Discovery of potent and selective c-Met inhibitors for MET-amplified hepatocellular carcinoma treatment.

Hepatocellular carcinoma (HCC) is a prevalent and lethal malignancy worldwide. The MET gene, which encodes receptor tyrosine kinase c-Met, is aberrantly activated in various solid tumors, including non-small cell lung cancer and HCC. In this study, we identified a novel c-Met inhibitor 54 by virtual screening and structural optimization. Compound 54 showed potent c-Met inhibition with an IC50 value of 0.45 ± 0.06 nM. It also exhibited high selectivity among 370 kinases and potent anti-proliferative activity against MET-amplified HCC cells. Moreover, compound 54 displayed significant anti-tumor efficacy in vivo, making it a potential candidate for HCC treatment in future studies.

Effectiveness and Safety of Different Postoperative Adjuvant Regimens in Patients with Low-Grade Gliomas: A Network Meta-Analysis.

OBJECTIVE: This study aimed to investigate the effectiveness and safety of various adjuvant regimens in patients with low-grade gliomas and to further explore the optimal adjuvant treatment for patients with low-grade gliomas and the differences in the efficacy of each treatment regimens in different tumor types. METHODS: A comprehensive search of the PubMed, Cochrane Library, Ovid, Embase, and Web of Science databases was conducted to screen randomized and nonrandomized controlled trials related to adjuvant therapy in patients with low-grade gliomas. The Cochrane quality assessment method and the Newcastle-Ottawa Scale were used to assess the quality of the included randomized and nonrandomized controlled trials, respectively. The data from previous studies were extracted using Excel and GetData Graph Digitizer 2.26 software, and network meta-analysis was performed using RevMan 5.3 and Stata 16.0 statistical software. RESULTS: The specific ranking of 5-year progression-free survival (5-year PFS) for each treatment regimen from the best to the worst in patients with low-grade gliomas was surgery (S) combined with procarbazine, lomustine, and vincristine (S + PCV); surgery combined with standard radiotherapy and PCV multidrug chemotherapy (S + RT + PCV); surgery combined with standard radiotherapy and temozolomide monotherapy (S + RT + TMZ); surgery combined with enhanced radiotherapy (S + H-RT); surgery combined with standard radiotherapy (S + RT); surgery combined with TMZ (S + TMZ); and S. The 5-year overall survival (OS) ranking was S + RT + TMZ, S + RT + PCV, surgery combined with enhanced radiotherapy and TMZ monotherapy (S + H-RT + TMZ), S + H-RT, S + RT, and S. The 2-year progression-free survival ranking was S + RT + TMZ, S + PCV, S + RT, S + RT + PCV, S + TMZ, S + H-RT, and S. The 2-year overall survival ranking was S + RT + TMZ, S + H-RT + TMZ, S + RT, S + RT + PCV, S + H-RT, and S. The incidence of adverse events (≥3) was ranked from highest to lowest as follows: S + RT + PCV, S + RT + TMZ, S + PCV, S + H-RT, S + TMZ, and S + RT. In the isocitrate dehydrogenase 1/2 mutation nonchromosome 1p and 19q chromosome whole arm codeletion (IDHmt/noncoder) group, the S + RT + PCV and S + H-RT regimens had better 5-year PFS and 5-year OS. In the isocitrate dehydrogenase 1/2 mutation and chromosome 1p and 19q chromosome whole arm codeletion (IDHmt/coder) group, the 5-year PFS of each treatment regimen ranked from the best to the worst was S + RT + TMZ, S + RT + PCV, S + H-RT, S + RT, S + TMZ, and S. The order of 5-year OS from the best to the worst was S + H-RT, S + RT + TMZ, S + RT + PCV, S + RT, and S. In the isocitrate dehydrogenase 1/2 wild-type (IDHwt) group, the S + H-RT and S + TMZ regimens had better 5-year PFS. CONCLUSIONS: This study revealed that both the S + RT + TMZ and S + RT + PCV regimens might be effective therapies for treating patients with low-grade gliomas. Among these, the S + RT + TMZ regimen seemed to be safer but might lead to tumor deterioration. In the IDHmt/coder type, the S + RT + TMZ scheme might have a significant advantage. In the IDHmt/noncoder type, the S + RT + PCV scheme might be more dominant, while in the IDHwt type, the S + H-RT and S + TMZ schemes also might be good treatment options.

