Induction-concurrent chemoradiotherapy with or without sintilimab in patients with locoregionally advanced nasopharyngeal carcinoma in China (CONTINUUM): a multicentre, open-label, parallel-group, randomised, controlled, phase 3 trial.

BACKGROUND: Anti-PD-1 therapy and chemotherapy is a recommended first-line treatment for recurrent or metastatic nasopharyngeal carcinoma, but the role of PD-1 blockade remains unknown in patients with locoregionally advanced nasopharyngeal carcinoma. We assessed the addition of sintilimab, a PD-1 inhibitor, to standard chemoradiotherapy in this patient population. METHODS: This multicentre, open-label, parallel-group, randomised, controlled, phase 3 trial was conducted at nine hospitals in China. Adults aged 18-65 years with newly diagnosed high-risk non-metastatic stage III-IVa locoregionally advanced nasopharyngeal carcinoma (excluding T3-4N0 and T3N1) were eligible. Patients were randomly assigned (1:1) using blocks of four to receive gemcitabine and cisplatin induction chemotherapy followed by concurrent cisplatin radiotherapy (standard therapy group) or standard therapy with 200 mg sintilimab intravenously once every 3 weeks for 12 cycles (comprising three induction, three concurrent, and six adjuvant cycles to radiotherapy; sintilimab group). The primary endpoint was event-free survival from randomisation to disease recurrence (locoregional or distant) or death from any cause in the intention-to-treat population. Secondary endpoints included adverse events. This trial is registered with ClinicalTrials.gov (NCT03700476) and is now completed; follow-up is ongoing. FINDINGS: Between Dec 21, 2018, and March 31, 2020, 425 patients were enrolled and randomly assigned to the sintilimab (n=210) or standard therapy groups (n=215). At median follow-up of 41·9 months (IQR 38·0-44·8; 389 alive at primary data cutoff [Feb 28, 2023] and 366 [94%] had at least 36 months of follow-up), event-free survival was higher in the sintilimab group compared with the standard therapy group (36-month rates 86% [95% CI 81-90] vs 76% [70-81]; stratified hazard ratio 0·59 [0·38-0·92]; p=0·019). Grade 3-4 adverse events occurred in 155 (74%) in the sintilimab group versus 140 (65%) in the standard therapy group, with the most common being stomatitis (68 [33%] vs 64 [30%]), leukopenia (54 [26%] vs 48 [22%]), and neutropenia (50 [24%] vs 46 [21%]). Two (1%) patients died in the sintilimab group (both considered to be immune-related) and one (<1%) in the standard therapy group. Grade 3-4 immune-related adverse events occurred in 20 (10%) patients in the sintilimab group. INTERPRETATION: Addition of sintilimab to chemoradiotherapy improved event-free survival, albeit with higher but manageable adverse events. Longer follow-up is necessary to determine whether this regimen can be considered as the standard of care for patients with high-risk locoregionally advanced nasopharyngeal carcinoma. FUNDING: National Natural Science Foundation of China, Key-Area Research and Development Program of Guangdong Province, Natural Science Foundation of Guangdong Province, Overseas Expertise Introduction Project for Discipline Innovation, Guangzhou Municipal Health Commission, and Cancer Innovative Research Program of Sun Yat-sen University Cancer Center. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Enhanced N2 Adsorption and Activation by Combining Re Clusters and In Vacancies as Dual Sites for Efficient and Selective Electrochemical NH3 Synthesis.

The electrochemical N2 reduction reaction (NRR) is a green and energy-saving sustainable technology for NH3 production. However, high activity and high selectivity can hardly be achieved in the same catalyst, which severely restricts the development of the electrochemical NRR. In2Se3 with partially occupied p-orbitals can suppress the H2 evolution reaction (HER), which shows excellent selectivity in the electrochemical NRR. The presence of VIn can simultaneously provide active sites and confine Re clusters through strong charge transfer. Additionally, well-isolated Re clusters stabilized on In2Se3 by the confinement effect of VIn result in Re-VIn active sites with maximum availability. By combining Re clusters and VIn as dual sites for spontaneous N2 adsorption and activation, the electrochemical NRR performance is enhanced significantly. As a result, the Re-In2Se3-VIn/CC catalyst delivers a high NH3 yield rate (26.63 µg h-1 cm-2) and high FEs (30.8%) at -0.5 V vs RHE.

Recent Progress of Transition Metal Selenides for Electrochemical Oxygen Reduction to Hydrogen Peroxide: From Catalyst Design to Electrolyzers Application.

