Infrared laser moxibustion for cancer-related fatigue in breast cancer survivors: a randomized controlled trial.

BACKGROUND: Cancer-related fatigue (CRF) is a pervasive, persistent, and distressing symptom experienced by cancer patients, for which few treatments are available. We investigated the efficacy and safety of infrared laser moxibustion (ILM) for improving fatigue in breast cancer survivors. METHODS: A three-arm, randomized, sham-controlled clinical trial (6-week intervention plus 12-week observational follow-up) was conducted at a tertiary hospital in Shanghai, China. The female breast cancer survivors with moderate to severe fatigue were randomized 2:2:1 to ILM (n = 56) sham ILM (n = 56), and Waitlist control (WLC)(n = 28) groups. Patients in the ILM and sham ILM (SILM) groups received real or sham ILM treatment, 2 sessions per week for 6 weeks, for a total of 12 sessions. The primary outcome was change in the Brief Fatigue Inventory (BFI) score from baseline to week 6 with follow-up until week 18 assessed in the intention-to-treat population. RESULTS: Between June 2018 and July 2021, 273 patients were assessed for eligibility, and 140 patients were finally enrolled and included in the intention-to-treat analysis. Compared with WLC, ILM reduced the average BFI score by 0.9 points (95% CI, 0.3 to 1.6, P = .007) from baseline to week 6, with a difference between the groups of 1.1 points (95% CI, 0.4 to 1.8, P = .002) at week 18. Compared with SILM, ILM treatment resulted in a non-significant reduction in the BFI score (0.4; 95% CI, -0.2 to 0.9, P = .206) from baseline to week 6, while the between-group difference was significant at week 18 (0.7; 95% CI, 0.2 to 1.3, P = .014). No serious adverse events were reported. CONCLUSION: While ILM was found to be safe and to significantly reduce fatigue compared with WLC, its promising efficacy against the sham control needs to be verified in future adequately powered trials. TRIAL REGISTRATION: Clinicaltrials.gov: NCT04144309. Registered 12 June 2018.

Effects of light qualities on growth and physiological-biochemical traits of Scutellaria baicalensis.

Canopy spectral composition significantly affects growth and functional traits of understory plants. In this study, we explored the optimal light condition suitable for enhancing Scutellaria baicalensis's yield and quality, aiming to provide scientific reference for the exploitation and utilization of medicinal plant resources in the understory of forests. We measured the responses of growth, morphology, biomass allocation, physiological traits, and secon-dary metabolites of S. baicalensis to different light qualities. S. baicalensis was cultured under five LED-light treatments including full spectrum light (control), ultraviolet-A (UV-A) radiation, blue, green, and red light. Results showed that UV-A significantly reduced plant height, base diameter, leaf thickness, leaf area ratio, and biomass of each organ. Red light significantly reduced base diameter, biomass, effective quantum yield of photosystem Ⅱ (ФPSⅡ), and total flavonoid concentration. Under blue light, root length and total biomass of S. baicalensis significantly increased by 48.0% and 10.8%, respectively, while leaf number and chlorophyll content significantly decreased by 20.0% and 31.6%, respectively. The other physiological and biochemical traits were consistent with their responses in control. Our results suggested that blue light promoted photosynthesis, biomass accumulation, and secondary metabolite synthesis of S. baicalensis, while red light and UV-A radiation negatively affected physiological and biochemical metabolic processes. Therefore, the ratio of blue light could be appropriately increased to improve the yield and quality of S. baicalensis.

The potential mechanism of Aidi injection against neuroblastoma-an investigation based on network pharmacology analysis.

