Deficiency of histone deacetylases 3 in macrophage alleviates monosodium urate crystals-induced gouty inflammation in mice.

BACKGROUND: Gout is caused by monosodium urate (MSU) crystals deposition to trigger immune response. A recent study suggested that inhibition of Class I Histone deacetylases (HDACs) can significantly reduce MSU crystals-induced inflammation. However, which one of HDACs members in response to MSU crystals was still unknown. Here, we investigated the roles of HDAC3 in MSU crystals-induced gouty inflammation. METHODS: Macrophage specific HDAC3 knockout (KO) mice were used to investigate inflammatory profiles of gout in mouse models in vivo, including ankle arthritis, foot pad arthritis and subcutaneous air pouch model. In the in vitro experiments, bone marrow-derived macrophages (BMDMs) from mice were treated with MSU crystals to assess cytokines, potential target gene and protein. RESULTS: Deficiency of HDAC3 in macrophage not only reduced MSU-induced foot pad and ankle joint swelling but also decreased neutrophils trafficking and IL-1ß release in air pouch models. In addition, the levels of inflammatory genes related to TLR2/4/NF-κB/IL-6/STAT3 signaling pathway were significantly decreased in BMDMs from HDAC3 KO mice after MSU treatment. Moreover, RGFP966, selective inhibitor of HDAC3, inhibited IL-6 and TNF-α production in BMDMs treated with MSU crystals. Besides, HDAC3 deficiency shifted gene expression from pro-inflammatory macrophage (M1) to anti-inflammatory macrophage (M2) in BMDMs after MSU challenge. CONCLUSIONS: Deficiency of HDAC3 in macrophage alleviates MSU crystals-induced gouty inflammation through inhibition of TLR2/4 driven IL-6/STAT3 signaling pathway, suggesting that HDAC3 could contribute to a potential therapeutic target of gout.

Advanced Progress of Histone Deacetylases in Rheumatic Diseases.

Rheumatic disease is a disease which is not yet fully clarified to etiology and also involved in a local pathological injury or systemic disease. With the continuous improvement of clinical medical research in recent years, the development process of rheumatic diseases has been gradually elucidated; with the intensely study of epigenetics, it is realized that environmental changes can affect genetics, among which histone acetylation is one of the essential mechanisms in epigenetics. Histone deacetylases (HDACs) play an important role in regulating gene expression in various biological processes, including differentiation, development, stress response, and injury. HDACs are involved in a variety of physiological processes and are promising drug targets in various pathological conditions, such as cancer, cardiac and neurodegenerative diseases, inflammation, metabolic and immune disorders, and viral and parasitic infections. In this paper, we reviewed the roles of HDACs in rheumatic diseases in terms of their classification and function.

Natural products targeting the MAPK-signaling pathway in cancer: overview.

PURPOSE: This article summarizes natural products that target the MAPK-signaling pathway in cancer therapy. The classification, chemical structures, and anti-cancer mechanisms of these natural products are elucidated, and comprehensive information is provided on their potential use in cancer therapy. METHODS: Using the PubMed database, we searched for keywords, including "tumor", "cancer", "natural product", "phytochemistry", "plant chemical components", and "MAPK-signaling pathway". We also screened for compounds with well-defined structures that targeting the MAPK-signaling pathway and have anti-cancer effects. We used Kingdraw software and Adobe Photoshop software to draw the chemical compound structural diagrams. RESULTS: A total of 131 papers were searched, from which 85 compounds with well-defined structures were selected. These compounds have clear mechanisms for targeting cancer treatment and are mainly related to the MAPK-signaling pathway. Examples include eupatilin, carvacrol, oridonin, sophoridine, diosgenin, and juglone. These chemical components are classified as flavonoids, phenols, terpenoids, alkaloids, steroidal saponins, and quinones. CONCLUSIONS: Certain MAPK pathway inhibitors have been used for clinical treatment. However, the clinical feedback has not been promising because of genomic instability, drug resistance, and side effects. Natural products have few side effects, good medicinal efficacy, a wide range of sources, individual heterogeneity of biological activity, and are capable of treating disease from multiple targets. These characteristics make natural products promising drugs for cancer treatment.

Complete response of recurrent perihilar cholangiocarcinoma following sintilimab combined with lenvatinib plus S-1: a case report and review of literature.