Hydrogen peroxide (H2O2) is a highly value-added and environmental-friendly chemical with various applications. The production of H2O2 by electrocatalytic 2e- oxygen reduction reaction (ORR) has emerged as a promising alternative to the energy-intensive anthraquinone process. High selectivity Catalysts combining with superior activity are critical for the efficient electrosynthesis of H2O2. Earth-abundant transition metal selenides (TMSs) being discovered as a classic of stable, low-cost, highly active and selective catalysts for electrochemical 2e- ORR. These features come from the relatively large atomic radius of selenium element, the metal-like properties and the abundant reserves. Moreover, compared with the advanced noble metal or single-atom catalysts, the kinetic current density of TMSs for H2O2 generation is higher in acidic solution, which enable them to become suitable catalyst candidates. Herein, the recent progress of TMSs for ORR to H2O2 is systematically reviewed. The effects of TMSs electrocatalysts on the activity, selectivity and stability of ORR to H2O2 are summarized. It is intended to provide an insight from catalyst design and corresponding reaction mechanisms to the device setup, and to discuss the relationship between structure and activity.

LPS-induced senescence of macrophages aggravates calcification and senescence of vascular smooth muscle cells via IFITM3.

BACKGROUND: Cellular senescence, macrophages infiltration, and vascular smooth muscle cells (VSMCs) osteogenic transdifferentiation participate in the pathophysiology of vascular calcification in chronic kidney disease (CKD). Senescent macrophages are involved in the regulation of inflammation in pathological diseases. In addition, senescent cells spread senescence to neighboring cells via Interferon-induced transmembrane protein3 (IFITM3). However, the role of senescent macrophages and IFITM3 in VSMCs calcification remains unexplored. AIMS: To explore the hypothesis that senescent macrophages contribute to the calcification and senescence of VSMCs via IFITM3. METHODS: Here, the macrophage senescence model was established using Lipopolysaccharides (LPS). The VSMCs were subjected to supernatants from macrophages (MCFS) or LPS-induced macrophages (LPS-MCFS) in the presence or absence of calcifying media (CM). Senescence-associated ß-galactosidase (SA-ß-gal), Alizarin red (AR), immunofluorescent staining, and western blot were used to identify cell senescence and calcification. RESULTS: The expression of IFITM3 was significantly increased in LPS-induced macrophages and the supernatants. The VSMCs transdifferentiated into osteogenic phenotype, expressing higher osteogenic differentiation markers (RUNX2) and lower VSMCs constructive makers (SM22α) when cultured with senescent macrophages supernatants. Also, senescence markers (p16 and p21) in VSMCs were significantly increased by senescent macrophages supernatants treated. However, IFITM3 knockdown inhibited this process. CONCLUSIONS: Our study showed that LPS-induced senescence of macrophages accelerated the calcification of VSMCs via IFITM3. These data provide a new perspective linking VC and aging, which may provide clues for diagnosing and treating accelerated vascular aging in patients with CKD.

P-Block Metal-Based Electrocatalysts for Nitrogen Reduction to Ammonia: A Minireview.

Electrochemical nitrogen reduction reaction (NRR) to ammonia (NH3 ) using renewable electricity provides a promising approach towards carbon neutral. What's more, it has been regarded as the most promising alternative to the traditional Haber-Bosch route in current context of developing sustainable technologies. The development of a class of highly efficient electrocatalysts with high selectivity and stability is the key to electrochemical NRR. Among them, P-block metal-based electrocatalysts have significant application potential in NRR for which possessing a strong interaction with the N 2p orbitals. Thus, it offers a good selectivity for NRR to NH3 . The density of state (DOS) near the Fermi level is concentrated for the P-block metal-based catalysts, indicating the ability of P-block metal as active sites for N2 adsorption and activation by donating p electrons. In this work, we systematically review the recent progress of P-block metal-based electrocatalysts for electrochemical NRR. The effect of P-block metal-based electrocatalysts on the NRR activity, selectivity and stability are discussed. Specifically, the catalyst design, the nature of the active sites of electrocatalysts and some strategies for boosting NRR performance, the reaction mechanism, and the impact of operating conditions are unveiled. Finally, some challenges and outlooks using P-block metal-based electrocatalysts are proposed.

Hepatectomy After Conversion Therapy Using Tyrosine Kinase Inhibitors Plus Anti-PD-1 Antibody Therapy for Patients with Unresectable Hepatocellular Carcinoma.

