Ionic-liquid-gating- (ILG-) induced proton evolution has emerged as a novel strategy to realize electron doping and manipulate the electronic and magnetic ground states in complex oxides. While the ...study of a wide range of systems (e.g., SrCoO
, VO
, WO
, etc.) has demonstrated important opportunities to incorporate protons through ILG, protonation remains a big challenge for many others. Furthermore, the mechanism of proton intercalation from the ionic liquid/solid interface to whole film has not yet been revealed. Here, with a model system of inverse spinel NiCo
O
, an increase in system temperature during ILG forms a single but effective method to efficiently achieve protonation. Moreover, the ILG induces a novel phase transformation in NiCo
O
from ferrimagnetic metallic into antiferromagnetic insulating with protonation at elevated temperatures. This study shows that environmental temperature is an efficient tuning knob to manipulate ILG-induced ionic evolution.
Acute kidney injury (AKI) is commonly present in critically ill patients with sepsis. Early prediction of short-term reversibility of AKI is beneficial to risk stratification and clinical treatment ...decision. The study sought to use machine learning methods to discriminate between transient and persistent sepsis-associated AKI. Septic patients who developed AKI within the first 48 h after ICU admission were identified from the Medical Information Mart for Intensive Care III database. AKI was classified as transient or persistent according to the Acute Disease Quality Initiative workgroup consensus. Five prediction models using logistic regression, random forest, support vector machine, artificial neural network and extreme gradient boosting were constructed, and their performance was evaluated by out-of-sample testing. A simplified risk prediction model was also derived based on logistic regression and features selected by machine learning algorithms. A total of 5984 septic patients with AKI were included, 3805 (63.6%) of whom developed persistent AKI. The artificial neural network and logistic regression models achieved the highest area under the receiver operating characteristic curve (AUC) among the five machine learning models (0.76, 95% confidence interval CI 0.74-0.78). The simplified 14-variable model showed adequate discrimination, with the AUC being 0.76 (95% CI 0.73-0.78). At the optimal cutoff of 0.63, the sensitivity and specificity of the simplified model were 63% and 76% respectively. In conclusion, a machine learning-based simplified prediction model including routine clinical variables could be used to differentiate between transient and persistent AKI in critically ill septic patients. An easy-to-use risk calculator can promote its widespread application in daily clinical practice.
Background: Combined therapy with tyrosine kinase inhibitors (TKIs) and anti-PD-1 antibodies has shown high tumor response rates for patients with unresectable hepatocellular carcinoma (HCC). ...However, using this treatment strategy to convert initially unresectable HCC to resectable HCC was not reported. Methods: Consecutive patients with unresectable HCC who received first-line therapy with combined TKI/anti-PD-1 antibodies were analyzed. Tumor response and resectability were evaluated via imaging every 2 months (±2 weeks) using RECIST v1.1. Resectability criteria were (1) R0 resection could be achieved with sufficient remnant liver volume and function; (2) intrahepatic lesions were evaluated as partial responses or stable disease for at least 2 months; (3) no severe or persistent adverse effects occurred; and (4) hepatectomy was not contraindicated. Results: Sixty-three consecutive patients were enrolled. Of them, 10 (15.9%) underwent R0 resection in 3.2 months (range: 2.4–8.3 months) after the initiation of combination therapy. At baseline, these 10 patients had a median largest tumor diameter of 9.3 cm, 7 had Barcelona Clinic Liver Cancer stage C (vascular invasion) disease, 2 had stage B, and 1 had stage A. Before surgery, 6 patients were evaluated as a partial response, 3 stable disease, and 1 partial response in the intrahepatic lesion but a new metastatic lesion in the right adrenal gland. Six patients (60%) achieved a pathological complete response. One patient died from immune-related adverse effects 2.4 months after hepatectomy. After a median follow-up of 11.2 months (range: 7.8–15.9 months) for other 9 patients, 8 survived without disease recurrence, and 1 experienced tumor recurrence. Conclusions: Combination of TKI/anti-PD-1 antibodies is a feasible conversion therapy for patients with unresectable HCC to become resectable. This study represents the largest patient cohort on downstaging role of combinational systemic therapy on TKI and PD-1 antibody for HCC.
Ionic‐liquid‐gating‐ (ILG‐) induced proton evolution has emerged as a novel strategy to realize electron doping and manipulate the electronic and magnetic ground states in complex oxides. While the ...study of a wide range of systems (e.g., SrCoO2.5, VO2, WO3, etc.) has demonstrated important opportunities to incorporate protons through ILG, protonation remains a big challenge for many others. Furthermore, the mechanism of proton intercalation from the ionic liquid/solid interface to whole film has not yet been revealed. Here, with a model system of inverse spinel NiCo2O4, an increase in system temperature during ILG forms a single but effective method to efficiently achieve protonation. Moreover, the ILG induces a novel phase transformation in NiCo2O4 from ferrimagnetic metallic into antiferromagnetic insulating with protonation at elevated temperatures. This study shows that environmental temperature is an efficient tuning knob to manipulate ILG‐induced ionic evolution.
