Carnosine regulation of intracellular pH homeostasis promotes lysosome-dependent tumor immunoevasion.

Tumor cells and surrounding immune cells undergo metabolic reprogramming, leading to an acidic tumor microenvironment. However, it is unclear how tumor cells adapt to this acidic stress during tumor progression. Here we show that carnosine, a mobile buffering metabolite that accumulates under hypoxia in tumor cells, regulates intracellular pH homeostasis and drives lysosome-dependent tumor immune evasion. A previously unrecognized isoform of carnosine synthase, CARNS2, promotes carnosine synthesis under hypoxia. Carnosine maintains intracellular pH (pHi) homeostasis by functioning as a mobile proton carrier to accelerate cytosolic H+ mobility and release, which in turn controls lysosomal subcellular distribution, acidification and activity. Furthermore, by maintaining lysosomal activity, carnosine facilitates nuclear transcription factor X-box binding 1 (NFX1) degradation, triggering galectin-9 and T-cell-mediated immune escape and tumorigenesis. These findings indicate an unconventional mechanism for pHi regulation in cancer cells and demonstrate how lysosome contributes to immune evasion, thus providing a basis for development of combined therapeutic strategies against hepatocellular carcinoma that exploit disrupted pHi homeostasis with immune checkpoint blockade.

OXCT1 functions as a succinyltransferase, contributing to hepatocellular carcinoma via succinylating LACTB.

Metabolic reprogramming is an important feature of cancers that has been closely linked to post-translational protein modification (PTM). Lysine succinylation is a recently identified PTM involved in regulating protein functions, whereas its regulatory mechanism and possible roles in tumor progression remain unclear. Here, we show that OXCT1, an enzyme catalyzing ketone body oxidation, functions as a lysine succinyltransferase to contribute to tumor progression. Mechanistically, we find that OXCT1 functions as a succinyltransferase, with residue G424 essential for this activity. We also identified serine beta-lactamase-like protein (LACTB) as a main target of OXCT1-mediated succinylation. Extensive succinylation of LACTB K284 inhibits its proteolytic activity, resulting in increased mitochondrial membrane potential and respiration, ultimately leading to hepatocellular carcinoma (HCC) progression. In summary, this study establishes lysine succinyltransferase function of OXCT1 and highlights a link between HCC prognosis and LACTB K284 succinylation, suggesting a potentially valuable biomarker and therapeutic target for further development.

ENO1 promotes liver carcinogenesis through YAP1-dependent arachidonic acid metabolism.

Enolase 1 (ENO1) is a glycolytic enzyme that plays essential roles in various pathological activities including cancer development. However, the mechanisms underlying ENO1-contributed tumorigenesis are not well explained. Here, we uncover that ENO1, as an RNA-binding protein, binds to the cytosine-uracil-guanine-rich elements of YAP1 messenger RNA to promote its translation. ENO1 and YAP1 positively regulate alternative arachidonic acid (AA) metabolism by inverse regulation of PLCB1 and HPGD (15-hydroxyprostaglandin dehydrogenase). The YAP1/PLCB1/HPGD axis-mediated activation of AA metabolism and subsequent accumulation of prostaglandin E2 (PGE2) are responsible for ENO1-mediated cancer progression, which can be retarded by aspirin. Finally, aberrant activation of ENO1/YAP1/PLCB1 and decreased HPGD expression in clinical hepatocellular carcinoma samples indicate a potential correlation between ENO1-regulated AA metabolism and cancer development. These findings underline a new function of ENO1 in regulating AA metabolism and tumorigenesis, suggesting a therapeutic potential for aspirin in patients with liver cancer with aberrant expression of ENO1 or YAP1.

Camrelizumab plus rivoceranib versus sorafenib as first-line therapy for unresectable hepatocellular carcinoma (CARES-310): a randomised, open-label, international phase 3 study.