Background: Aidi injection, a classic traditional Chinese medicine (TCM) formula, has been used on a broader scale in treating a variety of cancers. In this study, we aimed to explore the potential anti-tumor effects of Aidi injection in the treatment of neuroblastoma (NB) using network pharmacology (NP). Methods: To elucidate the anti-NB mechanism of Aidi injection, an NP-based approach and molecular docking validation were employed. The compounds and target genes were collected from the Traditional Chinese Medicine Systems Pharmacology (TCMSP) database and Bioinformatics Analysis Tool for Molecular mechANism of Traditional Chinese Medicine (BATMAN-TCM) database. The protein-protein interaction network was constructed using the STRING database. clusterProfiler (R package) was utilized to annotate the bioinformatics of hub target genes. The gene survival analysis was performed on R2, a web-based genomic analysis application. iGEMDOCK was used for molecular docking validation, and GROMACS was utilized to validate molecular docking results. Furthermore, we investigated the anticancer effects of gomisin B and ginsenoside Rh2 on human NB cells using a cell viability assay. The Western blot assay was used to validate the protein levels of target genes in gomisin B- and ginsenoside Rh2-treated NB cells. Results: A total of 2 critical compounds with 16 hub target genes were identified for treating NB. All 16 hub genes could potentially influence the survival of NB patients. The top three genes (EGFR, ESR1, and MAPK1) were considered the central hub genes from the drug-compound-hub target gene-pathway network. The endocrine resistance and estrogen signaling pathways were identified as the therapeutic pathways using the Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. Gomisin B and ginsenoside Rh2 showed a good binding ability to the target protein in molecular docking. The results of cell experiments showed the anti-NB effect of gomisin B and ginsenoside Rh2. In addition, the administration of gomisin B over-regulated the expression of ESR1 protein in MYCN-amplified NB cells. Conclusion: In the present study, we investigated the potential pharmacological mechanisms of Aidi against NB and revealed the anti-NB effect of gomisin B, providing clinical evidence of Aidi in treating NB and establishing baselines for further research.

Lenvatinib, sintilimab plus transarterial chemoembolization for advanced stage hepatocellular carcinoma: A phase II study.

BACKGROUND & AIMS: Our retrospective study has suggested encouraging outcomes of lenvatinib combined with PD-1 inhibitor and transarterial chemoembolization (TACE) on advanced hepatocellular carcinoma (HCC). This phase II trial was conducted to prospectively investigate the efficacy and safety of lenvatinib, sintilimab (a PD-1 inhibitor) plus TACE (Len-Sin-TACE) in patients with advanced stage HCC. METHODS: This was a single-arm phase II trial. Patients with BCLC stage C HCC were recruited. They received lenvatinib (bodyweight ≥60 kg, 12 mg; bodyweight <60 kg, 8 mg) orally once daily, sintilimab (200 mg) intravenously once every 3 weeks, and on demand TACE. The primary endpoint was progression-free survival (PFS) per mRECIST. RESULTS: Thirty patients were enrolled. The primary endpoint was met with a median PFS of 8.0 (95% confidence interval [CI]: 6.1-9.8) months per mRECIST, which was the same as that per RECIST 1.1. The objective response rate was 60.0% per mRECIST and 30.0% per RECIST 1.1. The disease control rate was 86.7% per mRECIST/RECIST 1.1. The median duration of response was 7.4 (95% CI: 6.6-8.2) months per mRECIST (n = 18) and 4.3 (95% CI: 4.0-4.6) months per RECIST 1.1 (n = 9). The median overall survival was 18.4 (95% CI: 14.5-22.3) months. Treatment-related adverse events (TRAEs) occurred in 28 patients (93.3%) and grade 3 TRAEs were observed in 12 patients (40.0%). There were no grade 4/5 TRAEs. CONCLUSIONS: Len-Sin-TACE showed promising antitumour activities with a manageable safety profile in patients with advanced stage HCC. The preliminary results need to be further evaluated with phase III randomized trials.

Postnatal treatment and evolution patterns of giant fetal hepatic hemangioma: a case series of 29 patients.

OBJECTIVES: To explore the clinical characteristics, postnatal treatment and prognosis of giant fetal hepatic hemangioma (GFHH). METHOD: Retrospective analysis was performed on children with giant fetal hepatic hemangioma (maximum tumor diameter > 40 mm) diagnosed by prenatal ultrasound and MRI from December 2016 to December 2020. These patients were observed and treated at the Children's Hospital of Fudan University after birth. The clinical data were collected to analyze the clinical characteristics, treatment, and prognosis of GFHH using independent sample t tests or Fisher's exact tests. RESULTS: Twenty-nine patients who were detected by routine ultrasound in the second and third trimester of pregnancy with giant fetal hepatic hemangiomas were included. The first prenatal ultrasound diagnosis of gestational age was 34.0 ± 4.3 weeks, ranging from 22 to 39 weeks. Of the patients, 28 had focal GFHHs and 1 had multifocal GFHHs. Surgery was performed, and the diagnosis was confirmed histopathologically in two patients. There were 8 cases with echocardiography-based evidence of pulmonary hypertension, 11 cases had a cardiothoracic ratio > 0.6, and 4 cases had hepatic arteriovenous fistula (AVF). The median follow-up time was 37 months (range: 14-70 months). During the follow-up, 12 patients received medical treatment with propranolol as the first-line therapy. The treatment group had a higher ratio of cardiothoracic ratio > 0.6 (P = 0.022) and lower albumin levels (P = 0.018). Four (14.8%) lesions showed postnatal growth before involuting. Complete response was observed in 13 (13/29) patients, and partial response was observed in 16 (16/29) patients. CONCLUSIONS: Fetal giant hepatic hemangioma is mainly localized, and its clinical outcome conforms to RICH (rapidly involuting) and PICH (partially involuting), but some fetal giant hepatic hemangiomas will continue to grow after birth and then gradually decrease. For uncomplicated giant fetal hepatic hemangioma, postnatal follow-up is the main concern, while those with complications require aggressive medical treatment. Propranolol may have no effect on the volume change of GFHH.