Perihilar cholangiocarcinoma is a refractory malignancy with an unfavorable prognosis and a high probability of recurrence. Systemic chemotherapy is critical for palliative treatment, but effective therapeutic strategies for perihilar cholangiocarcinoma after first-line chemotherapy failure are scarce. Here, we introduced a sustained benefit following sintilimab combined with lenvatinib plus S-1 in a patient with recurrent perihilar cholangiocarcinoma. A 52-year-old female patient was admitted to our hospital due to yellow skin and sclera, and further radiological examination revealed perihilar cholangiocarcinoma. The patient underwent surgery and histopathological results confirmed moderately differentiated adenocarcinoma with metastatic lymph nodes. Postoperative adjuvant chemotherapy with gemcitabine and S-1 was given. One year after surgery, the patient experienced hepatic recurrence. Then, she received radiofrequency ablation combined with gemcitabine and cisplatin. Unfortunately, radiological assessment revealed progressive disease with multiple liver metastases after treatment. Subsequently, she received sintilimab combined with lenvatinib plus S-1 and the lesions were completely regressed following 14 cycles of combination therapy. The patient recovered well without disease recurrence at the last follow-up. Sintilimab combined with lenvatinib plus S-1 may be an alternative therapeutic option for chemotherapy-refractory perihilar cholangiocarcinoma, and further evaluation in a larger number of patients is needed.

Prediction of Tumor Microenvironment Characteristics and Treatment Response in Lung Squamous Cell Carcinoma by Pseudogene OR7E47P-related Immune Genes.

OBJECTIVE: Pseudogenes are initially regarded as nonfunctional genomic sequences, but some pseudogenes regulate tumor initiation and progression by interacting with other genes to modulate their transcriptional activities. Olfactory receptor family 7 subfamily E member 47 pseudogene (OR7E47P) is expressed broadly in lung tissues and has been identified as a positive regulator in the tumor microenvironment (TME) of lung adenocarcinoma (LUAD). This study aimed to elucidate the correlation between OR7E47P and tumor immunity in lung squamous cell carcinoma (LUSC). METHODS: Clinical and molecular information from The Cancer Genome Atlas (TCGA) LUSC cohort was used to identify OR7E47P-related immune genes (ORIGs) by weighted gene correlation network analysis (WGCNA). Based on the ORIGs, 2 OR7E47P clusters were identified using non-negative matrix factorization (NMF) clustering, and the stability of the clustering was tested by an extreme gradient boosting classifier (XGBoost). LASSO-Cox and stepwise regressions were applied to further select prognostic ORIGs and to construct a predictive model (ORPScore) for immunotherapy. The Botling cohorts and 8 immunotherapy cohorts (the Samstein, Braun, Jung, Gide, IMvigor210, Lauss, Van Allen, and Cho cohorts) were included as independent validation cohorts. RESULTS: OR7E47P expression was positively correlated with immune cell infiltration and enrichment of immune-related pathways in LUSC. A total of 57 ORIGs were identified to classify the patients into 2 OR7E47P clusters (Cluster 1 and Cluster 2) with distinct immune, mutation, and stromal programs. Compared to Cluster 1, Cluster 2 had more infiltration by immune and stromal cells, lower mutation rates of driver genes, and higher expression of immune-related proteins. The clustering performed well in the internal and 5 external validation cohorts. Based on the 7 ORIGs (HOPX, STX2, WFS, DUSP22, SLFN13, GGCT, and CCSER2), the ORPScore was constructed to predict the prognosis and the treatment response. In addition, the ORPScore was a better prognostic factor and correlated positively with the immunotherapeutic response in cancer patients. The area under the curve values ranged from 0.584 to 0.805 in the 6 independent immunotherapy cohorts. CONCLUSION: Our study suggests a significant correlation between OR7E47P and TME modulation in LUSC. ORIGs can be applied to molecularly stratify patients, and the ORPScore may serve as a biomarker for clinical decision-making regarding individualized prognostication and immunotherapy.

Genus Litophyton: A Hidden Treasure Trove of Structurally Unique and Diversely Bioactive Secondary Metabolites.

Marine soft corals are prolific sources of various natural products that have served as a wealthy reservoir of diverse chemical scaffolds with potential as new drug leads. The genus Litophyton contains almost 100 species but only a small proportion of them has been chemically investigated, which calls for more attentions from global researchers. In the current work, 175 secondary metabolites have been discussed, drawing from published data spanning almost five decades, up to July 2023. The studied species of the genus Litophyton resided in various tropical and temperate regions and encompassed a broad range of biologically active natural products including terpenes, steroids, nitrogen-containing metabolites, lipids, and other metabolites. A wide spectrum of pharmacological effects of these compounds had been evaluated, such as cytotoxic, antiviral, antibacterial, antifungal, anti-malarial, antifeedant, anti-inflammatory, molluscicidal, PTP1B inhibitory, insect growth inhibitory, and neuroprotective activities. This review aims to offer an up-to-date survey of the literature and provide a comprehensive understanding of the chemical structures, taxonomical distributions, and biological activities of the reported metabolites from the title genus whenever available.

