Liquid-colloid-solid modular assembly for three-dimensional electrochemical biosensing of small molecules.

Electrochemical biosensors hold promise for advanced analytical applications in modern life analysis due to their miniaturization and cost-effectiveness. Nevertheless, their implementation in complex biological systems necessitates overcoming challenges related to timeliness, sensitivity, and interference resistance. Here, we developed a novel DNA hydrogel three-dimensional electron transporter through liquid-colloid-solid assembly, integrating electronic mediators and employing porous electrode covers with 3D printing technology. Our approach facilitated the fabrication of a high-performance electrochemical sensor for small molecule detection, leveraging target-specific aptamers and catalytic hairpin assembly (CHA) elements within the DNA hydrogel, which exhibited outstanding selectivity, sensitivity, and universality, achieving detection limits of 0.047 nM for kanamycin and 2.67 pM for ATP. Furthermore, this sensor could detect kanamycin in real samples, demonstrating good accuracy and robust anti-interference capabilities in human serum. Our work not only possesses substantial application value in clinical sample analysis but also represents a breakthrough in traditional strategies, thereby contributing to advancements in the application of electrochemical biosensors for life analysis.

Catalytic hairpin assembly-based AIEgen/graphene oxide nanocomposite for fluorescence-enhanced and high-precision spatiotemporal imaging of microRNA in living cells.

The low abundance, heterogeneous expression, and temporal changes of miRNA in different cellular locations pose significant challenges for both the detection sensitivity of miRNA liquid biopsy and intracellular imaging. In this work, we report an intelligently assembled biosensor based on catalytic hairpin assembly (CHA) and aggregation-induced emission (AIE), named as catalytic hairpin aggregation-induced emission (CHAIE), for the ultrasensitive detection and intracellular imaging of miRNA-155. To achieve such goal, tetraphenylethylene-N3 (TPE-N3) is used as AIE luminogen (AIEgen), while graphene oxide is introduced to quench the fluorescence. When the target miRNA is present, CHA reaction is triggered, causing the AIEgen to self-assemble with the hairpin DNA. This will restrict the intramolecular rotation of the AIEgen and produce a strong AIE fluorescence. Interestingly, CHAIE does not require any enzyme or expensive thermal cycling equipment, and therefore provides a rapid detection. Under optimal conditions, the proposed biosensor can determine miRNA in the concentration range from 2 pM to 200 nM within 30 min, with the detection limit of 0.42 pM. The proposed CHAIE biosensor in this work offers a low background signal and high sensitivity, making it applicable for highly precise spatiotemporal imaging of target miRNA in living cells.

Opioid-free anaesthesia reduces postoperative nausea and vomiting after thoracoscopic lung resection: a randomised controlled trial.

BACKGROUND: Intraoperative opioid use has a positive relationship with postoperative nausea and vomiting (PONV), and opioid-free anaesthesia (OFA) might reduce PONV. We investigated whether OFA compared with opioid-based anaesthesia would reduce PONV during the first 2 postoperative days among patients undergoing thoracoscopic lung resection. METHODS: In this randomised controlled trial, 120 adult patients were randomly assigned (1:1, stratified by sex) to receive either OFA with esketamine, dexmedetomidine, and sevoflurane, or opioid-based anaesthesia with sufentanil and sevoflurane. A surgical pleth index (SPI) of 20-50 was applied for intraoperative analgesia provision. All subjects received PONV prophylaxis (dexamethasone and ondansetron) and multimodal analgesia (flurbiprofen axetil, ropivacaine wound infiltration, and patient-controlled sufentanil). The primary outcome was the occurrence of PONV during the first 48 h after surgery. RESULTS: The median age was 53 yr and 66.7% were female. Compared with opioid-based anaesthesia, OFA significantly reduced the incidence of PONV (15% vs 31.7%; odds ratio [OR]=0.38, 95% confidence interval [CI], 0.16-0.91; number needed to treat, 6; P=0.031). Secondary and safety outcomes were comparable between groups, except that OFA led to a lower rate of vomiting (OR=0.23, 95% CI, 0.08-0.77) and a longer length of PACU stay (median difference=15.5 min, 95% CI, 10-20 min). The effects of OFA on PONV did not differ in the prespecified subgroups of sex, smoking status, and PONV risk scores. CONCLUSIONS: In the context of PONV prophylaxis and multimodal analgesia, SPI-guided opioid-free anaesthesia halved the incidence of PONV after thoracoscopic lung resection, although it was associated with a longer stay in the PACU. CLINICAL TRIAL REGISTRATION: Chinese Clinical Trial Registry (ChiCTR2200059710).