The effect of NK cell therapy on sepsis secondary to lung cancer: A case report.

Patients with sepsis face high mortality rates and a bleak prognosis, prompting the need for advanced therapeutic interventions. A male patient diagnosed with moderately low-differentiated squamous cell carcinoma received diverse treatments, including radiotherapy, chemotherapy, immunotherapy, and targeted therapy to inhibit angiogenesis. Subsequently, he developed sepsis after comprehensive treatment, and conventional antibiotic combinations proved ineffective in combating the infection. As an experimental approach, allogeneic natural killer (NK) cell infusion was administered. Following the NK cell infusion, the patient regained consciousness, and laboratory analyses showed reduced infection-related markers, suppressed serum inflammatory cytokines, and elevated anti-tumor cytokines. However, the therapeutic effect only lasted 2-3 days. In vitro investigations demonstrated that the allogeneic NK cell product reduced interleukin-6 levels in the patient's serum. Moreover, subsequent co-cultivation of the NK cell product with the patient's serum resulted in a decrease in the proportion of cytotoxic subpopulations of NK cells and a downregulation of the expression of NK-mediated killing molecules. In conclusion, adoptive transfusion of allogeneic NK cells may improve sepsis symptoms in patients with tumor-related sepsis. In vitro co-culture tests hold promise in providing predictive biomarkers for treatment effectiveness.

[Prognosis of patients planned and unplanned admission to the intensive care unit after surgery: a comparative study].

OBJECTIVE: To compare and analyze the effect of unplanned versus planned admission to the intensive care unit (ICU) on the prognosis of high-risk patients after surgery, so as to provide a clinical evidence for clinical medical staff to evaluate whether the postoperative patients should be transferred to ICU or not after surgery. METHODS: The clinical data of patients who were transferred to ICU after surgery admitted to the Affiliated Hospital of Guizhou Medical University from January to December in 2021 were retrospectively analyzed, including gender, age, body mass index, past history (whether combined with hypertension, diabetes, pulmonary disease, cardiac disease, renal failure, liver failure, hematologic disorders, tumor, etc.), acute physiology and chronic health evaluation II (APACHE II), elective surgery, pre-operative hospital consultation, length of surgery, worst value of laboratory parameters within 24 hours of ICU admission, need for invasive mechanical ventilation (IMV), duration of IMV, length of ICU stay, total length of hospital stay, ICU mortality, in-hospital mortality, and survival status at 30th day postoperative. The unplanned patients were further divided into the immediate transfer group and delayed transfer group according to the timing of their ICU entrance after surgery, and the prognosis was compared between the two groups. Cox regression analysis was used to find the independent risk factors of 30-day mortality in patients transferred to ICU after surgery. RESULTS: Finally, 377 patients were included in the post-operative admission to the ICU, including 232 in the planned transfer group and 145 in the unplanned transfer group (42 immediate transfers and 103 delayed transfers). Compared to the planned transfer group, patients in the unplanned transfer group had higher peripheral blood white blood cell count (WBC) at the time of transfer to the ICU [×109/L: 10.86 (7.09, 16.68) vs. 10.11 (6.56, 13.27)], longer total length of hospital stay [days: 23.00 (14.00, 34.00) vs. 19.00 (12.00, 29.00)], and 30-day post-operative mortality was higher [29.66% (43/145) vs. 17.24% (40/232)], but haemoglobin (Hb), arterial partial pressure of carbon dioxide (PaCO2), oxygenation index (PaO2/FiO2), and IMV requirement rate were lower [Hb (g/L): 95.00 (78.00, 113.50) vs. 98.00 (85.00, 123.00), PaCO2 (mmHg, 1 mmHg ≈ 0.133 kPa): 36.00 (29.00, 41.50) vs. 39.00 (33.00, 43.00), PaO2/FiO2 (mmHg): 197.00 (137.50, 283.50) vs. 238.00 (178.00, 350.25), IMV requirement rate: 82.76% (120/145) vs. 93.97% (218/232)], all differences were statistically significant (all P < 0.05). Kaplan-Meier survival curve showed that the 30-day cumulative survival rate after surgery was significantly lower in the unplanned transfer group than in the planned transfer group (Log-Rank test: χ2 = 7.659, P = 0.006). Univariate Cox regression analysis showed that unplanned transfer, APACHE II score, whether deeded IMV at transfer, total length of hospital stay, WBC, blood K+, and blood lactic acid (Lac) were associated with 30-day mortality after operation (all P < 0.05). Multifactorial Cox analysis showed that unplanned transfer [hazard ratio (HR) = 2.45, 95% confidence interval (95%CI) was 1.54-3.89, P < 0.001], APACHE II score (HR = 1.03, 95%CI was 1.00-1.07, P = 0.031), the total length of hospital stay (HR = 0.86, 95%CI was 0.83-0.89, P < 0.001), the need for IMV on admission (HR = 4.31, 95%CI was 1.27-14.63, P = 0.019), highest Lac value within 24 hours of transfer to the ICU (HR = 1.17, 95%CI was 1.10-1.24, P < 0.001), and tumor history (HR = 3.12, 95%CI was 1.36-7.13, P = 0.007) were independent risk factors for patient death at 30 days post-operative, and the risk of death was 2.45 times higher in patients unplanned transferred than in those planned transferred. Subgroup analysis showed that patients in the delayed transfer group had significantly longer IMV times than those in the immediate transfer group [hours: 43.00 (11.00, 121.00) vs. 17.50 (2.75, 73.00), P < 0.05]. CONCLUSIONS: The 30-day mortality, WBC and total length of hospital stay were higher in patients who were transferred to ICU after surgery, and PaO2/FiO2 was lower. Unplanned transfer, oncology history, use of IMV, APACHE II score, total length of hospital stay, and Lac were independent risk factors for patient death at 30 days postoperatively, and patients with delayed transfer to ICU had longer IMV time.