Advancement and Applications of Nanotherapy for Cancer Immune Microenvironment.

Cancer treatment has evolved rapidly due to major advances in tumor immunity research. However, due to the complexity, heterogeneity, and immunosuppressive microenvironment of tumors, the overall efficacy of immunotherapy is only 20%. In recent years, nanoparticles have attracted more attention in the field of cancer immunotherapy because of their remarkable advantages in biocompatibility, precise targeting, and controlled drug delivery. However, the clinical application of nanomedicine also faces many problems concerning biological safety, and the synergistic mechanism of nano-drugs with immunity remains to be elucidated. Our study summarizes the functional characteristics and regulatory mechanisms of nanoparticles in the cancer immune microenvironment and how nanoparticles activate and long-term stimulate innate immunity and adaptive immunity. Finally, the current problems and future development trends regarding the application of nanoparticles are fully discussed and prospected to promote the transformation and application of nanomedicine used in cancer treatment.

Does the timing of surgery affect outcomes in young and middle-aged patients undergoing surgical stabilization of rib fractures? Feedback was based on real data from physicians, patients, and family caregivers.

BACKGROUND: There is a general clinical consensus that early surgical stabilization of rib fractures (SSRF, ≤ 48-72 h after admission) can benefit patients, and this is only regarding the surgeon's opinions. This study assessed the true outcomes of young and middle-aged patients at different surgical timings. METHODS: This retrospective cohort study was conducted among patients aged 30-55 years who were hospitalized with a diagnosis of isolated rib fractures and underwent SSRF between July 2017 and September 2021. The patients were divided into early (≤ 3 days), mid- (4-7 days) and late (8-14 days) groups, according to the interval (days) between surgery and injury date. The impact of different surgical timings on clinical outcomes, patients, and families was assessed by comparing SSRF-related data during hospitalization and follow-up studies of clinicians, patients themselves, and family caregivers 1-2 months after surgery. RESULTS: In this study, 155 complete patient data were finally included, including 52, 64, and 39 patients in the early, mid, and late groups, respectively. Length of operation, preoperative closed chest drainage rate, length of hospital stay, intensive care unit length of stay, duration of invasive mechanical ventilation in the early group were lower than those in the intermediate and late groups. Additionally, hemothorax and excess pleural fluid incidence after SSRF was lower in the early group than in the intermediate and late groups. Postoperative follow-up results showed that patients in the early group had higher SF-12 physical component summary scores and shorter duration of absence from work. Family caregivers had lower Zarit Burden Interview scores than those in the mid- and late groups. CONCLUSION: From the experience of our institution's SSRF, early surgery is safe and offers additional potential benefits for young and middle-aged patients and families with isolated rib fractures.

Adjuvant immune checkpoint inhibitors associated with higher recurrence-free survival in postoperative hepatocellular carcinoma (PREVENT): a prospective, multicentric cohort study.

BACKGROUND: Adjuvant therapy may improve survival of patients with hepatocellular carcinoma (HCC) after curative resection. This study compared safety and efficacy outcomes between patients at high risk of recurrence who received different types of adjuvant therapy or no such therapy after hepatic resection for HCC. METHODS: Recurrence-free survival (RFS), overall survival, and adverse events were compared among patients who received adjuvant immune checkpoint inhibitors (ICIs) alone, ICIs with tyrosine kinase inhibitors (TKIs), or no adjuvant therapy between 13 March 2019 and 19 March 2022. This study was registered on ClinicalTrials.gov (NCT05221398). RESULTS: Of the 517 patients in final analysis, 432 (83.6%) received no adjuvant therapy, 53 (10.2%) received ICIs alone, and 32 (6.2%) received adjuvant ICIs and TKIs. During median follow-up of 34.0 months (IQR 27.8 to 41.6 months), RFS was significantly longer among patients who received either type of adjuvant therapy (25.2 months, 95%CI 16.4-34.0) than among those who received none (16.1 months, 95%CI 12.9-19.4), and this difference remained significant after propensity score matching (HR 0.52, 95%CI 0.35-0.76, P = 0.004). Overall survival was unaffected by either type of adjuvant therapy, while significant difference was observed between patients who received adjuvant therapy or not after propensity score matching (HR 0.31, 95%CI 0.17-0.59, P = 0.005). The rate of grade 3 or 4 adverse events was similar between the two types of adjuvant therapy. CONCLUSIONS: ICIs alone or with TKIs may improve RFS of patients at high risk of HCC recurrence after curative resection.