Ionic‐liquid‐gating‐induced protonation is realized in the inverse spinel NiCo2O4 with an elevated environmental temperature, and has a major impact on the electronic and magnetic states. This study takes the understanding of the ionic‐liquid‐gating‐induced protonation process a step further and provides a generic strategy to boost this effect in extended material systems.
Objective
Lenvatinib plus anti‐programmed death‐1 (anti‐PD‐1) antibody combinations have shown potent anti‐tumor effect in phase I/II trials in advanced or unresectable hepatocellular carcinoma ...(HCC), but real‐world data are limited.
Methods
To investigate the effectiveness and safety of lenvatinib plus anti‐PD‐1 antibodies in a real‐world cohort, we retrospectively evaluated 210 patients with unresectable or advanced HCC treated with these regimens between October 2018 and February 2022.
Results
The objective response rate and disease control rate per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 were 28.1% and 75.2%. Median overall survival (OS) and progression‐free survival (PFS) in the overall cohort were 17.2 and 8.4 months, respectively. Median OS and PFS of patients receiving first‐line treatment reached 18.9 and 9.6 months. Median OS was significantly longer in patients with Child‐Pugh class A versus B (18.8 vs. 5.9 months, respectively), as was median PFS (9.1 vs. 4.4 months). Patients with albumin–bilirubin (ALBI) grade 1 versus grade 2/3 also had significantly greater median OS (23.5 vs. 13.4 months). Treatment‐related adverse events (AEs) occurred in 79.5% of patients. Patients with ALBI grade 2/3 had a higher rate of grade 3/4 AEs than patients with ALBI grade 1 (57.5% vs. 38.5%).
Conclusion
Lenvatinib combined with anti‐PD‐1 antibody therapy was effective in patients with sufficient liver function reserve. Further study is needed to improve therapeutic efficacy and AE management in patients with Child‐Pugh class B or ALBI grade 2/3.
The present study evaluated a real‐life cohort of 210 patients with unresectable or advanced hepatocellular carcinoma who received treatment with lenvatinib plus anti‐programmed death‐1 antibodies between October 2018 and March 2022. The results are encouraging, with median overall survival of 17.2 months and objective response rate of 28.1%.
Understanding the roles of mammalian autophagy in cancer highlights recent advances in the pharmacologic manipulation of autophagic pathways as a therapeutic strategy for cancer. However, autophagy ...status and corresponding functions in hepatocellular carcinoma (HCC) after therapeutic stress remain to be clarified. This study was to determine whether the autophagic machinery could be activated after chemotherapy and the contribution of autophagy to tolerance of oxaliplatin in HCC.
Autophagy activation and cell death induced by oxaliplatin were examined in two HCC cell lines as well as in vivo using an HCC model in nude mice. HCC tissue samples with or without locoregional chemotherapy before surgery were also examined by immunohistochemical and electron microscopic analysis.
Autophagy was functionally activated in HCC cell lines and xenografts after oxaliplatin treatment. Suppression of autophagy using either pharmacologic inhibitors or RNA interference of essential autophagy gene enhanced cell death induced by oxaliplatin in HCC cells. Generation of reactive oxygen species has an important role in the induction of cell death by oxaliplatin in combination with autophagy inhibitors. Critically, the combination of oxaliplatin with autophagy inhibitor chloroquine resulted in a more pronounced tumor suppression in HCC xenografts. Furthermore, autophagy-specific protein LC3 and autophagic autophagosome formation were induced to a significantly higher level in HCC specimens that had been subjected to locoregional chemotherapy.
Autophagy activation under therapy stress contributes to HCC tumor cell survival. Targeting the autophagy pathway is a promising therapeutic strategy to enhance the effects of chemotherapy and improve clinical outcomes in HCC patients.
Autophagy is an important adaptive survival mechanism, which has been postulated to be involved in cancer metastasis. The purpose of this study was to investigate autophagy in metastasis of ...hepatocellular carcinoma (HCC).
Immunohistochemical analysis of autophagic activity in metastatic and paired primary HCC tissues using LC3 as autophagosome marker was performed in samples from 216 HCC patients diagnosed with metastasis (including 158 intravascular, 42 intrabiliary, 8 lymph node, 4 bone and 4 lung metastases). Then a mouse model of pulmonary metastasis was established using a highly metastatic HCC cell line (HCCLM3). Autophagy in pulmonary metastases and paired primary tumors were analyzed by LC3 immunohistochemistry, transmission electron microscopy (TEM) and western blot analysis. Further, mouse model of pulmonary metastasis and in vitro cell migration, invasion and detachment models were established using a stable GFP-LC3-expressing HCCLM3 cell line (HCCLM3-GFP-LC3). Autophagic alterations during metastatic colonization, migration, invasion and detachment were determined by GFP-LC3 analysis and western blot analysis.