Situs Ambiguus Is Associated With Adverse Clinical Outcomes in Children With Primary Ciliary Dyskinesia.

BACKGROUND: Primary ciliary dyskinesia (PCD) is a rare disorder of motile cilia associated with situs abnormalities. At least 12% of patients with PCD have situs ambiguus (SA), including organ laterality defects falling outside normal arrangement (situs solitus [SS]) or mirror image inversion (situs inversus totalis [SIT]). RESEARCH QUESTION: Do patients with PCD and SA achieve worse clinical outcomes compared with those with SS or SIT? STUDY DESIGN AND METHODS: This cross-sectional, multicenter study evaluated participants aged 21 years or younger with PCD. Participants were classified as having SA, including heterotaxy, or not having SA (SS or SIT). Markers of disease severity were compared between situs groups, adjusting for age at enrollment and severe CCDC39 or CCDC40 genotype, using generalized linear models and logistic and Poisson regression. RESULTS: In 397 participants with PCD (mean age, 8.4 years; range, 0.1-21), 42 patients were classified as having SA, including 16 patients (38%) with complex cardiovascular malformations or atrial isomerism, 13 patients (31%) with simple CVM, and 13 patients (31%) without cardiovascular malformations. Of these, 15 patients (36%) underwent cardiac surgery, 24 patients (57%) showed an anatomic spleen abnormality, and seven patients (17%) showed both. The remaining 355 participants did not have SA, including 152 with SIT and 203 with SS. Overall, 70 participants (17%) harbored the severe CCDC39 or CCDC40 genotype. Compared with participants without SA, those with SA showed lower median BMI z scores (P = .03), lower FVC z scores (P = .01), and more hospitalizations and IV antibiotic courses for acute respiratory infections during the 5 years before enrollment (P < .01). Participants with cardiovascular malformations requiring surgery or with anatomic spleen abnormalities showed lower median BMI z scores and more hospitalizations and IV therapies for respiratory illnesses compared with participants without SA. INTERPRETATION: Children with PCD and SA achieve worse nutritional and pulmonary outcomes with more hospitalizations for acute respiratory illnesses than those with SS or SIT combined. Poor nutrition and increased hospitalizations for respiratory infections in participants with SA and PCD are associated with cardiovascular malformations requiring cardiac surgery, splenic anomalies, or both. TRIAL REGISTRY: ClinicalTrials.gov; Nos.: NCT02389049 and NCT00323167; URL: www. CLINICALTRIALS: gov.

The Efficacy, Safety, and Economic Outcomes of Using Ferric Derisomaltose for the Management of Iron Deficiency in China: A Rapid Health Technology Assessment.

Intravenous (IV) iron supplementation is the preferred treatment option for managing severe iron deficiency (ID) and ID anemia (IDA). Three of the available IV iron preparations are ferric derisomaltose (FDI), ferric carboxymaltose (FCM), and iron sucrose (IS). The objective of the present work was to review the published literature about the efficacy, safety, quality of life (QoL), and economic outcomes of using FDI, FCM, and IS for the treatment of ID. A systematic literature search was performed following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Eligible studies were assessed for quality using appropriate tools, and data were extracted and analyzed for key outcomes. The evidence synthesis was based on published systematic literature reviews (SLRs), meta-analyses (MAs), indirect treatment comparisons (ITCs), and health technology assessments (HTAs); we also included economic evaluations performed from a Chinese perspective. Out of 337 initial hits, the review included 12 studies. The findings indicated that FDI, FCM, and IS had comparable efficacy in terms of hemoglobin (Hb) improvement. FDI showed a better safety profile with a lower risk of hypophosphatemia, hypersensitivity reactions, and cardiovascular adverse events (AEs) compared to IS and FCM. FDI also demonstrated better cost-effectiveness compared to IS, with potential cost savings attributed to fewer infusions and improved compliance. None of the included studies evaluated QoL after IV iron administration for ID. FDI offers a safe, efficacious, and cost-effective treatment option for ID. It exhibits comparable efficacy to FCM and IS but presents a better safety profile and economic advantage. FDI fulfills the criteria of efficacy, safety, economy, innovation, suitability, and accessibility, making it a promising choice for ID management in China.