BACKGROUND: Immunotherapy with immune checkpoint inhibitors combined with an anti-angiogenic tyrosine-kinase inhibitor (TKI) has been shown to improve overall survival versus anti-angiogenic therapy alone in advanced solid tumours, but not in hepatocellular carcinoma. Therefore, a clinical study was conducted to compare the efficacy and safety of the anti-PD-1 antibody camrelizumab plus the VEGFR2-targeted TKI rivoceranib (also known as apatinib) versus sorafenib as first-line treatment for unresectable hepatocellular carcinoma. METHODS: This randomised, open-label, international phase 3 trial (CARES-310) was done at 95 study sites across 13 countries and regions worldwide. Patients with unresectable or metastatic hepatocellular carcinoma who had not previously received any systemic treatment were randomly assigned (1:1) to receive either camrelizumab 200 mg intravenously every 2 weeks plus rivoceranib 250 mg orally once daily or sorafenib 400 mg orally twice daily. Randomisation was done via a centralised interactive response system. The primary endpoints were progression-free survival, as assessed by the blinded independent review committee per Response Evaluation Criteria in Solid Tumours version 1.1, and overall survival in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of the study drugs. We report the findings from the prespecified primary analysis for progression-free survival and interim analysis for overall survival. This study is registered with ClinicalTrials.gov (NCT03764293). FINDINGS: Between June 28, 2019, and March 24, 2021, 543 patients were randomly assigned to the camrelizumab-rivoceranib (n=272) or sorafenib (n=271) group. At the primary analysis for progression-free survival (May 10, 2021), median follow-up was 7·8 months (IQR 4·1-10·6). Median progression-free survival was significantly improved with camrelizumab-rivoceranib versus sorafenib (5·6 months [95% CI 5·5-6·3] vs 3·7 months [2·8-3·7]; hazard ratio [HR] 0·52 [95% CI 0·41-0·65]; one-sided p<0·0001). At the interim analysis for overall survival (Feb 8, 2022), median follow-up was 14·5 months (IQR 9·1-18·7). Median overall survival was significantly extended with camrelizumab-rivoceranib versus sorafenib (22·1 months [95% CI 19·1-27·2] vs 15·2 months [13·0-18·5]; HR 0·62 [95% CI 0·49-0·80]; one-sided p<0·0001). The most common grade 3 or 4 treatment-related adverse events were hypertension (102 [38%] of 272 patients in the camrelizumab-rivoceranib group vs 40 [15%] of 269 patients in the sorafenib group), palmar-plantar erythrodysaesthesia syndrome (33 [12%] vs 41 [15%]), increased aspartate aminotransferase (45 [17%] vs 14 [5%]), and increased alanine aminotransferase (35 [13%] vs eight [3%]). Treatment-related serious adverse events were reported in 66 (24%) patients in the camrelizumab-rivoceranib group and 16 (6%) in the sorafenib group. Treatment-related death occurred in two patients: one patient in the camrelizumab-rivoceranib group (ie, multiple organ dysfunction syndrome) and one patient in the sorafenib group (ie, respiratory failure and circulatory collapse). INTERPRETATION: Camrelizumab plus rivoceranib showed a statistically significant and clinically meaningful benefit in progression-free survival and overall survival compared with sorafenib for patients with unresectable hepatocellular carcinoma, presenting as a new and effective first-line treatment option for this population. FUNDING: Jiangsu Hengrui Pharmaceuticals and Elevar Therapeutics.

Efficacy and safety of tislelizumab plus lenvatinib as first-line treatment in patients with unresectable hepatocellular carcinoma: a multicenter, single-arm, phase 2 trial.