BACKGROUND: Combined treatment with tyrosine kinase inhibitors (TKI) plus anti-PD-1 antibodies showed high anti-tumor efficacy and made conversion resection possible for patients with unresectable hepatocellular carcinoma (HCC). However, long-term survival has not been reported. METHODS: A cohort of consecutive patients who received combined TKI/anti-PD-1 antibodies as first-line treatment for initially unresectable HCC at the authors' hospital between August 2018 and September 2020 was eligible for this study. Patients who were responding to systemic therapy and met the criteria for hepatectomy underwent liver resection with curative intention. The study also investigated the association of clinical factors with successful conversion resection and postoperative recurrence. RESULTS: The study enrolled 101 patients including 24 patients (23.8 %) who underwent R0 resection a median of 3.9 months (interquartile range: 2.5-5.9 months) after initiation of systemic therapy. Patients with an Eastern cooperative oncology group performance status of 0, fewer intrahepatic tumors, or a radiographic response to systemic therapy were more likely to be able to receive curative resection. After a median follow-up period of 21.5 months, hepatectomy was independently associated with a favorable overall survival (hazard ratio [HR], 0.050; 95 % confidence interval [CI], 0.007-0.365; P = 0.003). For the 24 patients who underwent surgery, the 12-month recurrence-free survival and overall survival rates were respectively 75% and 95.8%. Achieving a pathologic complete response (n = 10) to systemic therapy was associated with a favorable recurrence-free survival after resection, with a trend toward significance (HR, 0.345; 95% CI, 0.067-1.785; P = 0.187). CONCLUSIONS: Selected patients with initially unresectable HCC can undergo hepatectomy after systemic therapy with combined TKI/anti-PD-1 antibodies. In this study, conversion resection was associated with a favorable prognosis.

Radiographic and α-fetoprotein response predict pathologic complete response to immunotherapy plus a TKI in hepatocellular carcinoma: a multicenter study.

BACKGROUND: Pathologic complete response (pCR) following preoperative systemic therapy is associated with improved outcomes after subsequent liver transplant/resection in hepatocellular carcinoma (HCC). However, the relationship between radiographic and histopathological response remains unclear. METHODS: We retrospectively examined patients with initially unresectable HCC who received tyrosine kinase inhibitor (TKI) plus anti-programmed death 1 (PD-1) therapy before undergoing liver resection between March 2019 and September 2021 across 7 hospitals in China. Radiographic response was evaluated using mRECIST. A pCR was defined as no viable tumor cells in resected samples. RESULTS: We included 35 eligible patients, of whom 15 (42.9%) achieved pCR after systemic therapy. After a median follow-up of 13.2 months, tumors recurred in 8 non-pCR and 1 pCR patient. Before resection, there were 6 complete responses, 24 partial responses, 4 stable disease cases, and 1 progressive disease case, per mRECIST. Predicting pCR by radiographic response yielded an area under the receiver operating characteristic curve (AUC) of 0.727 (95% CI: 0.558-0.902), with an optimal cutoff value of 80% reduction in the enhanced area in MRI (called major radiographic response), which had a 66.7% sensitivity, 85.0% specificity, and a 77.1% diagnostic accuracy. When radiographic response was combined with α-fetoprotein response, the AUC was 0.926 (95% CI: 0.785-0.999); the optimal cutoff value was 0.446, which had a 91.7% sensitivity, 84.6%, specificity, and an 88.0% diagnostic accuracy. CONCLUSIONS: In patients with unresectable HCC receiving combined TKI/anti-PD 1 therapy, major radiographic response alone or combined with α-fetoprotein response may predict pCR.

Long-term outcomes of chemoradiotherapy versus radiotherapy alone in patients with intermediate-risk nasopharyngeal carcinoma: a population-based analysis.

