macrophages.

The fruit of Rosa laevigata Michx. (FR), a traditional Chinese herb utilized for the treatment of a variety diseases, has notably diverse pharmacological activities including hepatoprotective, anti-oxidant, and anti-inflammatory effects. Despite ongoing research on illustrating the underlying anti-inflammatory mechanism of FR, the principal mechanism remained inadequately understood. In this study, we investigated in depth the molecular mechanism of the anti-inflammatory actions of the ethanol extract of FR (EFR) and its potential targets using lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages in vitro. We showed that EFR effectively ameliorated the overproduction of inflammatory mediators and cytokines, as well as the expression of related genes. It was further demonstrated that LPS-induced activation of nuclear factor kappa B (NF-κB) and mitogen-activated protein kinases (MAPKs) were significantly inhibited by pretreatment with EFR, accompanied by a concomitant decrease in the nuclear translocation of the p65 subunit of NF-κB and activator protein 1 (AP-1). In addition, EFR pretreatment potently prevented LPS-induced decreased phosphorylation of adenosine monophosphate-activated protein kinase (AMPK). Our data also revealed that the activation of AMPK and subsequent inhibition of the mammalian target of the rapamycin (mTOR) signaling pathway was probably responsible for the inhibitory effect of EFR on LPS-induced inflammatory responses, evidenced by reverse changes observed under the condition of AMPK inactivation following co-treatment with the AMPK-specific inhibitor Compound C. Finally, the main components with an anti-inflammatory effect in EFR were identified as madecassic acid, ellagic acid, quinic acid, and procyanidin C1 by LC-MS and testified based on the inhibition of NO production and inflammatory mediator expression. Taken together, our results indicated that EFR was able to ameliorate inflammatory responses via the suppression of MAPKs/NF-κB signaling pathways following AMPK activation, suggesting the therapeutic potential of EFR for inflammatory diseases.

Medial retropharyngeal nodal region sparing radiotherapy versus standard radiotherapy in patients with nasopharyngeal carcinoma: open label, non-inferiority, multicentre, randomised, phase 3 trial.

OBJECTIVES: To address whether sparing the medial retropharyngeal lymph node (MRLN) region from elective irradiation volume provides non-inferior local relapse-free survival versus standard radiotherapy in patients with nasopharyngeal carcinoma. DESIGN: Open-label, non-inferiority, multicentre, randomised, phase 3 trial. SETTING: Three Chinese hospitals between 20 November 2017 and 3 December 2018. PARTICIPANTS: Adults (18-65 years) with newly diagnosed, non-keratinising, non-distant metastatic nasopharyngeal carcinoma without MRLN involvement. INTERVENTIONS: Randomisation was done centrally by the Clinical Trials Centre at Sun Yat-sen University Cancer Center. Eligible patients were randomly assigned (1:1; block size of four) to receive MRLN sparing radiotherapy or standard radiotherapy (both medial and lateral retropharyngeal lymph node groups), and stratified by institution and treatment modality as follows: radiotherapy alone; concurrent chemoradiotherapy; induction chemotherapy plus radiotherapy or concurrent chemoradiotherapy. MAIN OUTCOME MEASURES: Non-inferiority was met if the lower limit of the one sided 97.5% confidence interval of the absolute difference in three year local relapse-free survival (MRLN sparing radiotherapy minus standard radiotherapy) was greater than -8%. RESULTS: 568 patients were recruited: 285 in the MRLN sparing radiotherapy group; 283 in the standard radiotherapy group. Median follow-up was 42 months (interquartile range 39-45), intention-to-treat analysis showed that the three year local relapse-free survival of the MRLN sparing radiotherapy group was non-inferior to that of the standard radiotherapy group (95.3% v 95.5%, stratified hazard ratio 1.04 (95% confidence interval 0.51 to 2.12), P=0.95) with a difference of -0.2% ((one sided 97.5% confidence interval -3.6 to ∞), Pnon-inferiority<0.001). In the safety set (n=564), the sparing group had a lower incidence of grade ≥1 acute dysphagia (25.5% v 35.1%, P=0.01) and late dysphagia (24.0% v 34.3%, P=0.008). Patient reported outcomes at three years after MRLN sparing radiotherapy were better in multiple domains after adjusting for the baseline values: global health status (mean difference -5.6 (95% confidence interval -9.1 to -2.0), P=0.002), role functioning (-5.5 (-7.4 to -3.6), P<0.001), social functioning (-6.2 (-8.9 to -3.6), P<0.001), fatigue (7.9 (4.0 to 11.8), P<0.001), and swallowing (11.0 (8.4 to 13.6), P<0.001). The difference in swallowing scores reached clinical significance (>10 points difference). CONCLUSION: Compared with standard radiotherapy, MRLN sparing radiotherapy showed non-inferiority in terms of risk of local relapse with fewer radiation related toxicity and improved patient reported outcomes in patients with non-metastatic nasopharyngeal carcinoma. TRIAL REGISTRATION: ClinicalTrials.gov NCT03346109.