Histologic characterization of primary ciliary dyskinesia chronic rhinosinusitis.

KEY POINTS: We present the largest cohort of structured histopathology reports on primary ciliary dyskinesia-related chronic rhinosinusitis (PCD-CRS). Despite endoscopic differences, PCD-CRS and cystic fibrosis-related chronic rhinosinusitis (CF-CRS) had similar structured histopathology reports. Compared to healthy patients and those with idiopathic chronic rhinosinusitis without nasal polyps, patients with PCD-CRS had an increased neutrophil count.

Effects of Subcostal Anterior Quadratus Lumborum Block with and without Dexmedetomidine on Postoperative Rehabilitation in Patients Undergoing Laparoscopic Renal Surgery: A Prospective Double-Blinded Randomized Controlled Study.

Background: The combination of different anesthesia techniques or adjuvant drugs can relieve the stress response to surgery, reduce adverse reactions and improve the clinical outcome. We investigated the effects of subcostal anterior quadratus lumborum block (SQLB) with and without dexmedetomidine (DEX) on postoperative rehabilitation for laparoscopic renal surgery (LRS). Methods: We included 90 patients in this single-center study. All were scheduled for elective laparoscopic radical or partial nephrectomy under general anesthesia (GA). We randomly and evenly assigned them to three groups: Group GA (GA alone), Group QG (SQLB with 30 mL of 0.25% ropivacaine and GA), and Group DQG (SQLB with 30 mL of 0.25% ropivacaine plus 1 µg/kg DEX and GA). The primary outcomes were serum creatinine (Cr) and blood urea nitrogen (BUN) levels; the secondary outcomes included the average numeric rating scale (NRS) scores at rest and during activity within 48 h postoperatively; perioperative opioid consumption; the time to first ambulation, exhaust, and fluid intake, and postoperative adverse reactions. Results: The serum Cr and BUN levels in Group DQG decreased significantly compared with Group GA (P < 0.05). The average NRS scores in Group DQG were significantly lower than other two groups (P < 0.05). Furthermore, the indexes reduced significantly in Group QG compared with Group GA (P < 0.05). Groups DQG and QG had lower consumption of opioid compared with Group GA (P < 0.05). The recovery indicators in Groups DQG and QG were higher quality than Group GA (P < 0.05). The incidences of adverse reactions in Group DQG was significantly lower than the other groups (P < 0.05). Conclusion: SQLB with and without DEX could attenuate postoperative pain, reduce opioids requirement and side effects, as well as facilitate postoperative early rehabilitation. More interesting, SQLB with DEX could confer kidney protection. Clinical Trial Registration Number: The Chinese Clinical Trial Registry (ChiCTR2200061554).

Radiographic and Patient-Reported Outcomes of a Low-Cost Modified Lapidus Bunion Correction Technique.

Background: The modified Lapidus (ML) is a powerful procedure for correction of hallux valgus (HV) with emerging techniques. Studies considering patient-reported outcomes, radiographic measures, complications, and implant costs are currently limited. Methods: Retrospective cohort with prospectively collected Patient Reported Outcome Information System Physical Function (PROMIS-PF) Computerized Adaptive Test (CAT) scores, radiographic parameters (intermetatarsal angle, IMA; hallux valgus angle, HVA; and tibial sesamoid position, TSP), complications, and total operative time and implant costs were reviewed from 2014 to 2019. Results: Seventy-three feet (68 patients) underwent bunion correction by ML with lag-screw fixation. Median age was 55.8 years (IQR 45.6, 53.9), 4 of 73 (5.5%) were male, 11 of 73 (15.1%) were smokers, and 15 of 73 (20.6%) were diabetic (median HbA1c 6.4% [IQR 6.0, 7.4], none insulin dependent, 5 of 15 with neuropathy). Complications included 6 of 73 (8.2%) wound issues resolved with topical or oral treatment, 9 of 73 (12.3%) painful or broken hardware requiring hardware removal. Two of 73 (2.7%) had persistent pain despite union. One of 73 (1.4%) was overcorrected and required first MTP arthrodesis. Of 3 nonunions (2.7%), 1 resolved with corrected hypothyroidism, 1 was asymptomatic and required no treatment, 1 had a hallux valgus recurrence and sought revision surgery elsewhere. Preoperative radiographic angles were HVA 35 degrees, IMA 14 degrees which improved at final postoperative follow up to HVA 10 degrees, IMA 6 degrees. Tibial sesamoid position improved from 6.05 ± 1.00 to 2.22 ± 1.38. Thirty-two patients had preoperative and 42 had 1-year postoperative outcomes. PROMIS-PF (51% collection rate) was 43 (IQR 37,52) preoperatively, 37 (31, 39) at 6 weeks, 46 (42, 51) at 3 months, and 49 (41, 53) at >360 days postoperatively. The drop in PROMIS-PF between preoperative and 6 weeks and the rise from 6 weeks to 3 months were statistically significant. Pre- and postoperative PROMIS-PF scores were not significantly different. Implant cost averaged US$146. Discussion/Conclusion: We report low complication rates and costs with high patient postoperative functional and radiographic outcomes. PROMIS-PF decreased acutely postoperatively but recovered and maintained high levels by 3 months postoperatively. Level of Evidence: Level IV, case series.