PURPOSE: To investigate the efficacy of chemotherapy among intermediate-risk (stage II/T3N0) nasopharyngeal carcinoma (NPC) patients receiving radiotherapy (RT). METHODS: We identified stage II/T3N0 NPC patients who received radiotherapy with or without chemotherapy from the Surveillance, Epidemiology and End Results database (2004-2019). Overall survival (OS) and cancer-specific survival (CSS) were assessed using the Kaplan-Meier method with log-rank test and Cox proportional hazards models to evaluate the efficacy of chemotherapy. Subgroup analysis was also conducted based on the baseline characteristics. Propensity score matching (PSM) was performed to balance the intergroup covariates. RESULTS: A total of 1623 patients were enrolled in the study, 1444 received chemoradiotherapy (CRT) and 179 received RT alone. CRT, compared to RT alone, was independently associated with a better OS (HR 0.57, 95% CI 0.45-0.71) and CSS (HR 0.55, 95% CI 0.39-0.79). After PSM, similar results were obtained, and CRT was superior to RT alone in terms of OS (HR 0.60, 95% CI 0.39-0.92) and CSS (HR 0.60, 95% CI 0.40-0.91). Subgroup analysis revealed that OS benefits from CRT were mainly observed in T0-2N1(HR 0.51, 95% CI 0.38-0.70) and T3N0 (HR 0.64, 95% CI 0.42-0.98) rather than T2N0 (HR 1.00, 95% CI 0.51-1.94). Interestingly, after PSM, OS benefits were still seen in T0-2N1 (HR 0.44, 95% CI 0.24-0.82), while not seen in T2N0 (HR 1.83, 95% CI 0.56-5.97) and T3N0 (HR 0.56, 95% CI 0.28-1.12). CONCLUSION: For T0-2N1 NPC patients, CRT was superior to RT alone with better survival, whereas, for T2-3N0 patients, CRT was comparable to RT alone. Prospective large studies should be encouraged to verify the results.

Metronomic capecitabine as adjuvant therapy in locoregionally advanced nasopharyngeal carcinoma: a multicentre, open-label, parallel-group, randomised, controlled, phase 3 trial.

BACKGROUND: Patients with locoregionally advanced nasopharyngeal carcinoma have a high risk of disease relapse, despite a high proportion of patients attaining complete clinical remission after receiving standard-of-care treatment (ie, definitive concurrent chemoradiotherapy with or without induction chemotherapy). Additional adjuvant therapies are needed to further reduce the risk of recurrence and death. However, the benefit of adjuvant chemotherapy for nasopharyngeal carcinoma remains controversial, highlighting the need for more effective adjuvant treatment options. METHODS: This multicentre, open-label, parallel-group, randomised, controlled, phase 3 trial was done at 14 hospitals in China. Patients (aged 18-65 years) with histologically confirmed, high-risk locoregionally advanced nasopharyngeal carcinoma (stage III-IVA, excluding T3-4N0 and T3N1 disease), no locoregional disease or distant metastasis after definitive chemoradiotherapy, an Eastern Cooperative Oncology Group performance status of 0 or 1, sufficient haematological, renal, and hepatic function, and who had received their final radiotherapy dose 12-16 weeks before randomisation, were randomly assigned (1:1) to receive either oral metronomic capecitabine (650 mg/m2 body surface area twice daily for 1 year; metronomic capecitabine group) or observation (standard therapy group). Randomisation was done with a computer-generated sequence (block size of four), stratified by trial centre and receipt of induction chemotherapy (yes or no). The primary endpoint was failure-free survival, defined as the time from randomisation to disease recurrence (distant metastasis or locoregional recurrence) or death due to any cause, in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of capecitabine or who had commenced observation. This trial is registered with ClinicalTrials.gov, NCT02958111. FINDINGS: Between Jan 25, 2017, and Oct 25, 2018, 675 patients were screened, of whom 406 were enrolled and randomly assigned to the metronomic capecitabine group (n=204) or to the standard therapy group (n=202). After a median follow-up of 38 months (IQR 33-42), there were 29 (14%) events of recurrence or death in the metronomic capecitabine group and 53 (26%) events of recurrence or death in the standard therapy group. Failure-free survival at 3 years was significantly higher in the metronomic capecitabine group (85·3% [95% CI 80·4-90·6]) than in the standard therapy group (75·7% [69·9-81·9]), with a stratified hazard ratio of 0·50 (95% CI 0·32-0·79; p=0·0023). Grade 3 adverse events were reported in 35 (17%) of 201 patients in the metronomic capecitabine group and in 11 (6%) of 200 patients in the standard therapy group; hand-foot syndrome was the most common adverse event related to capecitabine (18 [9%] patients had grade 3 hand-foot syndrome). One (<1%) patient in the metronomic capecitabine group had grade 4 neutropenia. No treatment-related deaths were reported in either group. INTERPRETATION: The addition of metronomic adjuvant capecitabine to chemoradiotherapy significantly improved failure-free survival in patients with high-risk locoregionally advanced nasopharyngeal carcinoma, with a manageable safety profile. These results support a potential role for metronomic chemotherapy as an adjuvant therapy in the treatment of nasopharyngeal carcinoma. FUNDING: The National Natural Science Foundation of China, the Key-Area Research and Development Program of Guangdong Province, the Natural Science Foundation of Guangdong Province, the Innovation Team Development Plan of the Ministry of Education, and the Overseas Expertise Introduction Project for Discipline Innovation. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Gemcitabine and Cisplatin Induction Chemotherapy in Nasopharyngeal Carcinoma.