Association of cataract extraction and the risk of dementia-A systematic review and meta-analysis.

Objectives: This research aims to investigate if cataract extraction lowers the risk of all-cause dementia. Methods: Original literature on cataract surgery associated with all-cause dementia as of November 27, 2022, was searched in several commonly used databases. Manual review was used to include eligible studies. Stata software (version 16) was used to perform statistical analysis on pertinent data. Publication bias can be precisely evaluated using funnel plots and Egger's test. Results: In the meta-analysis of 4 cohort studies with 245,299 participants. Pooled analysis indicated that cataract surgery was linked to a lower incidence of all-cause dementia (OR = 0.77, 95%CI: 0.66-0.89; I2= 54.7%; P < 0.001). Cataract surgery was linked to a lower risk of AD (OR = 0.60, 95%CI: 0.35-1.02; I2= 60.2%; P < 0.001). Conclusions: Cataract surgery is linked to a lower incidence of all-cause dementia and Alzheimer's disease. A cataract is a reversible visual impairment. Cataract surgery may be a protective factor against the onset of all-cause dementia and can reduce the economic and family burden caused by all-cause dementia worldwide. Given the restricted pool of included studies, our findings necessitate meticulous interpretation. Systematic review registration: http://www.crd.york.ac.uk/prospero retrieve registration details by searching CRD4202379371.

Regorafenib enhances anti-tumor efficacy of immune checkpoint inhibitor by regulating IFN-γ/NSDHL/SREBP1/TGF-ß1 axis in hepatocellular carcinoma.