BACKGROUND: Lenvatinib is widely used in treatment of unresectable hepatocellular carcinoma (uHCC), but the benefit of its combination with immunotherapy needs to be verified. This study evaluated the efficacy and safety of tislelizumab plus lenvatinib in systemic treatment-naïve patients with uHCC. METHODS: In this multicenter, single-arm, phase 2 study, systemic treatment-naïve patients with uHCC received tislelizumab 200 mg every three weeks plus lenvatinib (bodyweight ≥ 60 kg: 12 mg; < 60 kg: 8 mg; once daily). Dose-limiting toxicities (DLTs) were evaluated in safety run-in phase to determine whether to enter the expansion phase. The primary endpoint was objective response rate (ORR) assessed by independent review committee (IRC) per Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1). Based on Simon's two-stage design, > 6 responders were needed in stage 1 (n = 30) to continue the study, and ≥ 18 responders were needed by the end of stage 2 (n = 60) to demonstrate statistical superiority to a historical control of lenvatinib monotherapy. RESULTS: Sixty-four patients were enrolled. No DLTs were reported. The study achieved statistical superiority (p = 0.0003) with 23 responders assessed by IRC per RECIST v1.1 in the first 60 patients of the efficacy evaluable analysis set (n = 62). After a median follow-up of 15.7 months, confirmed ORR and disease control rate were 38.7% (24/62, 95% confidence interval [CI], 26.6-51.9) and 90.3% (56/62, 95% CI, 80.1-96.4), respectively. Median progression-free survival was 8.2 months (95% CI, 6.8-not evaluable). Overall survival rate at 12 months was 88.6% (95% CI, 77.7-94.4). Grade ≥ 3 treatment-related adverse events occurred in 18 (28.1%) patients. CONCLUSIONS: Tislelizumab plus lenvatinib demonstrated promising antitumor activity with favourable tolerability as first-line therapy for patients with uHCC. TRIAL REGISTRATION: ClinicalTrials.gov (NCT04401800).

Characterization of Root Hair Curling and Nodule Development in Soybean-Rhizobia Symbiosis.

Soybean plants form symbiotic nitrogen-fixing nodules with specific rhizobia bacteria. The root hair is the initial infection site for the symbiotic process before the nodules. Since roots and nodules grow in soil and are hard to perceive, little knowledge is available on the process of soybean root hair deformation and nodule development over time. In this study, adaptive microrhizotrons were used to observe root hairs and to investigate detailed root hair deformation and nodule formation subjected to different rhizobia densities. The result showed that the root hair curling angle increased with the increase of rhizobia density. The largest curling angle reached 268° on the 8th day after inoculation. Root hairs were not always straight, even in the uninfected group with a relatively small angle (<45°). The nodule is an organ developed after root hair curling. It was inoculated from curling root hairs and swelled in the root axis on the 15th day after inoculation, with the color changing from light (15th day) to a little dark brown (35th day). There was an error between observing the diameter and the real diameter; thus, a diameter over 1 mm was converted to the real diameter according to the relationship between the perceived diameter and the real diameter. The diameter of the nodule reached 5 mm on the 45th day. Nodule number and curling number were strongly related to rhizobia density with a correlation coefficient of determination of 0.92 and 0.93, respectively. Thus, root hair curling development could be quantified, and nodule number could be estimated through derived formulation.

An Ex Vivo Study of Filum Terminale in Children and Fetuses Based on Optical Coherence Tomography.

Objective: To distinguish ex vivo normal and abnormal filum terminale (FT) in pathology based on optical coherence tomography (OCT). Methods: A total of 14 ex vivo FTs, freshly imaged via OCT after being cut, were excised from the scanned region for histopathological examination (HPE). Qualitative analysis was performed by 2 blinded assessors. Results: We performed OCT imaging of all specimens and validated them qualitatively. In the fetal FTs, we observed large amounts of fibrous tissue scattered throughout with a few capillaries but no adipose tissue. In tight filum terminale syndrome (TFTS), adipose infiltration and capillaries were significantly increased, with obvious fibroplasia and disarrangement. OCT images showed increased adipose tissue in which the adipocytes were arranged in a grid-like pattern; dense, disordered fibrous tissue and vascular-like tissue were present. The diagnostic results of OCT and HPE were consistent (Kappa = 0.659; P = .009, <.01), and there was no statistically significant difference in diagnosing TFTS using a Chi-square test (P > .05). The area under the curve (AUC) for OCT (AUC = 0.966; 95% CI, 0.903 to 1.000) was better than magnetic resonance imaging (MRI) (AUC = 0.649; 95% CI, 0.403 to 0.896). Conclusion: OCT can quickly obtain clear images of FT's inner structure, contribute to diagnosing TFTS and will be an indispensable complement to MRI and HPE. More FT sample studies in vivo are needed to confirm the high accuracy rate of OCT.