BACKGROUND: Platinum-based concurrent chemoradiotherapy is the standard of care for patients with locoregionally advanced nasopharyngeal carcinoma. Additional gemcitabine and cisplatin induction chemotherapy has shown promising efficacy in phase 2 trials. METHODS: In a parallel-group, multicenter, randomized, controlled, phase 3 trial, we compared gemcitabine and cisplatin as induction chemotherapy plus concurrent chemoradiotherapy with concurrent chemoradiotherapy alone. Patients with locoregionally advanced nasopharyngeal carcinoma were randomly assigned in a 1:1 ratio to receive gemcitabine (at a dose of 1 g per square meter of body-surface area on days 1 and 8) plus cisplatin (80 mg per square meter on day 1), administered every 3 weeks for three cycles, plus chemoradiotherapy (concurrent cisplatin at a dose of 100 mg per square meter every 3 weeks for three cycles plus intensity-modulated radiotherapy) or chemoradiotherapy alone. The primary end point was recurrence-free survival (i.e., freedom from disease recurrence [distant metastasis or locoregional recurrence] or death from any cause) in the intention-to-treat population. Secondary end points included overall survival, treatment adherence, and safety. RESULTS: A total of 480 patients were included in the trial (242 patients in the induction chemotherapy group and 238 in the standard-therapy group). At a median follow-up of 42.7 months, the 3-year recurrence-free survival was 85.3% in the induction chemotherapy group and 76.5% in the standard-therapy group (stratified hazard ratio for recurrence or death, 0.51; 95% confidence interval [CI], 0.34 to 0.77; P = 0.001). Overall survival at 3 years was 94.6% and 90.3%, respectively (stratified hazard ratio for death, 0.43; 95% CI, 0.24 to 0.77). A total of 96.7% of the patients completed three cycles of induction chemotherapy. The incidence of acute adverse events of grade 3 or 4 was 75.7% in the induction chemotherapy group and 55.7% in the standard-therapy group, with a higher incidence of neutropenia, thrombocytopenia, anemia, nausea, and vomiting in the induction chemotherapy group. The incidence of grade 3 or 4 late toxic effects was 9.2% in the induction chemotherapy group and 11.4% in the standard-therapy group. CONCLUSIONS: Induction chemotherapy added to chemoradiotherapy significantly improved recurrence-free survival and overall survival, as compared with chemoradiotherapy alone, among patients with locoregionally advanced nasopharyngeal carcinoma. (Funded by the Innovation Team Development Plan of the Ministry of Education and others; ClinicalTrials.gov number, NCT01872962.).

Photoelectron Spectroscopy and Density Functional Investigation of the Structural Evolution, Electronic, and Magnetic Properties of CrSin- (n = 14-18) Clusters.

CrSin- (n = 14-18) cluster anions have been investigated by a combination of photoelectron spectroscopy (PES) and first-principles calculations. The lowest-lying structures of the clusters have been determined by a global minimum search based on the genetic algorithm, combined with density functional theory (DFT) calculations. The simulated PES spectra of the lowest-energy isomers are in agreement with the experimental results, which gives strong evidence that the correct structures have been found. While sizes n = 14 and n = 15 prefer cage-like structures based on multi-center bonding within the cage, the larger sizes adopt structures based on fullerene-type cages around the Cr atom, with the additional atoms attached to the cage surface. A Hirshfeld analysis shows that the Cr atoms act as electron donors in all clusters, thus enhancing the electron count in the cage. It also reveals that the magnetic moment of 1µB shown by all clusters is mainly contributed by the Cr atom. One interesting exception is size 17, where the Cr atom contributes a small moment antiparallel to that of the silicon cage.

Neutrophil CD64 index for diagnosis of infectious disease in the pediatric ICU: a single-center prospective study.