Co-exposure to low-dose lead, cadmium, and mercury promotes memory deficits in rats: Insights from the dynamics of dendritic spine pruning in brain development.

Lead (Pb), cadmium (Cd), and mercury (Hg) are environmentally toxic heavy metals that can be simultaneously detected at low levels in the blood of the general population. Although our previous studies have demonstrated neurodevelopmental toxicity upon co-exposure to these heavy metals at these low levels, the precise mechanisms remain largely unknown. Dendritic spines are the structural foundation of memory and undergo significant dynamic changes during development. This study focused on the dynamics of dendritic spines during brain development following Pb, Cd, and Hg co-exposure-induced memory impairment. First, the dynamic characteristics of dendritic spines in the prefrontal cortex were observed throughout the life cycle of normal rats. We observed that dendritic spines increased rapidly from birth to their peak value at weaning, followed by significant pruning and a decrease during adolescence. Dendritic spines tended to be stable until their loss in old age. Subsequently, a rat model of low-dose Pb, Cd, and Hg co-exposure from embryo to adolescence was established. The results showed that exposure to low doses of heavy metals equivalent to those detected in the blood of the general population impaired spatial memory and altered the dynamics of dendritic spine pruning from weaning to adolescence. Proteomic analysis of brain and blood samples suggested that differentially expressed proteins upon heavy metal exposure were enriched in dendritic spine-related cytoskeletal regulation and axon guidance signaling pathways and that cofilin was enriched in both of these pathways. Further experiments confirmed that heavy metal exposure altered actin cytoskeleton dynamics and disturbed the dendritic spine pruning-related LIM domain kinase 1-cofilin pathway in the rat prefrontal cortex. Our findings demonstrate that low-dose Pb, Cd, and Hg co-exposure may promote memory impairment by perturbing dendritic spine dynamics through dendritic spine pruning-related signaling pathways.

Involvement in treatment decision-making and self-reported efficacy among patients with advanced colorectal cancer: a nationwide multi-center cross-sectional study.

Introduction: This cross-sectional study evaluated the involvement of patients with advanced colorectal cancer (CRC) in treatment decision-making, assessed the treatment efficacy according to their self-reports, and investigated the influencing factors. Methods: Patients with advanced CRC were recruited from 19 hospitals from March 2020 to March 2021 by a multi-stage multi-level sampling method. A self-designed questionnaire was used to collect demographic and clinical characteristics, involvement of CRC patients in treatment decision-making, treatment methods, and self-reported efficacy. Univariate and unordered multinomial logistic regression analyses were used to evaluate the factors affecting the involvement in treatment decision-making and self-reported efficacy. Results: We enrolled 4533 patients with advanced CRC. The average age at diagnosis was 58.7 ± 11.8 years. For the treatment method, 32.4% of patients received surgery combined with chemotherapy, 13.1% of patients underwent surgery combined with chemotherapy and targeted therapy, and 9.7% of patients were treated with surgery alone. For treatment decision-making, 7.0% of patients were solely responsible for decision-making, 47.0% of patients shared treatment decision-making with family members, 19.0% of patients had family members solely responsible for treatment decision-making, and 27.0% of patients had their physicians solely responsible for treatment decision-making. Gender, age, education level, family income, marital status, treatment cost, hospital type, and treatment method were significantly associated with the involvement of patients in treatment decision-making. A total of 3824 patients submitted self-reported efficacy evaluations during treatment. The percentage of patients with good self-reported efficacy was 76.5% (for patients treated for the first time), 61.7% (for patients treated for the second time), and 43.2% (for patients treated after recurrence and metastasis), respectively. Occupation, education level, average annual family income, place of residence, time since cancer diagnosis, hospital type, clinical stage, targeted therapy, and involvement in treatment decision-making were the main influencing factors of self-reported efficacy of treatment. Discussion: Conclusively, CRC patients are not highly dominant in treatment decision-making and more likely to make treatment decisions with their family and doctors. Timely and effective communication between doctors and patients can bolster patient involvement in treatment decision-making.