Application of Indocyanine Green Fluorescence Imaging Combined with Laparoscopic Ultrasound in Laparoscopic Microwave Ablation of Liver Cancer.

BACKGROUND The aim of this study was to assess the effect of indocyanine green (ICG) fluorescence imaging combined with laparoscopic ultrasound in laparoscopic microwave ablation of liver cancer. MATERIAL AND METHODS This study retrospectively analyzed 61 patients who underwent laparoscopic microwave ablation of liver cancer, including laparoscopic microwave ablation with and without ICG fluoroscopy. RESULTS The operative times, ablation times, postoperative hospital stay, postoperative complication rate, hospitalization cost, postoperative liver function changes, and postoperative overall survival were similar between the 2 groups, but there was a statistically significant difference in recurrence-free survival (P<0.05). A total of 5 lesions were found in the fluorescence laparoscopy group that were not found by preoperative imaging, while no new lesions were found in the ordinary laparoscopy group. Fluorescence laparoscopy has obvious advantages over ordinary laparoscopy in finding small lesions that were not found before surgery. In terms of complete ablation rate, 3 patients in the ordinary laparoscopy group and 1 patient in the fluorescence laparoscopy group were judged to be incompletely ablated and were ablated again at 1 month after the operation. CONCLUSIONS For small hepatocellular carcinoma with severe liver cirrhosis and located on the liver surface, fluorescence laparoscopy can better reveal the location and boundary of the tumor, and fluorescence laparoscopy can detect tiny lesions that cannot be detected by preoperative imaging. The combination of fluorescence laparoscopy and microwave ablation has a good effect on the treatment of small hepatocellular carcinoma located on the surface of the liver that is difficult to distinguish.

Research progress on the synthesis and pharmacology of 1,3,4-oxadiazole and 1,2,4-oxadiazole derivatives: a mini review.

Oxadiazole is a five-membered heterocyclic compound containing two nitrogen atoms and one oxygen atom. The 1,3,4-oxadiazole and 1,2,4-oxadiazole have favourable physical, chemical, and pharmacokinetic properties, which significantly increase their pharmacological activity via hydrogen bond interactions with biomacromolecules. In recent years, oxadiazole has been demonstrated to be the biologically active unit in a number of compounds. Oxadiazole derivatives exhibit antibacterial, anti-inflammatory, anti-tuberculous, anti-fungal, anti-diabetic and anticancer activities. In this paper, we report a series of compounds containing oxadiazole rings that have been published in the last three years only (2020-2022) as there was no report or their activities described in any article in 2019, which will be useful to scientists in research fields of organic synthesis, medicinal chemistry, and pharmacology.

Sintilimab plus a bevacizumab biosimilar (IBI305) versus sorafenib in unresectable hepatocellular carcinoma (ORIENT-32): a randomised, open-label, phase 2-3 study.