BACKGROUND: Infection is a major cause of death in children, and it is particularly important to identify biological indicators of early infection. Previous studies showed that the neutrophil CD64 (nCD64) index may be a useful biomarker for infection. The purpose of this study was to investigate use of the nCD64 index to identify infection in children from a pediatric ICU (PICU) in China. METHODS: This prospective observational study enrolled 201 children who were admitted to our PICU and were divided into an infection group and a non-infection group. In each patient, C-reactive protein (CRP), nCD64 index, procalcitonin (PCT), and white blood cell count were measured during the first 24 h after admission. Receiver operating characteristic (ROC) analyses were used to determine the sensitivity, specificity, and diagnostic value of the nCD64 index for infection. RESULTS: Among all 201 children, the infection group had greater levels of CRP, nCD64 index, and PCT (all p < 0.05). ROC analysis indicated the nCD64 index had a sensitivity of 68.8%, specificity of 90.7%, accuracy of 80.5%, and an optimal cut-off value of 0.14, which had better diagnostic value than CRP or PCT. For children with postoperative fever, the nCD64 index also distinguished systemic inflammatory response syndrome (SIRS) from infection with accuracy of 79%. CONCLUSIONS: The nCD64 index is a useful biomarker for the diagnosis of early infection in children admitted to the PICU.

An mALBI-Child-Pugh-based nomogram for predicting post-hepatectomy liver failure grade B-C in patients with huge hepatocellular carcinoma: a multi-institutional study.

OBJECTIVE: Post-hepatectomy liver failure (PHLF) is a severe complication in patients with hepatocellular carcinoma (HCC) who underwent hepatectomy. This study aims to develop a nomogram of PHLF grade B-C in patients with huge HCC (diameter ≥ 10 cm). METHODS: We retrospectively collected clinical information of 514 and 97 patients who underwent hepatectomy for huge HCC at two medical centers between 2016 and 2021. Univariate and multivariate analysis were carried out to screen the independent risk factors of PHLF grade B-C, which were visualized as a nomogram. RESULTS: Three Hundred Forty Three Thousand One Hundred Seventy One  and 97 HCC patients were included in the training cohort, internal validation cohort, and external validation cohort, with probabilities of PHLF grade B-C of 15.1%, 12.9%, and 22.7%, respectively. Pre-operative modified albumin-bilirubin (mALBI) grade (p < 0.001), Child-Pugh classification (p = 0.044), international normalized ratio (INR) (p = 0.005), cirrhosis (p = 0.019), and intraoperative blood loss (p = 0.004) were found to be independently associated with PHLF grade B-C in the training cohort. All the five independent factors were considered in the establishment of the nomogram model. In the internal validation cohort and external validation cohort, the area under receiver operating characteristic curve for the nomogram in PHLF grade B-C prediction reached 0.823 and 0.740, respectively. Divided into different risk groups according to the optimal cut-off value, patients in the high-risk group reported significantly higher frequency of PHLF grade B-C than those in the low-risk group, both in the training cohort and the validation cohort (p < 0.001). CONCLUSIONS: The proposed noninvasive nomogram based on mALBI-Child-Pugh and three other indicators achieved optimal prediction performance of PHLF grade B-C in patients with huge HCC.

Future liver volume combined with platelet count predicts liver failure after major hepatectomy.

BACKGROUND: Major hepatectomy is associated with high incidence of post-hepatectomy liver failure (PHLF). This study aimed to evaluate the effect of future remnant liver volume combined with liver function tests on predicting PHLF. METHODS: Patients who underwent major hepatectomy from April 2009 to May 2017 were enrolled in the training cohort. Univariate and multivariate logistic regression analyses were performed to identify independent risk factors of PHLF and generate a logistic regression model for the prediction of PHLF. A conditional inference tree was generated based on the optimal cutoff value of independent predictive factors of PHLF. The precedent results were validated in an independent cohort from June 2017 to March 2018. RESULTS: One hundred and eighteen patients were included in the training cohort, while another 34 in the validation cohort. Future remnant liver volume/estimated standard total liver volume (FLV/eTV) and preoperative platelet count were independent predictive factors of PHLF (P = 0.0021 and P = 0.012, respectively). The conditional inference tree showed that patients with FLV/eTV ≤0.56 and PLT count ≤145 × 109/L were at high risk of developing PHLF. CONCLUSION: FLV/eTV combined with preoperative PLT count is effective in predicting PHLF after major hepatectomy.

Increase of Portal Vein Pressure Gradient After Hepatectomy Predicts Post-operative Liver Dysfunction.