Immune checkpoint inhibitor (ICI) shows low response rate in hepatocellular carcinoma (HCC) but the mechanisms underlying ICI resistance remains unclear. Interferon-γ (IFN-γ) has been widely determined as a prototypical antitumor cytokine. However, growing studies suggest that IFN-γ also mediates immunosuppression to promote tumor progression. Herein, we explored whether ICI-induced IFN-γ could activate immunosuppressive TGF-ß1 to mediate ICI resistance. We demonstrated that cholesterol biosynthetic enzyme, NSDHL, was decreased in HCC tissues and associated with poor clinical prognosis. ICI-induced IFN-γ decreased NSDHL to activate SREBP1, which promoted TGF-ß1 production, reduced T cell toxicity and enhanced Tregs infiltration, leading to ICI resistance. We also found that novel tyrosine kinase inhibitor, regorafenib, significantly reverse the above immunosuppressive effects by regulating NSDHL/SREBP1/TGF-ß1 axis, which strengthened the effects of regorafenib plus ICI therapy against HCC. Noteworthily, regorafenib plus ICI therapy was more effective in HCC patients with higher serum TGF-ß1. In conclusion, IFN-γ induced TGF-ß1 to mediate ICI resistance. Regorafenib promotes anti-tumor immune response of ICI by regulating IFN-γ/NSDHL/SREBP1/TGF-ß1 axis. Serum TGF-ß1 may serve as a biomarker for predicting efficacy of regorafenib plus ICI therapy in HCC.

Inhibition of CEMIP potentiates the effect of sorafenib on metastatic hepatocellular carcinoma by reducing the stiffness of lung metastases.

Hepatocellular carcinoma (HCC) with lung metastasis is associated with poor prognosis and poor therapeutic outcomes. Studies have demonstrated that stiffened stroma can promote metastasis in various tumors. However, how the lung mechanical microenvironment favors circulating tumor cells remains unclear in metastatic HCC. Here, we found that the expression of cell migration-inducing hyaluronan-binding protein (CEMIP) was closely associated with lung metastasis and can promote pre-metastatic niche formation by increasing lung matrix stiffness. Furthermore, upregulated serum CEMIP was indicative of lung fibrotic changes severity in patients with HCC lung metastasis. By directly targeting CEMIP, pirfenidone can inhibit CEMIP/TGF-ß1/Smad signaling pathway and reduce lung metastases stiffening, demonstrating promising antitumor activity. Pirfenidone in combination with sorafenib can more effectively suppress the incidence of lung metastasis compared with sorafenib alone. This study is the first attempt to modulate the mechanical microenvironment for HCC therapy and highlights CEMIP as a potential target for the prevention and treatment of HCC lung metastasis. CEMIP mediating an HCC-permissive microenvironment through controlling matrix stiffness. Meanwhile, Pirfenidone could reduce metastasis stiffness and increases the anti-angiogenic effect of Sorafenib by directly targeting CEMIP.

Mechanisms and therapeutic strategies to combat the recurrence and progression of hepatocellular carcinoma after thermal ablation.

Thermal ablation (TA), including radiofrequency ablation (RFA) and microwave ablation (MWA), has become the main treatment for early-stage hepatocellular carcinoma (HCC) due to advantages such as safety and minimal invasiveness. However, HCC is prone to local recurrence, with more aggressive malignancies after TA closely related to TA-induced changes in epithelial-mesenchymal transition (EMT) and remodeling of the tumor microenvironment (TME). According to many studies, various components of the TME undergo complex changes after TA, such as the recruitment of innate and adaptive immune cells, the release of tumor-associated antigens (TAAs) and various cytokines, the formation of a hypoxic microenvironment, and tumor angiogenesis. Changes in the TME after TA can partly enhance the anti-tumor immune response; however, this response is weak to kill the tumor completely. Certain components of the TME can induce an immunosuppressive microenvironment through complex interactions, leading to tumor recurrence and progression. How the TME is remodeled after TA and the mechanism by which the TME promotes HCC recurrence and progression are unclear. Thus, in this review, we focused on these issues to highlight potentially effective strategies for reducing and preventing the recurrence and progression of HCC after TA.

The characteristics of registered acupuncture clinical trials enrolling cancer patients.

PURPOSE: This study sought to explore and summarize the global state of acupuncture clinical trials enrolling cancer patients included in international registries to date. METHODS: All relevant trials evaluating acupuncture-related interventions for the treatment of cancer that were registered in 16 trial registries from January 1, 2001, through December 31, 2020, were identified. Subsequent publications related to these trials were additionally retrieved from the PubMed, Cochrane Library, Embase, CNKI (China National Knowledge Infrastructure), VIP (China Science and Technology Journal Database), and Wanfang databases. We compared information included in these registries regarding completed trials with any associated publications, with a focus on study design, sample size, and selective reporting, based on the registered protocol. RESULTS: In total, 222 eligible trials across 19 countries were identified. These trials included 17 specific cancer types and 32 symptoms. The five most common cancer types were breast cancer, head and neck cancer, colorectal cancer, lung cancer, and gastric cancer, accounting for almost half of all registered trials (48.2%). The top five symptoms included in these trials were chemotherapy-induced peripheral neuropathy (CIPN), cancer-related pain, cancer-related fatigue, chemotherapy-induced nausea and vomiting (CINV), and gastrointestinal dysfunction. The overall rate of article publication was low, with publications being associated with just 33.3% of these registered trials. CONCLUSIONS: This review is the first snapshot of the landscape of acupuncture clinical trials registered in international trial registries, providing a methodological basis for the management of common treatment- and disease-related side effects among cancer patients undergoing acupuncture and offering useful information that will guide future acupuncture-focused research.