BACKGROUND: China has a high burden of hepatocellular carcinoma, and hepatitis B virus (HBV) infection is the main causative factor. Patients with hepatocellular carcinoma have a poor prognosis and a substantial unmet clinical need. The phase 2-3 ORIENT-32 study aimed to assess sintilimab (a PD-1 inhibitor) plus IBI305, a bevacizumab biosimilar, versus sorafenib as a first-line treatment for unresectable HBV-associated hepatocellular carcinoma. METHODS: This randomised, open-label, phase 2-3 study was done at 50 clinical sites in China. Patients aged 18 years or older with histologically or cytologically diagnosed or clinically confirmed unresectable or metastatic hepatocellular carcinoma, no previous systemic treatment, and a baseline Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 were eligible for inclusion. In the phase 2 part of the study, patients received intravenous sintilimab (200 mg every 3 weeks) plus intravenous IBI305 (15 mg/kg every 3 weeks). In the phase 3 part, patients were randomly assigned (2:1) to receive either sintilimab plus IBI305 (sintilimab-bevacizumab biosimilar group) or sorafenib (400 mg orally twice daily; sorafenib group), until disease progression or unacceptable toxicity. Randomisation was done using permuted block randomisation, with a block size of six, via an interactive web response system, and stratified by macrovascular invasion or extrahepatic metastasis, baseline α-fetoprotein, and ECOG performance status. The primary endpoint of the phase 2 part of the study was safety, assessed in all patients who received at least one dose of study drug. The co-primary endpoints of the phase 3 part of the study were overall survival and independent radiological review committee (IRRC)-assessed progression-free survival according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 in the intention-to-treat population. The study is registered with ClinicalTrials.gov, NCT03794440. The study is closed to new participants and follow-up is ongoing for long-term outcomes. FINDINGS: Between Feb 11, 2019 and Jan 15, 2020, we enrolled 595 patients: 24 were enrolled directly into the phase 2 safety run-in and 571 were randomly assigned to sintilimab-bevacizumab biosimilar (n=380) or sorafenib (n=191). In the phase 2 part of the trial, 24 patients received at least one dose of the study drug, with an objective response rate of 25·0% (95% CI 9·8-46·7). Based on the preliminary safety and activity data of the phase 2 part, in which grade 3 or worse treatment-related adverse events occurred in seven (29%) of 24 patients, the randomised phase 3 part was started. At data cutoff (Aug 15, 2020), the median follow-up was 10·0 months (IQR 8·5-11·7) in the sintilimab-bevacizumab biosimilar group and 10·0 months (8·4-11·7) in the sorafenib group. Patients in the sintilimab-bevacizumab biosimilar group had a significantly longer IRRC-assessed median progression-free survival (4·6 months [95% CI 4·1-5·7]) than did patients in the sorafenib group (2·8 months [2·7-3·2]; stratified hazard ratio [HR] 0·56, 95% CI 0·46-0·70; p<0·0001). In the first interim analysis of overall survival, sintilimab-bevacizumab biosimilar showed a significantly longer overall survival than did sorafenib (median not reached [95% CI not reached-not reached] vs 10·4 months [8·5-not reached]; HR 0·57, 95% CI 0·43-0·75; p<0·0001). The most common grade 3-4 treatment-emergent adverse events were hypertension (55 [14%] of 380 patients in the sintilimab-bevacizumab biosimilar group vs 11 [6%] of 185 patients in the sorafenib group) and palmar-plantar erythrodysaesthesia syndrome (none vs 22 [12%]). 123 (32%) patients in the sintilimab-bevacizumab biosimilar group and 36 (19%) patients in the sorafenib group had serious adverse events. Treatment-related adverse events that led to death occurred in six (2%) patients in the sintilimab-bevacizumab biosimilar group (one patient with abnormal liver function, one patient with both hepatic failure and gastrointestinal haemorrhage, one patient with interstitial lung disease, one patient with both hepatic faliure and hyperkalemia, one patient with upper gastrointestinal haemorrhage, and one patient with intestinal volvulus) and two (1%) patients in the sorafenib group (one patient with gastrointestinal haemorrhage and one patient with death of unknown cause). INTERPRETATION: Sintilimab plus IBI305 showed a significant overall survival and progression-free survival benefit versus sorafenib in the first-line setting for Chinese patients with unresectable, HBV-associated hepatocellular carcinoma, with an acceptable safety profile. This combination regimen could provide a novel treatment option for such patients. FUNDING: Innovent Biologics. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Lin28 enhances de novo fatty acid synthesis to promote cancer progression via SREBP-1.

Lin28 plays an important role in promoting tumor development, whereas its exact functions and underlying mechanisms are largely unknown. Here, we show that both human homologs of Lin28 accelerate de novo fatty acid synthesis and promote the conversion from saturated to unsaturated fatty acids via the regulation of SREBP-1. By directly binding to the mRNAs of both SREBP-1 and SCAP, Lin28A/B enhance the translation and maturation of SREBP-1, and protect cancer cells from lipotoxicity. Lin28A/B-stimulated tumor growth is abrogated by SREBP-1 inhibition and by the impairment of the RNA binding properties of Lin28A/B, respectively. Collectively, our findings uncover that post-transcriptional regulation by Lin28A/B enhances de novo fatty acid synthesis and metabolic conversion of saturated and unsaturated fatty acids via SREBP-1, which is critical for cancer progression.

