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.
A method for the preparation of chiral triarylmethanes via organocatalytic 1,6‐addition of arylboronic acids to para‐quinone methides (p‐QMs) was established. Here the use of salicylaldehyde‐derived ...p‐QMs with an ortho‐hydroxy substituent as a directing group was essential for the remote stereocontrol. In the presence of a BINOL catalyst, chiral triarylmethanes can be obtained in high yields (up to 99%) with excellent enantioselectivities (up to 99% ee). This method shows broad substrate tolerance and can be easily scaled up, both electron‐rich and electron‐deficient arylboronic acids are suitable substrates for this addition reaction.
Gut microbiota interacts with host immune system in ways that influence the development of disease. Advances in respiratory immune system also broaden our knowledge of the interaction between host ...and microbiome in the lung. Increasing evidence indicated the intimate relationship between the gastrointestinal tract and respiratory tract. Exacerbations of chronic gut and lung disease have been shown to share key conceptual features with the disorder and dysregulation of the microbial ecosystem. In this review, we discuss the impact of gut and lung microbiota on disease exacerbation and progression, and the recent understanding of the immunological link between the gut and the lung, the gut-lung axis.
Heterodimeric tryptophan‐containing diketopiperazines (HTDKPs) are an important class of bioactive secondary metabolites. Biosynthesis offers a practical opportunity to access their bioactive ...structural diversity, however, it is restricted by the limited substrate scopes of the HTDKPs‐forming P450 dimerases. Herein, by genome mining and investigation of the sequence‐product relationships, we unveiled three important residues (F387, F388 and E73) in these P450s that are pivotal for selecting different diketopiperazine (DKP) substrates in the upper binding pocket. Engineering these residues in NasF5053 significantly expanded its substrate specificity and enabled the collective biosynthesis, including 12 self‐dimerized and at least 81 cross‐dimerized HTDKPs. Structural and molecular dynamics analysis of F387G and E73S revealed that they control the substrate specificity via reducing steric hindrance and regulating substrate tunnels, respectively.
The biosynthesis of heterodimeric tryptophan‐containing diketopiperazines (HTDKPs) is restricted by the limited substrate scopes of the HTDKP‐forming P450 dimerases. Engineering of three important residues (F387, F388, and E73) in NasF5053 significantly expanded its substrate specificity and enabled the collective biosynthesis of at least 93 HTDKPs.
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.
The prevalence of and risk factors for uncertainty stress among residents during the COVID-19 pandemic remain unclear. An online cross-sectional survey was conducted to explore and identify the risk ...factors for high perceived uncertainty stress among the general public in China during the COVID-19 outbreak. Information about the respondents' socioeconomic characteristics, knowledge of and attitudes towards COVID-19, perceived uncertainty stress, social capital, anxiety, and depressive symptoms was collected and analysed. Among the 1205 respondents, 45.3% (546) reported a high level of uncertainty stress. Multiple linear regression analysis indicated that anxiety (β=3.871,P<0.001) and depression symptoms (β=2.458, P<0.001), family residence (in towns or rural areas) (β=0.947, P<0.001), lack of support for local epidemic control strategies (β=1.253, P<0.001), worry about the pandemic (β=1.191, P<0.001), and symptoms of weakness among family members (β=1.525, P=0.002) were positively associated with perceived uncertainty stress. Cognitive social capital (β=-0.883, P<0.001) and social networks (β=-0.726, P<0.001) were negatively, but social participation (β=0.714, P<0.001) was positively associated with perceived uncertainty stress. Our findings identify factors associated with a higher level of uncertainty stress and should be helpful in the consideration of effective policies and interventions for uncertainty stress during the initial phases of public health emergencies.
is a valuable medicinal and edible plant, which is often used as a traditional tea by the Tujia people in China.
has numerous biological activities and is now widely used in the pharmaceutical and ...food industries. In this study, two new flavonoids (
-
) and seventeen known compounds (
-
) were isolated and identified from the dried stems and leaves of
. These isolated compounds were characterized by various spectroscopic data including mass spectrometry and nuclear magnetic resonance spectroscopy. All isolates were assessed for their α-glucosidase inhibitory, antioxidant, and hepatoprotective activities, and their structure-activity relationships were further discussed. The results indicated that compound
exhibited effective inhibitory activity against α-glucosidase, with an IC
value of 0.21 μM. In addition, compounds
-
demonstrated not only potent antioxidant activities but also superior hepatoprotective properties. The findings of this study could serve as a reference for the development of
products or drugs aimed at realizing their antidiabetic, antioxidant, and hepatoprotective functions.
Intrahepatic arterioportal fistula(IAPF)can be caused by many secondary factors.We report four cases of portal hypertension that were eventually determined to be caused by congenital hepatic ...arterioportal fistula.The clinical manifestations included ascites,variceal hemorrhage and hepatic encephalopathy.Computed tomography scans from all of the patients revealed the early enhancement of the portal branches in the hepatic arterial phase.All patients were diagnosed using digital subtraction angiography(DSA).DSA before embolization revealed an arteriovenous fistula with immediate filling of the portal venous radicles.All four patients were treated with interventional embolization.The four patients remained in good condition throughout follow-up and at the time of publication.IAPF is frequently misdiagnosed due to its rarity;therefore,clinicians should consider IAPF as a potential cause of non-cirrhotic portal hypertension.
Hypoxia is associated with the progression of hepatocellular carcinoma through promotion of spontaneous metastasis but the mechanism remains unclear. Here, we hypothesis that tumor cell-derived HMGB1 ...orchestrates macrophages infiltration and promotes metastasis of HCC via enhancing macrophage-secreted IL-6 under hypoxia. HMGB1 expression was robustly exacerbated in tumors of HCC patients with PVTT. Meanwhile, hypoxia exposure gave rise to HMGB1 expression in hepatoma cells of human and mouse in a HIF-1α-dependent manner and subsequently induced the infiltration and reprogramming of macrophages to augment the expression of Il-6. Further study demonstrated macrophage-derived IL-6 enhanced the invasiveness and metastasis of murine HCC cells. Therefore, our study provides a novel understanding of the relationship between tumor cells and tumor associated macrophages (TAMs) in the context of hypoxia.
•Hypoxia heightens HMGB1 expression in HCC via HIF1α.•Elevated HMGB1 exacerbates macrophage infiltration into tumor under hypoxia.•Macrophage-derived IL-6 promotes EMT of HCC cells under hypoxia.•Inhibition of HMGB1 attenuates tumor metastasis and macrophage infiltration.
Purpose
The aim of this study is to report the effect of different content of calcium oxide on the process of electromelting magnesia.
Design/methodology/approach
The process of molten magnesia was ...analyzed by finite element simulation and proved by scanning electron microscope.
Findings
The results show that with the increase of CaO content, the maximum temperature appreciation increases from 3,616°C To 3,729°C, showing an approximate nonlinear evolution. Low thermal conductivity and low specific heat of CaO result in higher temperature. With the increase of CaO content and temperature, the maximum flow velocity of MgO slag increases from 0.043 to 1.34 mm/s. Under different initial CaO contents, the distribution trend of CaO volume fraction is basically the same, and the CaO volume fraction is evenly distributed between 50 and 225 mm in the furnace.
Originality/value
The influence of different contents of impurity calcium oxide on the process of electromelting magnesia was analyzed and a theoretical system was established.
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