TEAD4 is a master regulator of high-risk nasopharyngeal carcinoma.

The molecular basis underlying nasopharyngeal carcinoma (NPC) remains unclear. Recent progress in transcriptional regulatory network analysis helps identify the master regulator (MR) proteins that transcriptionally define malignant tumor phenotypes. Here, we investigated transcription factor-target interactions and identified TEA domain transcription factor 4 (TEAD4) as an MR of high-risk NPC. Precisely, TEAD4 promoted NPC migration, invasion and cisplatin resistance, depending on its autopalmitoylation. Mechanistically, YTHDF2 (YTH domain family 2) recognized WTAP (Wilms tumor 1-associating protein)-mediated TEAD4 m6A methylation to facilitate its stability and led to aberrant up-regulation of TEAD4. Up-regulated TEAD4 further drove NPC progression by transcriptionally activating BZW2 (basic leucine zipper and W2 domains 2) to induce the oncogenic AKT pathway. Moreover, the transcriptional activity of TEAD4 was independent of its canonical coactivators YAP/TAZ. Clinically, TEAD4 serves as an independent predictor of unfavorable prognosis and cisplatin response in NPC. Our data revealed the crucial role of TEAD4 in driving tumor malignancy, thus, may provide therapeutic vulnerability in NPC.

Patterns and prognosis of regional recurrence in nasopharyngeal carcinoma after intensity-modulated radiotherapy.

OBJECTIVE: We analyzed the patterns of lymph node (LN) failure and prognosis in patients with regional recurrent nasopharyngeal carcinoma (rNPC) alone after primary intensity-modulated radiotherapy (IMRT). METHODS: A total of 175 patients who were treated with IMRT between 2010 and 2015 and who experienced regional recurrence alone were included. Recurrent LNs were re-located in the initial pretreatment imaging and IMRT plan and failures were classified as in-field or out-field based on target volume delineation. All patients underwent curative salvage treatment. Independent prognostic factors for overall survival (OS) were selected by multivariate Cox analysis. RESULTS: Level IIb (49.1%, 86/175) was the most frequent recurrence site, followed by level IIa (36%), level III (18.9%), level IVa (12%), the retropharyngeal region (8%), level Va (6.9%), and the parotid region (6.9%). A total of 264 recurrent LNs were recorded: 149 (56.4%) were classified as in-field failure with a prescribed dose ≥66 Gy, 60 (22.7%) with 60 to <66 Gy, 32 (12.1%) with 50 to <60 Gy, and 23 (8.7%) as an out-field failure, which mainly occurred in the parotid region and level Ib. After a median follow-up of 52.8 months, the estimated 5-year OS rate was 66.9%. Multivariate analysis showed that age, plasma Epstein-Barr virus DNA level, extranodal extension, lower neck involvement, and parotid LN recurrence were independent prognostic factors of OS. CONCLUSIONS: In-field failure represented the main pattern of regional recurrence and out-field failure mainly occurred in the parotid gland and level Ib. Patients with regional rNPC alone had a good prognosis after salvage treatment.