The trend of direct medical costs and associated factors in patients with chronic hepatitis B in Guangzhou, China: an eight-year retrospective cohort study.

BACKGROUND: Although the expenses of liver cirrhosis are covered by a critical illness fund under the current health insurance program in China, the medical costs associated with hepatitis B virus (HBV) related diseases is not well addressed. In order to provide evidence to address the problem, we investigated the trend of direct medical costs and associated factors in patients with chronic HBV infection. METHODS: A retrospective cohort study of 65,175 outpatients and 12,649 inpatients was conducted using a hospital information system database for the period from 2008 to 2015. Generalized estimating equations (GEE) were applied to explore associations between annual direct medical costs and corresponding factors, meanwhile quantile regression models were used to evaluate the effect of treatment modes on different quantiles of annual direct medical costs stratified by medical insurances. RESULTS: The direct medical costs increased with time, but the proportion of antiviral costs decreased with CHB progression. Antiviral costs accounted 54.61% of total direct medical costs for outpatients, but only 6.17% for inpatients. Non-antiviral medicine costs (46.06%) and lab tests costs (23.63%) accounted for the majority of the cost for inpatients. The direct medical costs were positively associated with CHB progression and hospitalization days in inpatients. The direct medical costs were the highest in outpatients with medical insurance and in inpatients with free medical service, and treatment modes had different effects on the direct medical costs in patients with and without medical insurance. CONCLUSIONS: CHB patients had a heavy economic burden in Guangzhou, China, which increased over time, which were influenced by payment mode and treatment mode.

Flurbiprofen axetil for postoperative analgesia in upper abdominal surgery: a randomized, parallel controlled, double-blind, multicenter clinical study.

PURPOSE: To investigate the efficacy and safety of flurbiprofen axetil in postoperative analgesia in upper abdominal surgery. METHODS: This was a multicenter, randomized, positive drug parallel controlled double-blind clinical study. Patients undergoing upper abdominal surgery were randomly divided to receive flurbiprofen axetil or tramadol. The VAS pain scores at rest and on coughing (pulmonary function training) were assessed immediately before drug usage (T1) to evaluate the efficacy of postoperative analgesia. Repeat assessment of the VAS was performed after T1. The timing of the recovery of the gastrointestinal function and the preoperative and postoperative IL-6, cortisol, and blood glucose levels were recorded as secondary endpoints. Vital signs and the occurrence of adverse reactions were evaluated for the assessment of safety. RESULTS: A total of 240 patients were enrolled in the current study; 119 used flurbiprofen axetil for postoperative analgesia. The VAS scores at rest and on coughing did not differ between the two groups to a statistically significant extent (P > 0.05). However, the reduction of the VAS score at rest in the flurbiprofen axetil group was greater than that in the tramadol group at 4-24 h after T1. The reduction of the VAS score on coughing at 8 h after T1 was greater in the flurbiprofen axetil group. The incidence of adverse reactions was significantly lower in the flurbiprofen axetil group, with only one adverse reaction recorded. In contrast, 18 adverse reactions were reported in the tramadol group. CONCLUSION: Flurbiprofen axetil showed superior efficacy to tramadol in early postoperative analgesia after upper abdominal surgery. Flurbiprofen axetil was associated with a significantly lower incidence of adverse reactions in comparison to tramadol.

Expression of Rho Guanine Nucleotide Exchange Factor 39 (ARHGEF39) and Its Prognostic Significance in Hepatocellular Carcinoma.