A review of invasive intracranial pressure monitoring following surgery for hypertensive cerebral hemorrhage.

Hypertensive cerebral hemorrhage, the most common prevalent of spontaneous cerebral hemorrhage, poses a significant threat to patient mortality and morbidity, while therapeutic options remain limited, making the disease a burden not only for patients' families but also a major challenge for national healthcare systems. The elevation of intracranial pressure subsequent to hypertensive cerebral hemorrhage is a critical contributor to mortality. However, it often manifests before the onset of clinical symptoms, which are typically atypical, leading to delayed treatment and irreversible consequences for the patient. Hence, early detection of intracranial pressure variations can aid in timely, efficient, and precise treatment, reducing patient mortality. Invasive intracranial pressure monitoring enables real-time, accurate monitoring of intracranial pressure changes, providing clinicians with therapeutic guidance and overcoming the limitations of empirical treatment. This article aims to review the use of invasive intracranial pressure monitoring in postoperative hypertensive cerebral hemorrhage and hopes to contribute to clinical and scientific research.

Concurrent chemoradiotherapy followed by adjuvant cisplatin-gemcitabine versus cisplatin-fluorouracil chemotherapy for N2-3 nasopharyngeal carcinoma: a multicentre, open-label, randomised, controlled, phase 3 trial.

BACKGROUND: Patients with N2-3 nasopharyngeal carcinoma have a high risk of treatment being unsuccessful despite the current practice of using a concurrent adjuvant cisplatin-fluorouracil regimen. We aimed to compare the efficacy and safety of concurrent adjuvant cisplatin-gemcitabine with cisplatin-fluorouracil in N2-3 nasopharyngeal carcinoma. METHODS: We conducted an open-label, randomised, controlled, phase 3 trial at four cancer centres in China. Eligible patients were aged 18-65 years with untreated, non-keratinising, stage T1-4 N2-3 M0 nasopharyngeal carcinoma, an Eastern Cooperative Oncology Group performance status score of 0-1, and adequate bone marrow, liver, and renal function. Eligible patients were randomly assigned (1:1) to receive concurrent cisplatin (100 mg/m2 intravenously) on days 1, 22, and 43 of intensity-modulated radiotherapy followed by either gemcitabine (1 g/m2 intravenously on days 1 and 8) and cisplatin (80 mg/m2 intravenously for 4 h on day 1) once every 3 weeks or fluorouracil (4 g/m2 in continuous intravenous infusion for 96 h) and cisplatin (80 mg/m2 intravenously for 4 h on day 1) once every 4 weeks, for three cycles. Randomisation was done using a computer-generated random number code with a block size of six, stratified by treatment centre and nodal category. The primary endpoint was 3-year progression-free survival in the intention-to-treat population (ie, all patients randomly assigned to treatment). Safety was assessed in all participants who received at least one dose of chemoradiotherapy. This study was registered at ClinicalTrials.gov, NCT03321539, and patients are currently under follow-up. FINDINGS: From Oct 30, 2017, to July 9, 2020, 240 patients (median age 44 years [IQR 36-52]; 175 [73%] male and 65 [27%] female) were randomly assigned to the cisplatin-fluorouracil group (n=120) or cisplatin-gemcitabine group (n=120). As of data cutoff (Dec 25, 2022), median follow-up was 40 months (IQR 32-48). 3-year progression-free survival was 83·9% (95% CI 75·9-89·4; 19 disease progressions and 11 deaths) in the cisplatin-gemcitabine group and 71·5% (62·5-78·7; 34 disease progressions and seven deaths) in the cisplatin-fluorouracil group (stratified hazard ratio 0·54 [95% CI 0·32-0·93]; log rank p=0·023). The most common grade 3 or worse adverse events that occurred during treatment were leukopenia (61 [52%] of 117 in the cisplatin-gemcitabine group vs 34 [29%] of 116 in the cisplatin-fluorouracil group; p=0·00039), neutropenia (37 [32%] vs 19 [16%]; p=0·010), and mucositis (27 [23%] vs 32 [28%]; p=0·43). The most common grade 3 or worse late adverse event (occurring from 3 months after completion of radiotherapy) was auditory or hearing loss (six [5%] vs ten [9%]). One (1%) patient in the cisplatin-gemcitabine group died due to treatment-related complications (septic shock caused by neutropenic infection). No patients in the cisplatin-fluorouracil group had treatment-related deaths. INTERPRETATION: Our findings suggest that concurrent adjuvant cisplatin-gemcitabine could be used as an adjuvant therapy in the treatment of patients with N2-3 nasopharyngeal carcinoma, although long-term follow-up is required to confirm the optimal therapeutic ratio. FUNDING: National Key Research and Development Program of China, National Natural Science Foundation of China, Guangdong Major Project of Basic and Applied Basic Research, Sci-Tech Project Foundation of Guangzhou City, Sun Yat-sen University Clinical Research 5010 Program, Innovative Research Team of High-level Local Universities in Shanghai, Natural Science Foundation of Guangdong Province for Distinguished Young Scholar, Natural Science Foundation of Guangdong Province, Postdoctoral Innovative Talent Support Program, Pearl River S&T Nova Program of Guangzhou, Planned Science and Technology Project of Guangdong Province, Key Youth Teacher Cultivating Program of Sun Yat-sen University, the Rural Science and Technology Commissioner Program of Guangdong Province, and Fundamental Research Funds for the Central Universities.