N6 -Methyladenosine-Modified CBX1 Regulates Nasopharyngeal Carcinoma Progression Through Heterochromatin Formation and STAT1 Activation.

Epitranscriptomic remodeling such as N6 -methyladenosine (m6 A) modification plays a critical role in tumor development. However, little is known about the underlying mechanisms connecting m6 A modification and nasopharyngeal carcinoma (NPC) progression. Here, CBX1 is identified, a histone methylation regulator, to be significantly upregulated with m6 A hypomethylation in metastatic NPC tissues. The m6 A-modified CBX1 mRNA transcript is recognized and destabilized by the m6 A reader YTHDF3. Furthermore, it is revealed that CBX1 promotes NPC cell migration, invasion, and proliferation through transcriptional repression of MAP7 via H3K9me3-mediated heterochromatin formation. In addition to its oncogenic effect, CBX1 can facilitate immune evasion through IFN-γ-STAT1 signaling-mediated PD-L1 upregulation. Clinically, CBX1 serves as an independent predictor for unfavorable prognosis in NPC patients. The results reveal a crosstalk between epitranscriptomic and epigenetic regulation in NPC progression, and shed light on the functions of CBX1 in tumorigenesis and immunomodulation, which may provide an appealing therapeutic target in NPC.

The relationship between red blood cell distribution width at admission and post-stroke fatigue in the acute phase of acute ischemic stroke.

Introduction: Post-stroke fatigue (PSF) is a common complication in the patients with acute ischemic stroke (AIS). This prospective study aimed to investigate the relationship between red blood cell distribution width (RDW) at admission and PSF in the acute phase. Methods: The AIS patients were enrolled in Nantong Third People's Hospital, consecutively. PSF in the acute phase was scored according to the Fatigue Severity Scale. Levels of RDW were measured at admission. The associations were analyzed using multivariate regression and restricted cubic splines (RCS). Results: From April 2021 to March 2022, a total of 206 AIS patients (mean age, 69.3 ± 10.7 years; 52.9% men) were recruited. After the adjustment for potential confounding factors, RDW at admission remained the independent associated factor with PSF in the acute phase (OR [odds ratio], 1.635; 95% CI [confidence interval], 1.153-2.318; P = 0.006). The linear dose-response associations of RDW with PSF in the acute phase were found, based on the RCS model (P for non-linearity = 0.372; P for linearity = 0.037). These results remained significant in other models. Conclusions: RDW at admission could serve as a novel biomarker of PSF in the acute phase of AIS.

Effect of Radiotherapy Alone vs Radiotherapy With Concurrent Chemoradiotherapy on Survival Without Disease Relapse in Patients With Low-risk Nasopharyngeal Carcinoma: A Randomized Clinical Trial.