Real-World Utilization, Barriers, and Factors Associated With the Targeted Treatment of Metastatic Colorectal Cancer Patients in China: A Multi-Center, Hospital-Based Survey Study.

Objectives: To explore the utilization, barriers, and factors associated with the targeted treatment of Chinese metastatic colorectal cancer (mCRC) patients. Methods: A total of 1,688 mCRC patients from 19 hospitals in 14 cities were enrolled from March 2020 to March 2021 using stratified, multistage cluster sampling. The use of targeted therapy and any barriers patients experienced were collected. Logistic regression analyses were conducted to identify the factors associated with initiating targeted treatment. Results: About 51.6% of the patients initiated targeted therapy, of whom 44.5%, 20.2%, and 35.2% started first-, second-, and third-line treatment, respectively. The most reported barriers were high medical costs and a lack of belief in the efficacy of targeted therapy. Patients treated in the general hospital, diagnosed at an older age, less educated, and who had a lower family income, no medical insurance, poor health-related quality of life, metastasis outside the liver/lung or systemic metastasis, a shorter duration of mCRC were less likely to initiate targeted therapy. Conclusion: Reduced medical costs and interventional education to improve public awareness could facilitate the use of targeted treatment for mCRC.

RNF114 facilitates the proliferation, stemness, and metastasis of colorectal cancer.

BACKGROUND: Colorectal cancer (CRC), the fourth of the world's major common malignancy, poses a serious threat to the physical and mental health of the population. Nevertheless, the prognosis of CRC patients remains unsatisfactory. Consequently, it is still imperative to continuously discover the CRC mechanisms. METHODS: The expression profiles of mRNAs were recognized by whole transcriptome sequencing to identity differentially expressed mRNA (DE-mRNA). TCGA COAD cohort, PPOGgene and Kaplan-Meier Plotter databases were utilized to validate RNF114 relevance to CRC prognosis. The effect of RNF114 on the malignant biological behavior of CRC was explored in CRC cells and subcutaneous tumor models and lung metastasis model after exogenous regulation of RNF114. RESULTS: A total of 1358 DE-mRNAs were identified, including 617 up-regulated and 741 down-regulated DE-mRNAs, and they were mainly involved in the term of receptor ligand activity, Wnt signaling pathway and pathway in cancer. Notably, RNF114 was hyper-expressed in tissues and cell of CRC, and significantly correlated with tumor invasion depth and TNM stage of CRC patients. RNF114 expression were significantly associated with overall survival, and had superior diagnostic value in CRC. In vitro, knockdown of RNF114 statistically diminished the proliferation, stemness, invasion and wound healing of CRC cells and facilitated their apoptosis, and the opposite result was observed for overexpression of RNF114. In vivo, knockdown of RNF114 effectively diminished the mass and volume of tumors, and lung metastasis in animal model. CONCLUSIONS: In summary, we identified DE-mRNAs in CRC, and elucidated that RNF114 facilitates CRC process. The discovery will contribute to theoretical foundation for RNF114 as a potential therapeutic target and biomarker, and offer new perspectives for CRC research.

Comparing Patient-Reported Outcomes Among Anti-TNF Experienced Patients With Ulcerative Colitis Initiating Vedolizumab Versus Tofacitinib.