Lenvatinib Combined With a PD-1 Inhibitor as Effective Therapy for Advanced Intrahepatic Cholangiocarcinoma.

Background: Lenvatinib combined with a PD-1 inhibitor has obtained a satisfactory antitumor effect in several solid tumors. However, the efficacy and tumor response of lenvatinib with a PD-1 inhibitor in advanced intrahepatic cholangiocarcinoma still need further exploration. Methods: This is a single-arm study for the assessment of the efficacy and tolerability of lenvatinib with a PD-1 inhibitor in intrahepatic cholangiocarcinoma patients who had chemotherapy failure. Efficacy was evaluated based on the Response Evaluation Criteria in Solid Tumors RECIST Version 1.1 (RECIST 1.1). Results: A total of 40 patients with advanced intrahepatic cholangiocarcinoma were enrolled after the chemorefractory effect. The median progression-free survival was 5.83 ± 0.76 months. The 3-month and 6-month progression-free survival rates were 80.0% and 32.5%, respectively. The median overall survival was 14.30 ± 1.30 months. The 12-month and 18-month overall survival rates were 61.4% and 34.7%. The 3-month RECIST 1.1 evaluation was that seven patients (17.5%) showed partial response, 23 patients (57.5%) had stable disease, and 10 patients (25.0%) had progressive disease. The objective response rate was 17.5%, and the disease control rate was 75.0%. All the recorded any-grade adverse events inducing treatment termination were controllable, and there were no AE-related deaths. Conclusion: Our study showed that a combination of lenvatinib with the PD-1 inhibitor could be an effective treatment for advanced intrahepatic cholangiocarcinoma after the chemorefractory effect.

MYBL2 accelerates epithelial-mesenchymal transition and hepatoblastoma metastasis via the Smad/SNAI1 pathway.

Hepatoblastoma (HB) accounts for the majority of hepatic malignancies in children. Although the prognosis of patients with HB has improved in past decades, metastasis is an indicator of poor overall survival. Herein, we applied single-cell RNA sequencing to explore the transcriptomic profiling of 25,264 metastatic cells isolated from the lungs of two patients with HB. The transcriptomes uncovered the heterogeneity of malignant cells after metastatic lung colonization, and these cells had varied expression signatures associated with the cell cycle, epithelial-mesenchymal plasticity, and hepatic differentiation. Single-cell regulatory network inference and clustering (SCENIC) was utilized to identify the co-expressed transcriptional factors which regulated and represented the different cell states. We further screened the key factor by bioinformatics analysis and found that MYBL2 upregulation was significantly associated with metastasis and poor prognosis. The relationship between ectopic MYBL2 and metastasis was subsequently proved by immunohistochemistry (IHC) of HB tissues, and the functions of MYBL2 in promoting proliferation, migration, and epithelial-to-mesenchymal transition (EMT) were verified by in vitro and in vivo assays. Importantly, the levels of Smad2/3 phosphorylation and SNAI1 expression were increased in MYBL2-transfected cells. Consequently, these results indicated that the MYBL2-controlled Smad/SNAI1 pathway induced EMT and promoted HB tumorigenesis and metastasis.

Impact of Changes in Early Respiratory Support Management on Respiratory Outcomes of Preterm Infants.