[Effects of Wastewater Treatment Processes on the Removal Efficiency of Microplastics Based on Meta-analysis].

Microplastics (MPs) are ubiquitous emerging pollutants that have been found in the marine, freshwater, air, and soil environments. Wastewater treatment plants (WWTPs) play an important role in releasing MPs to the environment. Therefore, understanding the occurrence, fate, and removal mechanism of MPs in WWTPs is of great importance towards microplastic control. In this review, the occurrence characteristics and removal rates of MPs in 78 WWTPs from 57 studies were discussed based on Meta-analysis. Specifically, the key aspects regarding MPs removal in WWTPs, such as wastewater treatment processes and MPs shapes, sizes, and polymer compositions were analyzed and compared. The results showed that:① the abundances of MPs in the influent and effluent were 1.56×10-2-3.14×104 n·L-1 and 1.70×10-3-3.09×102 n·L-1, respectively. The abundance of MPs in the sludge ranged from 1.80×10-1 to 9.38×103 n·g-1. ② The total removal rate (>90%) of MPs by WWTPs using oxidation ditch, biofilm, and conventional activated sludge treatment processes was higher than that using sequencing batch activated sludge, anaerobic-anoxic-aerobic, and anoxic-aerobic processes. ③ The removal rate of MPs in primary, secondary, and tertiary treatment process were 62.87%, 55.78%, and 58.45%, respectively. The combination process of "grid+ sedimentation tank+primary sedimentation tank" had the highest removal rate towards MPs in primary treatment processes, and the membrane bioreactor had the highest one beyond other secondary treatment processes. Filtration was the best process in tertiary treatment. ④ The film, foam, and fragment MPs were easier to remove (>90%) than fiber and spherical (<90%) MPs by WWTPs. The MPs with particle size larger than 0.5 mm were easier to remove than those with particle size smaller than 0.5 mm. The removal efficiencies of polyethylene (PE), polyethylene terephthalate (PET), and polypropylene (PP) MPs were higher than 80%.

Metal-organic framework-mediated construction of confined ultrafine nickel phosphide immobilized in reduced graphene oxide with excellent cycle stability for asymmetric supercapacitors.

Transition metal phosphides (TMPs) with unique metalloid features have been promised great application potential in developing high-efficiency electrode materials for electrochemical energy storage. Nevertheless, sluggish ion transportation and poor cycling stability are the critical hurdles limiting their application prospects. Herein, we presented the metal-organic framework-mediated construction of ultrafine Ni2P immobilized in reduced graphene oxide (rGO). Nano-porous two-dimensional (2D) Ni-metal-organic framework (Ni-MOF) was grown on holey graphene oxide (Ni(BDC)-HGO), followed by MOF-mediated tandem pyrolysis (carbonization and phosphidation; Ni(BDC)-HGO-X-P, X denoted carbonization temperature and P represented phosphidation). Structural analysis revealed that the open-framework structure in Ni(BDC)-HGO-X-Ps had endowed them with excellent ion conductivity. The Ni2P wrapped by carbon shells and the PO bonds linking between Ni2P and rGO ensured the better structural stability of Ni(BDC)-HGO-X-Ps. The resulting Ni(BDC)-HGO-400-P delivered a capacitance of 2333.3 F g-1 at 1 A g-1 in a 6 M KOH aqueous electrolyte. More importantly, Ni(BDC)-HGO-400-P//activated carbon, the assembled asymmetric supercapacitor with an energy density of 64.5 Wh kg-1 and a power density of 31.7 kW kg-1, almost maintained its initial capacitance after 10,000 cycles. Furthermore, in situ electrochemical-Raman measurements were exploited to demonstrate the electrochemical changes of Ni(BDC)-HGO-400-P throughout the charging and discharging processes. This study has further shed light on the design rationality of TMPs for optimizing supercapacitor performance.