Background: Primary and secondary nonresponse to anti-tumor necrosis factor (TNF) therapy is common in patients with ulcerative colitis (UC), yet limited research has compared the effectiveness of subsequent biological therapy. Objective: We sought to compare the effectiveness of vedolizumab and tofacitinib in anti-TNF experienced patients with UC, focusing on patient-prioritized patient-reported outcomes (PROs). Methods: We conducted a prospective cohort study nested within the Crohn's & Colitis Foundation's IBD Partners and SPARC IBD initiatives. We identified anti-TNF experienced patients with UC initiating vedolizumab or tofacitinib and analyzed PROs reported approximately 6 months later (minimum 4 months, maximum 10 months). Co-primary outcomes were Patient Reported Outcome Measurement Information System (PROMIS) domains of Fatigue and Pain Interference. Secondary outcomes included PRO2, treatment persistence, and need for colectomy. Results: We compared 72 vedolizumab initiators and 33 tofacitinib initiators. At follow-up, Pain Interference (P = .04), but not Fatigue (P = .53) was lower among tofacitinib initiators. A trend toward higher Social Role Satisfaction was not significant. The remainder of secondary outcomes (PRO2, treatment persistence, colectomy) did not differ between treatment groups. Conclusions: Among anti-TNF experienced patients with UC, Pain Interference 4-10 months after treatment initiation was lower among tofacitinib users as compared with vedolizumab users. Many, but not all, secondary endpoints and subanalyses also favored tofacitinib. Future studies with larger sample sizes are needed to further evaluate these findings.

Preoperative Ultrasound-Guided Internal Branch Block of Superior Laryngeal Nerve Reduces Postoperative Sore Throat Caused by Double Lumen Endotracheal Intubation: A Randomized Trial.

BACKGROUND: Postoperative sore throat (POST) is one of the more common side effects of tracheal intubation patients under general anesthesia (GA) after extubation using double-lumen endobronchial tubes (DLTs). The internal branches of the superior laryngeal nerve (SLN) block (iSLNB) have been reported to anesthetize the larynx for airway manipulation (such as awake tracheal intubation) and pain treatment efficiently. We hypothesized that ultrasound-guided iSLNB (US-guided iSLNB) combined with GA would ameliorate the incidence and severity of POST and hoarseness. METHODS: Patients (n = 82) undergoing thoracoscopic resection of pulmonary nodules/lobes/segments with one-lung ventilation (OLV) under GA were randomized into 2 groups depending on whether performed with iSLNB (S group, n = 41) or not (C group, n = 41) under GA. Patients in the S group received US-guided iSLNB bilaterally before surgery. POST and hoarseness were assessed at 2, 6, and 24 hours after surgery. The primary outcome of this study was the incidence of POST at 6 hours after surgery between groups. RESULTS: The overall accumulated incidence of POST was lower in the S goup than in the C group (9/41 vs 20/41; 95% CI, 0.30 [0.11-0.77]; P = .011). The incidence and severity of POST was lower in the S group than in the C group at 2 hours (9/41 vs 20/41; 95% CI, 0.30 [0.11-0.77]; P = .008 and P = .004) and 6 hours after (7/41 vs 17/41; 95% CI, 0.29 [0.10-0.81]; P = .012 and P = .015) surgery. The incidence and severity of POST at 24 hours after surgery was nonsignificant. However, the incidence and severity of hoarseness was comparable between the 2 groups at 2, 6, and 24 hours after surgery. CONCLUSIONS: Preoperative US-guided iSLNB could significantly ameliorate the incidence and severity of POST induced by double-lumen bronchial catheter intubation.

USP1 modulates hepatocellular carcinoma progression via the Hippo/TAZ axis.

Hepatocellular carcinoma (HCC) is one of the most lethal malignancies worldwide. The Hippo signaling pathway has emerged as a significant suppressive pathway for hepatocellular carcinogenesis. The core components of the Hippo pathway constitute a kinase cascade, which inhibits the functional activation of YAP/TAZ. Interestingly, the overactivation of YAP/TAZ is commonly observed in hepatocellular carcinoma, although the inhibitory kinase cascade of the Hippo pathway is still functional. Recent studies have indicated that the ubiquitin‒proteasome system also plays important roles in modulating Hippo signaling activity. Our DUB (deubiquitinase) siRNA screen showed that USP1 is a critical regulator of Hippo signaling activity. Analysis of TCGA data demonstrated that USP1 expression is elevated in HCC and associated with poor survival in HCC patients. RNA sequencing analysis revealed that USP1 depletion affects Hippo signaling activity in HCC cell lines. Mechanistic assays revealed that USP1 is required for Hippo/TAZ axis activity and HCC progression. USP1 interacted with the WW domain of TAZ, which subsequently enhanced TAZ stability by suppressing K11-linked polyubiquitination of TAZ. Our study identifies a novel mechanism linking USP1 and TAZ in regulating the Hippo pathway and one possible therapeutic target for HCC.