Importance: Concurrent chemoradiotherapy has been the standard treatment for stage II nasopharyngeal carcinoma (NPC) based on data using 2-dimensional conventional radiotherapy. There is limited evidence for the role of chemotherapy with use of intensity-modulated radiation therapy (IMRT). Objective: To assess whether concurrent chemotherapy can be safely omitted for patients with low-risk stage II/T3N0 NPC treated with IMRT. Design, Setting, and Participants: This multicenter, open-label, randomized, phase 3, noninferiority clinical trial was conducted at 5 Chinese hospitals, including 341 adult patients with low-risk NPC, defined as stage II/T3N0M0 without adverse features (all nodes <3 cm, no level IV/Vb nodes; no extranodal extension; Epstein-Barr virus DNA <4000 copies/mL), with enrollment between November 2015 and August 2020. The final date of follow-up was March 15, 2022. Interventions: Patients were randomly assigned to receive IMRT alone (n = 172) or concurrent chemoradiotherapy (IMRT with cisplatin, 100 mg/m2 every 3 weeks for 3 cycles [n = 169]). Main Outcomes and Measures: The primary end point was 3-year failure-free survival (time from randomization to any disease relapse or death), with a noninferiority margin of 10%. Secondary end points comprised overall survival, locoregional relapse-free survival, distant metastasis-free survival, adverse events, and health-related quality of life (QOL) measured by the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (QLQ-C30; range, 0-100 points; minimum clinically important difference ≥10 for physical function, symptom control, or health-related QOL; higher score indicates better functioning and global health status or worse symptoms). Results: Among 341 randomized patients (mean [SD] age, 48 [10] years; 30% women), 334 (98.0%) completed the trial. Median follow-up was 46 months (IQR, 34-58). Three-year failure-free survival was 90.5% for the IMRT-alone group vs 91.9% for the concurrent chemoradiotherapy group (difference, -1.4%; 1-sided 95% CI, -7.4% to ∞; P value for noninferiority, <.001). No significant differences were observed between groups in overall survival, locoregional relapse, or distant metastasis. The IMRT-alone group experienced a significantly lower incidence of grade 3 to 4 adverse events (17% vs 46%; difference, -29% [95% CI, -39% to -20%]), including hematologic toxicities (leukopenia, neutropenia) and nonhematologic toxicities (nausea, vomiting, anorexia, weight loss, mucositis). The IMRT-alone group had significantly better QOL scores during radiotherapy including the domains of global health status, social functioning, fatigue, nausea and vomiting, pain, insomnia, appetite loss, and constipation. Conclusions and Relevance: Among patients with low-risk NPC, treatment with IMRT alone resulted in 3-year failure-free survival that was not inferior to concurrent chemoradiotherapy. Trial Registration: ClinicalTrials.gov Identifier: NCT02633202.

Selection and validation of chemotherapy beneficiaries among elderly nasopharyngeal carcinoma (NPC) patients treated with intensity-modulated radiation therapy (IMRT): a large real-world study.

PURPOSE: Using real-world evidence, this study aimed to identify elderly nasopharyngeal carcinoma (NPC) patients who would benefit from chemotherapy. METHODS AND MATERIALS: 1714 elderly NPC patients between April 2007 and December 2017 were identified. Recursive partitioning analysis (RPA) was used to generate risk-stratified outcomes. Prognostic factors were performed for individual comparisons of different risk groups to assess chemotherapy benefits. RESULTS: The median follow-up was 59.3 (0.39-170.09) months. Epstein Barr virus (EBV) DNA and T stage were included in the RPA-generated risk stratification, categorizing patients into a good-prognosis group (EBV DNA ≤ 4000 copies/mL & T1-2), and a poor-prognosis group (EBV DNA ≤ 4000 copies/mL & T3-4 and EBV DNA > 4000 copies/mL & any T). Overall survival (OS) was significantly higher in the good-prognosis group compared with the training set (HR = 0.309, 95% CI 0.184-0.517; P < 0.001), and validated in the testing set (HR = 0.276, 95% CI 0.113-0.670; P = 0.002). In the poor-prognosis group, a significantly improved OS for chemoradiotherapy (CRT) compared with RT alone was observed (HR = 0.70, 95% CI 0.55-0.88; P = 0.003). Patients who received induction chemotherapy (IC) + concurrent chemoradiotherapy (CCRT) and CCRT had a significantly improved OS compared with RT alone (IC + CCRT vs. RT alone: P = 0.002; CCRT vs. RT alone: P = 0.008) but not in the IC + RT group (P = 0.306). The 5-year OS for CRT versus RT-alone with ACE-27 scores of 0, 1 and 2 were 76.0% versus 70.0% (P = 0.014), 80.5% versus 68.2% (P = 0.150) and 58.5% versus 62.2% (P = 0.490), respectively; for those aged 60-64, 65-70 and ≥ 70 years old they were 80.9% versus 75.9% (P = 0.068), 73.3% versus 63.4% (P = 0.270) and 64.8% versus 67.1% (P = 0.820), respectively. CONCLUSIONS: For elderly NPC patients a simple screening cutoff for chemotherapy beneficiaries might be EBV DNA < 4000 copies/ml & T3-4 and EBV DNA ≥ 4000 copies/ml & any T, but not for those > 70 years old and with an ACE-27 score > 1. IC + CCRT and CCRT were effective forms of chemotherapy.