Characteristics of local extension based on tumor distribution in nasopharyngeal carcinoma and proposed clinical target volume delineation.

OBJECTIVES: To summarize the characteristics of local extension of eccentric and central nasopharyngeal carcinoma (NPC) by magnetic resonance imaging (MRI) and to improve clinical target volume (CTV) delineation. METHODS: MRI of 870 newly diagnosed NPC patients were reviewed. According to tumor distribution features, the NPCs were divided into eccentric and central lesions. RESULTS: All local invasions presented as continuous invasion from gross lesions and structures adjacent to the nasopharynx were more likely to be invaded. There were 240 (27.6%) and 630 (72.4%) cases with central and eccentric lesions, respectively. The spread of eccentric lesions was centered on the ipsilateral Rosenmüller's fossa; and most anatomic sites had significantly higher invasion rates in the ipsilateral side than the contralateral side (P < 0.05). However, they were at low risk of concurrent bilateral tumor invasion (<10%), except the prevertebral muscle (15.4%) and nasal cavity (13.8%). The extension of central NPCs was centered on the nasopharyngeal superior-posterior wall and was more common in the superior-posterior direction. Furthermore, bilateral tumor invasion into the anatomical sites was common. CONCLUSION: Local invasion of NPC was characterized by continuous invasion from proximal to distal sites. The eccentric and central lesions showed different invasion features. Individual CTV delineation should be based on the distribution characteristics of tumors. The eccentric lesions had a very low probability of invasion into the contralateral tissue; thus routine prophylactic radiation of contralateral parapharyngeal space and skull base foramina may not be necessary.

Hyperfractionation compared with standard fractionation in intensity-modulated radiotherapy for patients with locally advanced recurrent nasopharyngeal carcinoma: a multicentre, randomised, open-label, phase 3 trial.

BACKGROUND: Reirradiation in standard fractionation for locally advanced recurrent nasopharyngeal carcinoma after a previous course of high-dose radiotherapy is often associated with substantial late toxicity, negating its overall benefit. We therefore aimed to investigate the efficacy and safety of hyperfractionation compared with standard fractionation in intensity-modulated radiotherapy. METHODS: This multicentre, randomised, open-label, phase 3 trial was done in three centres in Guangzhou, China. Eligible patients were aged 18-65 years with histopathologically confirmed undifferentiated or differentiated, non-keratinising, advanced locally recurrent nasopharyngeal carcinoma. Participants were randomly assigned (1:1) to either receive hyperfractionation (65 Gy in 54 fractions, given twice daily with an interfractional time interval of at least 6 h) or standard fractionation (60 Gy in 27 fractions, given once a day). Intensity-modulated radiotherapy was used in both groups. A computer program generated the assignment sequence and randomisation was stratified by treatment centre, recurrent tumour stage (T2-T3 vs T4), and recurrent nodal stage (N0 vs N1-N2), determined at the time of randomisation. The two primary endpoints were the incidence of severe late complications defined as the incidence of grade 3 or worse late radiation-induced complications occurring 3 months after the completion of radiotherapy until the latest follow-up in the safety population, and overall survival defined as the time interval from randomisation to death due to any cause in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT02456506. FINDINGS: Between July 10, 2015, and Dec 23, 2019, 178 patients were screened for eligibility, 144 of whom were enrolled and randomly assigned to hyperfractionation or standard fractionation (n=72 in each group). 35 (24%) participants were women and 109 (76%) were men. After a median follow-up of 45·0 months (IQR 37·3-53·3), there was a significantly lower incidence of grade 3 or worse late radiation-induced toxicity in the hyperfractionation group (23 [34%] of 68 patients) versus the standard fractionation group (39 [57%] of 68 patients; between-group difference -23% [95% CI -39 to -7]; p=0·023). Patients in the hyperfractionation group had better 3-year overall survival than those in the standard fractionation group (74·6% [95% CI 64·4 to 84·8] vs 55·0% [43·4 to 66·6]; hazard ratio for death 0·54 [95% CI 0·33 to 0·88]; p=0·014). There were fewer grade 5 late complications in the hyperfractionation group (five [7%] nasal haemorrhage) than in the standard fractionation group (16 [24%], including two [3%] nasopharyngeal necrosis, 11 [16%] nasal haemorrhage, and three [4%] temporal lobe necrosis). INTERPRETATION: Hyperfractionated intensity-modulated radiotherapy could significantly decrease the rate of severe late complications and improve overall survival among patients with locally advanced recurrent nasopharyngeal carcinoma. Our findings suggest that hyperfractionated intensity-modulated radiotherapy could be used as the standard of care for these patients. FUNDING: Key-Area Research and Development of Guangdong Province, the National Natural Science Foundation of China, the Special Support Program for High-level Talents in Sun Yat-sen University Cancer Center, the Guangzhou Science and Technology Plan Project, and the National Ten Thousand Talents Program Science and Technology Innovation Leading Talents, Sun Yat-Sen University Clinical Research 5010 Program.