LC3 immunohistochemistry of metastases and primary tumors from HCC patients revealed significantly higher LC3 expression in metastases than primary HCC, which suggested a higher level of autophagy in HCC metastases. Further immunohistochemical, TEM, western blot and in vivo GFP-LC3 analyses of lung metastases and primary tumors in mouse model of pulmonary metastasis confirmed that metastatic colonies displayed higher level of autophagy than primary tumors and the early metastatic colonies displayed highest level. The dynamic monitoring of autophagy in cell migration, invasion and detachment showed that autophagy did not significantly alter in those processes.
Autophagy is activated in metastatic colonization but not in invasion, migration and detachment of HCC cells. Autophagy may play a role in HCC metastasis via promoting metastatic colonization of HCC cells.
Microvascular invasion (MVI) is recognized as a prognostic factor associated with poor outcome in hepatocellular carcinoma (HCC) patients after curative resection. It remains unclear, however, ...whether MVI can provide prognostic information for patients at a specific tumor stage.
Consecutive HCC patients who underwent curative resection in years of 2007 and 2008 (discovery cohort) were enrolled in this retrospective study. Patients were stratified by the Barcelona Clinic Liver Cancer (BCLC) staging system. The prognostic significance of MVI for overall survival (OS) and recurrence-free survival (RFS) was studied in each subgroup. The clinical significance of MVI was validated in another cohort of patients underwent curative surgery in the year of 2006 (validation cohort).
Of the 1540 patients in the discovery cohort, 389 (25.3%) patients had detectable MVI. Occurrence rates of MVI in the BCLC stage 0, A, and B subgroups were 12.4, 26.2, and 34.4%, respectively. In univariate analysis, MVI was associated with poor OS and RFS (P < 0.001 for both) in HCC patients at stage A, with poor OS in patients at stage 0 (P = 0.028), and with poor RFS at stage B (P = 0.039). In multivariate analysis, MVI was an independent risk factor for OS (HR = 1.431, 95% CI, 1.163-1.761, P < 0.001) and RFS (HR = 1.400, 95% CI, 1.150-1.705, P = 0.001) in patients at stage A; and an independent risk factor for RFS (P = 0.043) in patients at stage B. A similar clinical significance of MVI was found in the validation cohort.
MVI has limited prognostic value for HCC patients at BCLC stages 0 and B. For those at stage A, MVI was associated with patient survival and may help to select patients with high risk of disease recurrence.
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 greater than or equai to 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. Keywords: Huge hepatocellular carcinoma, Modified albumin-bilirubin grade, Child-Pugh classification, Post-hepatectomy liver failure
Spontaneous imbibition of water-based frac- turing fluids into the shale matrix is considered to be the main mechanism responsible for the high volume of water loss during the flowback period. ...Understanding the matrix imbibition capacity and rate helps to determine the frac- turing fluid volume, optimize the flowback design, and to analyze the influences on the production of shale gas. Imbibition experiments were conducted on shale samples from the Sichuan Basin, and some tight sandstone samples from the Ordos Basin. Tight volcanic samples from the Songliao Basin were also investigated for comparison. The effects of porosity, clay minerals, surfactants, and KC1 solutions on the matrix imbibition capacity and rate were systematically investigated. The results show that the imbibition characteristic of tight rocks can be characterized by the imbibition curve shape, the imbibition capacity, the imbibition rate, and the diffusion rate. The driving forces of water imbibition are the capillary pressure and the clay absorption force. For the tight rocks with low clay contents, the imbibition capacity and rate are positively correlated with the porosity. For tight rocks with high clay content, the type and content of clay minerals are the most impor- tant factors affecting the imbibition capacity. The imbibed water volume normalized by the porosity increases with an increasing total clay content. Smectite and illite/smectite tend to greatly enhance the water imbibition capacity. Furthermore, clay-rich tight rocks can imbibe a volume of water greater than their measured pore volume. The aver- age ratio of the imbibed water volume to the pore volume is approximately 1.1 in the Niutitang shale, 1.9 in the Lujiaping shale, 2.8 in the Longmaxi shale, and 4.0 in the Yingcheng volcanic rock, and this ratio can be regarded as a parameter that indicates the influence of clay. In addition, surfactants can change the imbibition capacity due to alteration of the capillary pressure and wettability. A 10 wt% KC1 solution can inhibit clay absorption to reduce the imbibition capacity.
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