BACKGROUND: In the period immediately after birth, preterm infants are highly susceptible to lung injury. Ventilator-induced lung injury has been recognized as a major contributing factor for bronchopulmonary dysplasia (BPD) in preterm infants. Noninvasive respiratory support (NIRS) could decrease lung injury, and early respiratory support management might affect pulmonary outcomes. We conducted a study to evaluate the changes in early respiratory support management and their impact on respiratory outcome and complications of preterm infants in 3 different time periods over the last 13 years. METHODS: This study was a retrospective, single-center cohort study. We retrospectively reviewed the medical records of preterm infants < 32 weeks of gestational age born in our hospital from 2007-2020. The study period was divided into three 3-y discrete periods: 2007-2009 (period A), 2013-2015 (period B), and 2018-2020 (period C). Changes in early respiratory support management were assessed in the 3 periods. The outcomes measured included mortality, BPD, other major neonatal complications, initial respiratory support, and duration of mechanical ventilation. RESULTS: In all, 1,880 clinical records were assessed in our study, with 358 in period A, 825 in period B, and 697 in period C. The use of antenatal corticosteroids increased over time (56.1% in period A, 56.7% in period B, and 74.0% in period C (P < .001). The need for surfactant decreased from 65.6% in period A to 40.7% in period B and 45.9% in period C. Increased utilization of NIRS was associated with decreased invasive mechanical ventilation within 24 h after birth. NIRS only during the hospital stay increased from 22.9% in period A to 36.8% and 45.1% in the latter 2 periods (P < .001). Oxygen therapy duration decreased from 24.3 d in period A to 14.4 d in period B and 17.2 d in period C (P < .001). The overall incidence of BPD was 32.4% in the first period, 23.9% in the second period, and 25.4% in the third period (P < .001). The moderate-to-severe forms of BPD decreased from 12.8% in period A to 7.9% in period B and 7.6% in period C (P = .009). Other neonatal complications, such as pneumothorax, pulmonary hemorrhage, persistent pulmonary hypertension of the newborn, surgical necrotizing enterocolitis, intraventricular hemorrhage grade III/IV, and periventricular leukomalacia, were unchanged among the 3 periods. CONCLUSIONS: From 2007-2020, respiratory management was characterized by a marked reduction in invasive mechanical ventilation and an increase in the use of NIRS. Changes in early respiratory support management resulted in improved respiratory outcomes with a decrease in the overall incidence of BPD. It is likely that our aim to reduce lung injury by improving our respiratory management has contributed to a favorable outcome.

Tumor Suppressive Role of MUC6 in Wilms Tumor via Autophagy-Dependent ß-Catenin Degradation.

Wilms tumor is the most common renal malignancy in children. Known gene mutations account for about 40% of all wilms tumor cases, but the full map of genetic mutations in wilms tumor is far from clear. Whole genome sequencing and RNA sequencing were performed in 5 pairs of wilms tumor tissues and adjacent normal tissues to figure out important genetic mutations. Gene knock-down, CRISPR-induced mutations were used to investigate their potential effects in cell lines and in-vivo xenografted model. Mutations in seven novel genes (MUC6, GOLGA6L2, GPRIN2, MDN1, MUC4, OR4L1 and PDE4DIP) occurred in more than one patient. The most prevalent mutation was found in MUC6, which had 7 somatic exonic variants in 4 patients. In addition, TaqMan assay and immunoblot confirmed that MUC6 expression was reduced in WT tissues when compared with control tissues. Moreover, the results of MUC6 knock-down assay and CRISPR-induced MUC6 mutations showed that MUC6 inhibited tumor aggression via autophagy-dependent ß-catenin degradation while its mutations attenuated tumor-suppressive effects of MUC6. Seven novel mutated genes (MUC6, GOLGA6L2, GPRIN2, MDN1, MUC4, OR4L1 and PDE4DIP) were found in WT, among which MUC6 was the most prevalent one. MUC6 acted as a tumor suppressive gene through autophagy dependent ß-catenin pathway.

Dual inhibition of reactive oxygen species and spleen tyrosine kinase as a therapeutic strategy in liver fibrosis.

Hepatic stellate cells (HSCs) play key roles in liver fibrosis (LF) and hepatocellular carcinoma (HCC). We previously reported that spleen tyrosine kinase (SYK) is critical for HSCs activation, however, the mechanisms are insufficiently understood. In the present study, we found that SYK facilitated autophagy to promote HSCs activation by enhancing reactive oxygen species (ROS) generation. However, SYK inhibitor GS-9973 could efficiently reduce HSCs ROS generation in vitro but not in vivo. Mechanistically, hepatocytes (HCs) would release ROS outside and then diffuse into HSCs to promote autophagy and activation in vitro in the context of inflammation. We then further examined the ROS contents in liver sections and primary liver cells of carbon tetrachloride (CCl4) induced mice treated with or without different doses of Silybin, a natural compound characterized by a well-established antioxidant and hepatoprotective properties, and found that ROS intensities in both liver sections and their deprived primary cells were efficiently inhibited in a dose-dependent fashion. Lastly, we evaluated the rational combination of Silybin and GS-9973 in the treatment of CCl4 induced mice and found that this combination is well tolerated and acts synergistically against HSCs activity, LF and HCC. The combinational use of Silybin and GS-9973 could be a promising therapeutic strategy in patients suffering from LF and even HCC.