Real-world experience of postoperative adjuvant chemoimmunotherapy in patients with perihilar cholangiocarcinoma at high risk of recurrence.

BACKGROUND: This study aimed to assess whether postoperative adjuvant chemoimmunotherapy could lead to better clinical outcomes for high-risk patients with perihilar cholangiocarcinoma (pCCA). METHODS: In the cohort study, we retrospectively reviewed patients who received surgical resection for pCCA with curative intent from January 2018 to December 2021 at the Sun Yat-sen Memorial Hospital. The patients at high risk for relapse were further analyzed. Among them, 20 patients received adjuvant chemoimmunotherapy, 28 patients received adjuvant chemotherapy, and 33 patients received surgery alone. The oncological outcomes and drug-associated adverse events were evaluated. RESULTS: The 2-year overall survival (OS) rates in patients treated with adjuvant chemoimmunotherapy, adjuvant chemotherapy, and surgery alone were 80.0%, 49.4% and 22.6%, respectively. Univariable and multivariable Cox analyses showed that the treatment regimen and TNM stage were associated with adverse OS. Adjuvant chemoimmunotherapy led to an increase in OS compared with adjuvant chemotherapy [hazard ratio (HR) = 3.253; 95% confidence interval (CI) 1.072-9.870; P = 0.037] or surgery alone (HR = 7.560; 95% CI 2.508-22.785; P < 0.001). The median recurrence-free survival was 22.0 months for the adjuvant chemoimmunotherapy group, 17.0 months for the adjuvant chemotherapy group, and 13.2 months for the surgery alone group (P = 0.177); these differences were not significant. The chemoimmunotherapy group was associated with more frequent hematological side effects than the chemotherapy group, but the difference was not statistically significant. CONCLUSION: Postoperative adjuvant chemoimmunotherapy for resected pCCA patients showed improved OS compared with adjuvant chemotherapy or surgery alone, and further prospectively randomized controlled trials are necessary to validate these results.

XBP1-elicited environment by chemotherapy potentiates repopulation of tongue cancer cells by enhancing miR-22/lncRNA/KAT6B-dependent NF-κB signalling.

BACKGROUND: Tumour repopulation initiated by residual tumour cells in response to cytotoxic therapy has been described clinically and biologically, but the mechanisms are unclear. Here, we aimed to investigate the mechanisms for the tumour-promoting effect in dying cells and for tumour repopulation in surviving tongue cancer cells. METHODS: Tumour repopulation in vitro and in vivo was represented by luciferase activities. The differentially expressed cytokines in the conditioned medium (CM) were identified using a cytokine array. Gain or loss of function was investigated using inhibitors, neutralising antibodies, shRNAs and ectopic overexpression strategies. RESULTS: We found that dying tumour cells undergoing cytotoxic therapy increase the growth of living tongue cancer cells in vitro and in vivo. Dying tumour cells create amphiregulin (AREG)- and basic fibroblast growth factor (bFGF)-based extracellular environments via cytotoxic treatment-induced endoplasmic reticulum stress. This environment stimulates growth by activating lysine acetyltransferase 6B (KAT6B)-dependent nuclear factor-kappa B (NF-κB) signalling in living tumour cells. As direct targets of NF-κB, miR-22 targets KAT6B to repress its expression, but long noncoding RNAs (lncRNAs) (XLOC_003973 and XLOC_010383) counter the effect of miR-22 to enhance KAT6B expression. Moreover, we detected increased AREG and bFGF protein levels in the blood of tongue cancer patients with X-box binding protein-1 (XBP1) activation in tumours under cytotoxic therapy and found that XBP1 activation is associated with poor prognosis of patients. We also detected activation of miR-22/lncRNA/KAT6B/NF-κB signalling in recurrent cancers compared to paired primary tongue cancers. CONCLUSIONS: We identified the molecular mechanisms of cell death-induced tumour repopulation in tongue cancer. Such insights provide new avenues to identify predictive biomarkers and effective strategies to address cancer progression.