BACKGROUND Previous studies have reported that ARHGEF39 might be frequently upregulated in different cancer types and relevant to cancer progression. However, the expression pattern and clinicopathological features of ARHGEF39 in patients with hepatocellular carcinoma (HCC) needs further exploration. MATERIAL AND METHODS ARHGEF39 expression level of HCC in The Cancer Genome Atlas (TCGA) dataset was analyzed. Quantitative real-time polymerase chain reaction and immunohistochemistry were employed to determine ARHGEF39 mRNA and protein levels in our own study collected HCC tissues and matched non-cancerous tissues. Moreover, the association of ARHGEF39 expression with the clinicopathological factors and prognosis of HCC were investigated. RESULTS The level of ARHGEF39 in HCC tissues was significantly higher than that in adjacent normal tissues (P<0.05) from TCGA database. High level of ARHGEF39 was a significant prognostic factor of poor overall survival (OS) (TCGA, P=0.006). Consistently, the expression levels of ARHGEF39 mRNA and protein in HCC specimens were significantly higher than those in adjacent liver specimens (P<0.05) from our cohort. Further analysis revealed that high ARHGEF39 level was significantly associated with poor OS (P<0.001) and short disease-free survival (DFS) (P<0.001). Cox multivariate analysis indicated that ARHGEF39 was an independent, unfavorable prognostic factor (P=0.000) of OS and DFS. CONCLUSIONS ARHGEF39 might act as an oncogene in the progression of HCC and might serve as a promising potential prognostic indicator and therapeutic target for HCC.

Effectiveness of Parecoxib Sodium Combined with Transversus Abdominis Plane Block for Pain Management After Hepatectomy for Hepatocellular Carcinoma: A Prospective Controlled Study.

BACKGROUND This study aimed to investigate the effectiveness of perioperative parecoxib sodium combined with transversus abdominis plane (TAP) block on postoperative pain management following hepatectomy in patients with hepatocellular carcinoma (HCC). MATERIAL AND METHODS One hundred patients with HCC who underwent hepatectomy were randomized into a study group (n=51) and a control group (n=49). The study group received 40 mg of parecoxib sodium 30 minutes before anesthetic induction, and 150 mg of 0.375% ropivacaine with 5 mg dexamethasone as TAP inhibitors, before closing the abdominal incision. The control group received 40 mg of placebo 30 minutes before anesthetic induction, without TAP block. Postoperatively, all patients received patient-controlled intravenous analgesia (PCIA) and evaluation with subjective visual analog scale (VAS) pain scores. Data on adverse events, postoperative ambulation (>6 hours/day), time of flatus and defecation, and hospitalization duration were recorded. RESULTS Pain scores of the study group were significantly lower compared with the control group on the first three postoperative days. No significant differences were found between the two groups in terms of adverse events. In the study group, the number of cases of postoperative ambulation was significantly more than the control group. The onset of flatus and defecation and duration of hospital stay in the study group were significantly shorter in the study group compared with the control group. CONCLUSIONS Parecoxib sodium combined with TAP block effectively reduced postoperative pain, improved ambulation, improved gastrointestinal function, and shortened hospitalization time following hepatectomy in patients with HCC without adverse effects.

Monitoring of the Pesticide Droplet Deposition with a Novel Capacitance Sensor.

Rapid detection of spraying deposit can contribute to the precision application of plant protection products. In this study, a novel capacitor sensor system was implemented for measuring the spray deposit immediately after herbicide application. Herbicides with different formulations and nozzles in different mode types were included to test the impact on the capacitance of this system. The results showed that there was a linear relationship between the deposit mass and the digital voltage signals of the capacitance on the sensor surface with spray droplets. The linear models were similar for water and the spray mixtures with non-ionized herbicides usually in formulations of emulsifiable concentrates and suspension concentrates. However, the ionized herbicides in formulation of aqueous solutions presented a unique linear model. With this novel sensor, it is possible to monitor the deposit mass in real-time shortly after the pesticide application. This will contribute to the precision application of plant protection chemicals in the fields.

Erratum: Wang, P., et al. Monitoring of the Pesticide Droplet Deposition with a Novel Capacitance Sensor. Sensors 2019, 19, 537.

The authors wish to make the following correction to this paper [...].

A Fluorescence Sensor Capable of Real-Time Herbicide Effect Monitoring in Greenhouses and the Field.