Sublethal heat stress-induced O-GlcNAcylation coordinates the Warburg effect to promote hepatocellular carcinoma recurrence and metastasis after thermal ablation.

The malignant transformation of residual hepatocellular carcinoma (HCC) cells after thermal ablation is considered as the main factor promoting postoperative HCC progression, which greatly limits the improvement of long-term survival, and at present there is no effective targeted therapeutic strategies. The Warburg effect is a metabolic feature correlated highly with malignant transformation (e.g. epithelial-to-mesenchymal transition [EMT]). Here, we showed that sublethal heat stress triggered a stronger Warburg effect of HCC cells, which contributed to the thermotolerance and invasion of HCC cells. Sublethal heat stress-induced O-GlcNAcylation was involved in this process. Such enhanced Warburg effect in HCC cells may be eliminated through O-GlcNAcylation inhibition, resulting in impaired thermotolerance and EMT, and thereby preventing tumor recurrence and metastasis of HCC-bearing mice after insufficient thermal ablation. Finally, we present evidence that sublethal heat stress-induced O-GlcNAcylation regulates the Warburg effect in HCC cells by promoting hypoxia-inducible factor 1α (HIF-1α) stability. In conclusion, the present study suggests that O-GlcNAcylation coordinates the Warburg effect to promote HCC progression after thermal ablation, which may serve as a novel potential target for controlling postoperative HCC recurrence and metastasis.

USP7 promotes hepatoblastoma progression through activation of PI3K/AKT signaling pathway.

BACKGROUND: Hepatoblastoma (HB) is an embryonic solid tumor and the most common primary malignant liver tumor in children. HB usually occurs in infants and children. Although treatment diversity is increasing, some patients still have very poor prognosis. Many studies have investigated USP7 inhibitors for tumors. Using database information, we found that USP7 is highly expressed in HB. METHODS: Lentivirus-mediated USP7 knockdown and overexpression was performed in HB cell lines HepG2 and Huh6. CCK8 and transwell assays were used to determine cell viability and metastasis. Flow cytometry was used to study cell cycle and apoptosis. Levels of proteins were detected using western blots. RESULTS: Downregulation of USP7 resulted in significant decrease in cell proliferation, clonal formation, and cell migration and invasion. With overexpression of USP7, cellular malignant behavior increased. Cell cycle assays showed that USP7 knockdown inhibited G1 to S phase transition in the cell cycle. Upregulation of USP7 promoted the transition. Animal experiments showed USP7 facilitated tumor growth in vivo. Western blots indicated that USP7 may affect HB tumorigenesis through the PI3K/AKT signaling pathway. Furthermore, USP7 inhibitor P5091 inhibited HB development and PI3K/AKT pathway. CONCLUSION: USP7 upregulation contributed to HB genesis and development through the PI3K/AKT signaling pathway. USP7 could be a potential target for future HB treatment.

ARID1B/SUB1-activated lncRNA HOXA-AS2 drives the malignant behaviour of hepatoblastoma through regulation of HOXA3.

It has been becoming increasingly evident that long non-coding RNAs (lncRNAs) play important roles in various human cancers. However, the biological processes and clinical significance of most lncRNAs in hepatoblastoma (HB) remain unclear. In our previous study, genome-wide analysis with a lncRNA microarray found that lncRNA HOXA-AS2 was up-regulated in HB. Stable transfected cell lines with HOXA-AS2 knockdown or overexpression were constructed in HepG2 and Huh6 cells, respectively. Our data revealed knockdown of HOXA-AS2 increased cell apoptosis and inhibited cell proliferation, migration and invasion in HB. Up-regulation of HOXA-AS2 promoted HB malignant biological behaviours. Mechanistic investigations indicated that HOXA-AS2 was modulated by chromatin remodelling factor ARID1B and transcription co-activator SUB1, thereby protecting HOXA3 from degradation. Therefore, HOXA-AS2 positively regulates HOXA3, which might partly demonstrate the involvement of HOXA3 in HOXA-AS2-mediated HB carcinogenesis. In conclusion, HOXA-AS2 is significantly overexpressed in HB and the ARID1B/HOXA-AS2/HOXA3 axis plays a critical role in HB tumorigenesis and development. These results might provide a potential new target for HB diagnosis and therapy.