Effect of intubation in the lateral position under general anesthesia induction on the position of double-lumen tube placement in patients undergoing unilateral video-assisted thoracic surgery: study protocol for a prospective, single-center, parallel group, randomized, controlled trial.

BACKGROUND: The double-lumen tube (DLT) is an essential equipment for thoracic anesthesia and the precise position of DLT placement is particularly important for anesthesia and surgery. However, the incidence of DLT malposition remains high and it leads to lung isolation failure and hypoxemia during one-lung ventilation. This trial aims to explore the clinical application and efficacy of intubation in the lateral position under general anesthesia induction to reduce the incidence of DLT malposition in patients undergoing unilateral video-assisted thoracic surgery (VATS). METHODS: In this prospective, single-center, parallel group, randomized, controlled trial, we will recruit 108 patients, aged 18-80 years, scheduled for elective unilateral VATS with DLT intubation under general anesthesia, and they will be randomly assigned to two groups: a lateral DLT intubation group (group L) and a conventional supine DLT intubation group (group C). The left-sided DLT will be used to intubate in patients of both groups. The position of DLT will be confirmed and adjusted by using the fiberoptic bronchoscopy (FOB). The primary outcome is the incidence of DLT malposition observed via the FOB, and the secondary outcomes include the time of intubation, the frequency and duration of re-adjustments of DLT placement under FOB, whether to re-intubate, intraoperative vital signs, and postoperative recovery. DISCUSSION: Accurate DLT positioning is crucially important for thoracic surgery, but the incidence of DLT malposition is still high in the present clinical practice of thoracic anesthesia. This trial aims to investigate whether lateral DLT intubation can reduce the incidence of DLT malposition, with more stable intraoperative vital signs and less postoperative complications. TRIAL REGISTRATION: The study protocol was registered at Chinese Clinical Trial Registry ( http://www.chictr.org.cn ) with registration number: ChiCTR2200060794 on June 11, 2022.

Bioinformatic and Experimental Analyses Reveal That KIF4A Is a Biomarker of Therapeutic Sensitivity and Predicts Prognosis in Cervical Cancer Patients.

OBJECTIVE: This study aims to investigate the expression, prognostic value, and function of kinesin superfamily 4A (KIF4A) in cervical cancer. METHODS: Cervical cancer cell lines (Hela and SiHa) and TCGA data were used for experimental and bioinformatic analyses. Overall survival (OS) and progression free survival (PFS) were compared between patients with high or low KIF4A expression. Copy number variation (CNV) and somatic mutations of patients were visualized and GISTIC 2.0 was used to identify significantly altered sites. The function of KIF4A was also explored based on transcriptome analysis and validated by experimental methods. Chemotherapeutic and immunotherapeutic benefits were inferred using multiple reference databases and algorithms. RESULTS: Patients with high KIF4A expression had better OS and PFS. KIF4A could inhibit proliferation and migration and induce G1 arrest of cervical cancer cells. Higher CNV load was observed in patients with low KIF4A expression, while the group with low KIF4A expression displayed more significantly altered sites. A total of 13 genes were found to mutate more in the low KIF4A expression group, including NOTCH1 and PUM1. The analysis revealed that low KIF4A expression may indicate an immune escape phenotype, and patients in this group may benefit more from immunotherapy. With respect to chemotherapy, cisplatin and gemcitabine may respond better in patients with high KIF4A expression, while 5-fluorouracil etc. may be responded better in patients with low KIF4A expression CONCLUSION: KIF4A is a tumor suppressor gene in cervical cancer, and it can be used as a prognostic and therapeutic biomarker in cervical cancer.