Background. Post-hepatectomy liver failure (PHLF) is an important cause of mortality and morbidity. Whether Child-Pugh A patients with varying degrees of cirrhosis are good candidates for hepatectomy is disputed. The purpose of this study was to analyze the impact of portal venous pressure gradient (PVPG) variation during surgery on PHLF. Methods. PVPG, the pressure gradient between the portal vein and central vein, was measured in consecutive patients before and after liver resection. The optimal cutoff of PVPG to predict PHLF was determined by receiver operating characteristic curve analysis. Risk factors for PHLF were subjected to univariate and multivariable analysis. Results. Sixty Child-Pugh A patients were recruited. The mean PVPG was increased from 5.17 ± 4.78 mm of mercury (mmHg) to 6.37 ± 4.44 mmHg after liver resection. The optimal cutoff value of PVPG increments to predict PHLF was 1.5 mmHg. Multivariable analysis showed prothrombin time (PT), post-hepatectomy PVPG increments of 1.5 mmHg or greater, and resected liver segments of 3 or more to be independent predictors of PHLF. Conclusions. Acute PVPG increase after hepatectomy is associated with a higher risk of PHLF in Child-Pugh A patients.

SMRI: A New Method for siRNA Design for COVID-19 Therapy.

First discovered in Wuhan, China, SARS-CoV-2 is a highly pathogenic novel coronavirus, which rapidly spread globally and became a pandemic with no vaccine and limited distinctive clinical drugs available till March 13th, 2020. Ribonucleic Acid interference (RNAi) technology, a gene-silencing technology that targets mRNA, can cause damage to RNA viruses effectively. Here, we report a new efficient small interfering RNA (siRNA) design method named Simple Multiple Rules Intelligent Method (SMRI) to propose a new solution of the treatment of COVID-19. To be specific, this study proposes a new model named Base Preference and Thermodynamic Characteristic model (BPTC model) indicating the siRNA silencing efficiency and a new index named siRNA Extended Rules index (SER index) based on the BPTC model to screen high-efficiency siRNAs and filter out the siRNAs that are difficult to take effect or synthesize as a part of the SMRI method, which is more robust and efficient than the traditional statistical indicators under the same circumstances. Besides, to silence the spike protein of SARS-CoV-2 to invade cells, this study further puts forward the SMRI method to search candidate high-efficiency siRNAs on SARS-CoV-2's S gene. This study is one of the early studies applying RNAi therapy to the COVID-19 treatment. According to the analysis, the average value of predicted interference efficiency of the candidate siRNAs designed by the SMRI method is comparable to that of the mainstream siRNA design algorithms. Moreover, the SMRI method ensures that the designed siRNAs have more than three base mismatches with human genes, thus avoiding silencing normal human genes. This is not considered by other mainstream methods, thereby the five candidate high-efficiency siRNAs which are easy to take effect or synthesize and much safer for human body are obtained by our SMRI method, which provide a new safer, small dosage and long efficacy solution for the treatment of COVID-19. Supplementary Information: The online version contains supplementary material available at 10.1007/s11390-021-0826-x.

[Features of unintentional injury in children under the impact of coronavirus disease 2019]. / æ–°åž‹å† çŠ¶ç— æ¯’è‚ºç‚Žç–«æƒ ä¸‹å„¿ç«¥æ„å¤–ä¼¤å®³çš„ç‰¹å¾.

OBJECTIVES: To study the features of unintentional injury in children under the impact of coronavirus disease 2019 (COVID-19). METHODS: A retrospective analysis was performed on the medical data of 2 526 children with unintentional injury in Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine from July 2019 to June 2022. The study period was divided into 5 stages: before the epidemic (July to December, 2019), the Wuhan epidemic period (January to April, 2020), the epidemic remission period in China (May 2020 to February 2022), the Shanghai epidemic period (March to May, 2022), and the epidemic remission period in Shanghai (June 2022). The incidences of unintentional injury in children at different time stages and different ages were compared. A questionnaire survey was conducted on 107 children of the 2 526 children to explore the features of unintentional injury. RESULTS: There were significant differences in gender composition, age, age distribution and proportion of many types of unintentional injuries among the five time stages (P<0.05). There was a reduction in the number of children who attended the emergency department due to unintentional injury during the Wuhan epidemic and the Shanghai epidemic. The proportion of children with trauma-related unintentional injuries in each stage reached more than 50%, and the proportion of children with trauma-related unintentional injuries reached 63.9% and 82.0%, respectively during the Wuhan epidemic and the Shanghai epidemic. Most children suffering from unintentional injury were mainly school-aged and preschool children (1 823 children, 72.17%). Compared with the same period of Shanghai epidemic in 2021, the age of children with unintentional injury was younger (median 7 years vs 11 years), and the proportion of children with trauma-related unintentional injuries increased (97% vs 69%) during the Shanghai epidemic (P<0.05). CONCLUSIONS: Under the COVID-19 epidemic, there is a reduction in the number of children with unintentional injury, while there is an increase in the proportion of children with trauma-related unintentional injuries. Unintentional injury is more common among school-aged and preschool children.