Herbicide resistant weeds need to be identified early so that yield loss can be avoided by applying proper field management strategies. A novel chlorophyll-fluorescence-imaging sensor has been developed to conduct real-time herbicide effect evaluation. In this research, greenhouse and field experiments were conducted to calibrate the capability of the sensor in monitoring herbicide effects on different biotypes of two grass weeds (Alopecurus myosuroides, Apera spica-venti) in southwestern Germany. Herbicides with different modes of action were applied for the effect monitoring. Chlorophyll fluorescence yield of the plants was measured 3⁻15 days after treatment (DAT) using the new fluorescence sensor. Visual assessment of the weeds was carried out on 21 DAT. The results showed that the maximal PS II quantum yield (Fv/Fm) of herbicide sensitive weeds was significantly lower than the values of resistant populations in 5 DAT. The new technology was capable of quickly identifying the herbicide's effect on plants. It can be used to optimize management strategies to control herbicide resistant weeds.

Prognostic value of polarized macrophages in patients with hepatocellular carcinoma after curative resection.

As the most predominant tumour-infiltrating immune cells, tumour-associated macrophages (TAMs) are significant for fostering tumour growth, progression and metastasis. CD68-positive TAMs display dissimilarly polarized programmes comprising CD11c-positive pro-inflammatory macrophages (M1) and CD206-positive immunosuppressive macrophages (M2). The aim of this study is to determine the prognostic significance of diametrically polarized TAMs in hepatocellular carcinoma (HCC) and their application to risk stratification of patients according to their specific prognostic values. This study included 80 consecutive patients with HCC, and we evaluated diametrically polarized functional status of macrophages by immunohistochemical staining of CD68, CD11c and CD206. Prognostic values and clinicopathologic features were assessed in these patients. High versus low CD11c-positive TAM density (P = 0.005) and low versus high CD206-positive TAM density (P = 0.002) were associated with better overall survival, whereas CD68-positive TAM density had no prognostic significance (low versus high, P = 0.065). Furthermore, the presence of these positive staining macrophages did not show any prognostic significance for recurrence-free survival (all P > 0.05). Multivariate Cox regression analysis identified CD11c-positive and CD206-positive TAMs as an independent prognostic factor (P < 0.001, P = 0.031, respectively). Intratumoural infiltration of diametrically polarized TAMs, a novel identified independent prognostic factor for survival in patients with HCC, could be combined with the TNM stage and the Barcelona Clinic Liver Cancer stage to improve a risk stratification system.

ECM1 promotes migration and invasion of hepatocellular carcinoma by inducing epithelial-mesenchymal transition.

BACKGROUND: Extracellular matrix protein 1 (ECM1) is a glycoprotein involved in many biologic processes. To determine the expression of ECM1 in hepatocellular carcinoma (HCC), and to study the role of ECM1 in inducing epithelia-mesenchymal transition (EMT) to analyze the effect of ECM1 on the migration and invasion of HCC cells. METHODS: The expression of ECM1 in HCC specimens was examined by immunohistochemistry staining, and the correlations were analyzed between the expression of ECM1 and the clinicopathological data. The ECM1 expression plasmid was transfected into Bel-7402 cells to induce exogenous overexpression of ECM1 protein. The changes of the expression of ECM1, EMT-related protein (E-cadherin, Vimentin), in Bel-7402 cells were detected by Western blot after transfection of ECM1; the wound healing and invasion assay in vitro were used to determine the role of ECM1 gene transfection on the ability of migration and invasive potential of Bel-7402 cells. RESULTS: Immumohistochemistry staining method displayed the ECM1 expression was positively associated with vascular invasion, TNM stage, and poor prognosis. A significant positive correlation was found between the expressions of ECM1 and Vimentin. After ECM1 overexpression, Western blot exhibited that the expression of E-cadherin was down-regulated and Vimentin expression was up-regulated in Bel-7402 cells; the wound healing and invasion assay showed that the migration and invasion potentials of Bel-7402 cells were significantly enhanced. CONCLUSIONS: ECM1, which displayed a high expression in HCC specimens, was closely associated with clinicopathologic data and may promote migration and invasion of HCC cells by inducing EMT.