[Antifungal activity and genomic analysis of Bacillus velezensis X49].

Proteolytic enzymes and lipopeptides contain broad-spectrum antimicrobial activities, which have great potential for research and development. A microbial strain X49 obtained from protease screening plate showed antifungal activities against six fungi. Biochemical analysis, 16S rRNA sequencing, API identification system, and electron microscope analysis were carried out to identify the bacterium. Azocasein method was used to analyze the protease activity. Lipopeptides were extracted for antifungal analysis. The result indicated that strain X49 grew in the range of 10-50 ℃ and pH 4.0-9.0. Moreover, it survived in 10% NaCl, showing good halotolerance. Strain X49 was identified as Bacillus velezensis. Genomic analysis of B. velezensis X49 revealed eleven genes encoding serine protease. The ID 1_894 belonging to S8 subtilisin family was 99% similar to the serine protease with known antifungal ability. On the other hand, thirty genes encoding non-ribosomal peptide synthetase involved in the lipopeptide biosynthesis, including surfactin, iturin, fengycin, bacitracin, and gramicidin, were identified. Part of the extracellular proteolytic activity remained under high temperature. After co-fermentation of B. velezensis X49 with Zingiber officinale Rosc., the antifungal activity of the lipopeptide extract from the co-fermentation was greatly improved. In conclusion, B. velezensis X49 showed clear inhibitory effect on both plant and human pathogens. The active substances co-fermented with Chinese herbs and microbes can be utilized for further drug development.

Identification of the high-yield monacolin K strain from Monascus spp. and its submerged fermentation using different medicinal plants.

BACKGROUND: Medical plants confer various benefits to human health and their bioconversion through microbial fermentation can increase efficacy, reduce toxicity, conserve resources and produce new chemical components. In this study, the cholesterol-lowering monacolin K genes and content produced by Monascus species were identified. The high-yield monacolin K strain further fermented with various medicinal plants. The antioxidant and anti-inflammatory activities, red pigment and monacolin K content, total phenolic content, and metabolites in the fermented products were analyzed. RESULTS: Monacolin K was detected in Monascus pilosus (BCRC 38072), and Monascus ruber (BCRC 31533, 31523, 31534, 31535, and 33323). It responded to the highly homologous mokA and mokE genes encoding polyketide synthase and dehydrogenase. The high-yield monacolin K strain, M. ruber BCRC 31535, was used for fermentation with various medicinal plants. A positive relationship between the antioxidant capacity and total phenol content of the fermented products was observed after 60 days of fermentation, and both declined after 120 days of fermentation. By contrast, red pigment and monacolin K accumulated over time during fermentation, and the highest monacolin K content was observed in the fermentation of Glycyrrhiza uralensis, as confirmed by RT-qPCR. Moreover, Monascus-fermented medicinal plants including Paeonia lactiflora, Alpinia oxyphylla, G. uralensis, and rice were not cytotoxic. Only the product of Monascus-fermented G. uralensis significantly exhibited the anti-inflammatory capacity in a dose-dependent manner in lipopolysaccharide-induced Raw264.7 cells. The metabolites of G. uralensis with and without fermentation (60 days) were compared by LC/MS. 2,3-Dihydroxybenzoic acid, 3,4-dihydroxyphenylglycol, and 3-amino-4-hydroxybenzoate were considered to enhance the antioxidant and anti-inflammatory ability. CONCLUSIONS: Given that highly homologous monacolin K and citrinin genes can be observed in Monascus spp., monacolin K produced by Monascus species without citrinin genes can be detected through the complementary methods of PCR and HPLC. In addition, the optimal fermentation time was important to the acquisition of antioxidants, red pigment and monacolin K. These bioactive substances were significantly affected by medicinal plants over fermentation time. Consequently, Monascus-fermented G. uralensis had a broad spectrum of biological activities.