Effect of esketamine on postoperative depressive symptoms in patients undergoing thoracoscopic lung cancer surgery: A randomized controlled trial.

Background: Depressive symptoms are common among patients with lung cancer. We aimed to assess the effects of esketamine on postoperative depressive symptoms after thoracoscopic lung cancer surgery. Methods: In this randomized, double-blind, placebo-controlled trial, 156 patients undergoing thoracoscopic lung cancer surgery were randomly allocated in a 1:1 ratio to receive intravenous esketamine (intraoperatively and in patient-controlled analgesia until 48 h postoperatively) or normal saline placebo. The primary outcome was the proportion of patients with depressive symptoms at 1 month postoperatively, assessed using the Beck Depression Inventory-II (BDI-II). Secondary outcomes included depressive symptoms at 48 h postoperatively, hospital discharge and 3 months postoperatively, BDI-II scores, anxious symptoms, Beck Anxiety Inventory scores, Quality of Recovery-15 (QoR-15) scores, and 1- and 3-month mortality. Main results: A total of 151 patients (75 in the esketamine group and 76 in the normal saline group) completed the 1-month follow-up. The esketamine group had a significantly lower incidence of depressive symptoms at 1 month compared to the normal saline group (1.3% vs. 11.8%; risk difference = -10.5, 95%CI = -19.6% to -0.49%; p = 0.018). After excluding patients without lung cancer diagnosis, the incidence of depressive symptoms was also lower in the esketamine group (1.4% vs. 12.2%; risk difference = -10.8, 95%CI = -20.2% to -0.52%; p = 0.018). The secondary outcomes were similar between groups, except that the esketamine group had higher QoR-15 scores at 1 month postoperatively (median difference = 2; 95%CI = 0 to 5; p = 0.048). The independent risk factors for depressive symptoms were hypertension (odds ratio = 6.75, 95%CI = 1.13 to 40.31; p = 0.036) and preoperative anxious symptoms (odds ratio = 23.83, 95%CI = 3.41 to 166.33; p = 0.001). Conclusion: Perioperative administration of esketamine reduced the incidence of depressive symptoms at 1 month after thoracoscopic lung cancer surgery. History of hypertension and preoperative anxious symptoms were independent risk factors for depressive symptoms.Clinical trial registration: Chinese Clinical Trial Registry http://www.chictr.org.cn, Identifier (ChiCTR2100046194).

Lantern-shaped flexible RNA origami for Smad4 mRNA delivery and growth suppression of colorectal cancer.

mRNA delivery has shown high application value in the treatment of various diseases, but its effective delivery is still a major challenge at present. Herein, we propose a lantern-shaped flexible RNA origami for mRNA delivery. The origami is composed of a target mRNA scaffold and only two customized RGD-modified circular RNA staples, which can compress the mRNA into nanoscale and facilitate its endocytosis by cells. In parallel, the flexible structure of the lantern-shaped origami allows large regions of the mRNA to be exposed and translated, exhibiting a good balance between endocytosis and translation efficiency. The application of lantern-shaped flexible RNA origami in the context of the tumor suppressor gene, Smad4 in colorectal cancer models demonstrates promising potential for accurate manipulation of protein levels in in vitro and in vivo settings. This flexible origami strategy provides a competitive delivery method for mRNA-based therapies.

Discrimination between Precancerous Gastric Lesions and Gastritis Using a Gastric Cancer Risk Stratification Model.