CircRNA UBAP2 serves as a sponge of miR-1294 to increase tumorigenesis in hepatocellular carcinoma through regulating c-Myc expression.

Circular RNAs (circRNAs) are a class of regulatory RNAs with complex roles in healthy and diseased tissues. However, the oncogenic role of circRNAs in hepatocellular carcinoma (HCC) remains poorly understood, including the mechanisms by which the circular ubiquitin-binding associated protein 2 (circUBAP2) contributes to tumorigenesis. We analyzed the expression of circUBAP2 in 20 paired samples of HCC and healthy tissue as well as in seven HCC cell lines via quantitative real-time polymerase chain reaction. Functional experiments, such as CCK8 viability assays, colony formation assays, wound healing, transwell assays and flow cytometry, were conducted to assess the effects of circUBAP2 in vitro. To further elucidate the mechanisms by which circUBAP2 acts, we conducted dual-luciferase assays, western blots, RNA pull-down assays and rescue experiments. CircUBAP2 was highly upregulated in most HCC tissues and was associated with poor prognosis. HCC patients with high circUBAP2 expression had greater vascular invasion and worse differentiation. Functionally, circUBAP2 overexpression enhanced HCC cell proliferation, migration and invasion and inhibited apoptosis. Furthermore, we found that circUBAP2 upregulated c-Myc expression by sponging miR-1294, thus contributing to hepatocarcinogenesis. Inhibiting circUBAP2 expression in HCC attenuated the oncogenic effects of c-Myc. These findings suggest that circUBAP2 promotes HCC growth and metastasis. CircUBAP2 may have value as an independent prognostic biomarker or as a new target for the treatment of HCC.

Cross talk between oxidative stress and hypoxia via thioredoxin and HIF-2α drives metastasis of hepatocellular carcinoma.

Oxidative stress and hypoxia are two opposite microenvironments involved in HCC metastasis. Thioredoxin (TXN) and hypoxia-inducible factor 2α (HIF-2α) are typical proteins involved in these two different microenvironments, respectively. How these two factors interact to influence the fate on tumor cells remains unknown. Hypoxia facilitated HCC cells withstood oxidative stress and eventually promoted HCC cells metastasis, in which TXN and HIF-2α were mostly involved. Upregulation of TXN/HIF-2α correlated with poor HCC prognosis and promoted HCC metastasis both in vitro and in vivo. Epithelial-mesenchymal transition (EMT) process was involved in TXN/HIF-2α-enhanced invasiveness of HCC cells. Additionally, the stability and activity of HIF-2α were precisely regulated by TXN via SUMOylation and acetylation, which contributed to HCC metastasis. Our data revealed that the redox protein TXN and HIF-2α are both associated with HCC metastasis, and the fine regulation of TXN on HIF-2α contributes essentially during the process of metastasis. Our study provides new insight into the interaction mechanism between hypoxia and oxidative stress and implies potential therapeutic benefits by targeting both TXN and HIF-2α in the treatment of HCC metastasis.

Establishment and Verification of a Prediction Model for Symptomatic Radiation Pneumonitis in Patients with Esophageal Cancer Receiving Radiotherapy.

BACKGROUND This study aimed to determine the value of the significant index in predicting symptomatic radiation pneumonitis (RP) in esophageal cancer patients, establish a nomogram prediction model, and verify the model. MATERIAL AND METHODS The patients enrolled were divided into 2 groups: a model group and a validation group. According to the logistic regression analysis, the independent predictors for symptomatic RP were obtained, and the nomogram prediction model was established according to these independent predictors. The consistency index (C-index) and calibration curve were used to evaluate the accuracy of the model, and the prediction ability of the model was verified in the validation group. Recursive partitioning analysis (RPA) was used for the risk stratification analysis. RESULTS The ratio of change regarding the pre-albumin at the end of treatment (P=0.001), platelet-to-lymphocyte ratio during treatment (P=0.027), and neutrophil-to-lymphocyte ratio at the end of treatment (P=0.001) were the independent predictors for symptomatic RP. The C-index of the nomogram model was 0.811. According to the risk stratification of RPA, the whole group was divided into 3 groups: a low-risk group, a medium-risk group, and a high-risk group. The incidence of symptomatic RP was 0%, 16.9%, and 57.6%, respectively. The receiver operating characteristic curve also revealed that the nomogram model has good accuracy in the validation group. CONCLUSIONS The developed nomogram and corresponding risk classification system have superior prediction ability for symptomatic RP and can predict the occurrence of RP in the early stage.