BACKGROUND: Seropositivity to certain Helicobacter pylori proteins may affect development of gastric lesions that could become cancerous. Previously, we developed a model of gastric cancer risk including gender, age, HP0305 sero-positivity, HP1564 sero-positivity, UreA antibody titer and serologically defined chronic atrophic gastritis (termed: "Lasso model"). METHODS: We evaluated the Lasso model's ability to discriminate individuals with precancerous gastric lesions (n=320) from individuals with superficial or mild atrophic gastritis (n=226) in Linqu County, China, a population at high risk for gastric cancer. We also compared its performance to the ABC Method, a gastric cancer risk stratification tool currently used in East Asia. RESULTS: For distinguishing precancerous lesions from those with gastritis, the receiver operating characteristic curve had an area under the curve (AUC) of 73.41% (95% CI: 69.10%, 77.71%) and, at Youden's Index, a sensitivity of 78.44% (59.38%, 82.50%) and specificity of 64.72% (95% CI: 58.85%, 81.42%). Positive predictive value (PPV) was 75.38% (72.78%, 82.51%). Specificity, AUC and PPV were significantly greater (p < 0.05) than those of the ABC Method. When specificity was held constant, the Lasso model had greater sensitivity, PPV and negative predictive value (NPV) than the ABC Method. However, adjusting the ABC Method for age and gender negated the Lasso model's significant improvement in AUC. CONCLUSIONS: The Lasso model for gastric cancer risk prediction can classify precancerous lesions with significantly greater AUC than the ABC Method and, at constant specificity, with greater sensitivity, PPV and NPV. However, adding age and gender to the ABC Method, as included in the Lasso model, substantially improved its performance and negated the Lasso model's advantage.

Cognitive outcomes caused by low-level lead, cadmium, and mercury mixture exposure at distinct phases of brain development.

Contaminated water and food are the main sources of lead, cadmium, and mercury in the human body. Long-term and low-level ingestion of these toxic heavy metals may affect brain development and cognition. However, the neurotoxic effects of exposure to lead, cadmium, and mercury mixture (Pb + Cd + Hg) at different stages of brain development are rarely elucidated. In this study, different doses of low-level Pb + Cd + Hg were administered to Sprague-Dawley rats via drinking water during the critical stage of brain development, late stage, and after maturation, respectively. Our findings showed that Pb + Cd + Hg exposure decreased the density of memory- and learning-related dendritic spines in the hippocampus during the critical period of brain development, resulting in hippocampus-dependent spatial memory deficits. Only the density of learning-related dendritic spines was reduced during the late phase of brain development and a higher-dose of Pb + Cd + Hg exposure was required, which led to hippocampus-independent spatial memory abnormalities. Exposure to Pb + Cd + Hg after brain maturation revealed no significant change in dendritic spines or cognitive function. Further molecular analysis indicated that morphological and functional changes caused by Pb + Cd + Hg exposure during the critical phase were associated with PSD95 and GluA1 dysregulation. Collectively, the effects of Pb + Cd + Hg on cognition varied depending on the brain development stages.

The effect of a brief, unplanned treatment delay on neovascular age-related macular degeneration patients: a retrospective cohort study.

Non-compliance to intravitreal anti-vascular endothelial growth factor (anti-VEGF) therapy can result in increased disease activity in neovascular age-related macular degeneration (nAMD). Our study aims to determine effects of unplanned delay in anti-VEGF injection treatment for nAMD. This retrospective observational study included patients with delays in receiving intravitreal injections for nAMD treatment from March to May 2020 by at least 21 days. Baseline demographic and clinical characteristics, visual acuity (VA), central macular thickness (CMT) measured on optical coherence tomography (OCT), and duration of delayed treatment were analyzed for 3 time points, the pre-delay visit (v1) and post-delay visits (v2 and v3). Data were compared to age-matched controls treated for nAMD in 2019 without delay. Demographic characteristics were compared using two-sample t-tests for continuous variables and Pearson's chi-square tests for categorical variables. For the two primary outcomes of interest, VA and CMT, means and standard deviations were reported for each combination of group and time. Each outcome was modeled using a linear mixed model with the group, time and group-time interaction as fixed effects. A total of 69 patients (99 eyes) in the treatment delay group and 44 patients (69 eyes) in the control group were identified. Statistically significant differences between control and delayed groups were detected for VA (difference in mean logMAR = 0.16; 95% CI 0.06, 0.27; p = 0.002) and CMT (difference in mean CMT = 29; 95% CI 12, 47; p = 0.001) at v2. No differences were detected for v1 and v3 time points for both outcomes. An unplanned delay in intravitreal injection treatment for nAMD resulted in an increase in CMT and worsening of VA compared to controls observed at v2. At v3, CMT and VA recovered to near v1 levels. This study demonstrates that a one-time, brief interruption in treatment for nAMD results in reversible, temporary worsening.