Photoacoustic spectroscopy-based ppb-level multi-gas sensor using symmetric multi-resonant cavity photoacoustic cell.

In this paper, we propose and experimentally demonstrate a symmetric multi-resonant cavity photoacoustic cell (MR-PAC) with dual microphones detection, based on multi-resonator photoacoustic spectroscopy (MR-PAS). The designed photoacoustic cell contains three interconnected acoustic resonators to facilitate simultaneous control of three lasers for multi-gas sensing. Two microphones are symmetrically located at both sides of photoacoustic cell to implement two-point detection. The length of acoustic resonator is about 50 mm to minimize the photoacoustic cell, and the resonant frequency is around 3000 Hz. Feasibility and performance of the MR-PAC was demonstrated by simultaneous detection of C2H2, NO and CF4 using a near infrared diode laser and two mid infrared quantum cascade lasers. The minimum detection limits (MDLs) of C2H2, NO and CF4 are 480 ppb, 260 ppb and 0.57 ppb respectively with a 1 s integration time at normal atmospheric pressure. This minimized MR-PAS system is promising for the portable multi-gas sensing.

Laser Linewidth Analysis and Filtering/Fitting Algorithms for Improved TDLAS-Based Optical Gas Sensor.

Tunable Diode Laser Absorption Spectroscopy (TDLAS) has been widely applied in in situ and real-time monitoring of trace gas concentrations. In this paper, an advanced TDLAS-based optical gas sensing system with laser linewidth analysis and filtering/fitting algorithms is proposed and experimentally demonstrated. The linewidth of the laser pulse spectrum is innovatively considered and analyzed in the harmonic detection of the TDLAS model. The adaptive Variational Mode Decomposition-Savitzky Golay (VMD-SG) filtering algorithm is developed to process the raw data and could significantly eliminate the background noise variance by about 31% and signal jitters by about 12.5%. Furthermore, the Radial Basis Function (RBF) neural network is also incorporated and applied to improve the fitting accuracy of the gas sensor. Compared with traditional linear fitting or least squares method (LSM), the RBF neural network brings along the enhanced fitting accuracy within a large dynamic range, achieving an absolute error of below 50 ppmv (about 0.6%) for the maximum 8000 ppmv methane. The proposed technique in this paper is universal and compatible with TDLAS-based gas sensors without hardware modification, allowing direct improvement and optimization for current optical gas sensors.

Feedback loop promotes sucrose accumulation in cotyledons to facilitate sugar-ethylene signaling-mediated, etiolated-seedling greening.

De-etiolation is indispensable for seedling survival and development. However, how sugars regulate de-etiolation and how sugars induce ethylene (ET) for seedlings to grow out of soil remain elusive. Here, we reveal how a sucrose (Suc) feedback loop promotes de-etiolation by inducing ET biosynthesis. Under darkness, Suc in germinating seeds preferentially induces 1-amino-cyclopropane-1-carboxylate synthase (ACS7; encoding a key ET biosynthesis enzyme) and associated ET biosynthesis, thereby activating ET core component ETHYLENE-INSENSITIVE3 (EIN3). Activated EIN3 directly inhibits the function of Suc transporter 2 (SUC2; a major Suc transporter) to block Suc export from cotyledons and thereby elevate Suc accumulation of cotyledons to induce ET. Under light, ET-activated EIN3 directly inhibits the function of phytochrome A (phyA; a de-etiolation inhibitor) to promote de-etiolation. We therefore propose that under darkness, the Suc feedback loop (Suc-ACS7-EIN3-|SUC2-Suc) promotes Suc accumulation in cotyledons to guarantee ET biosynthesis, facilitate de-etiolation, and enable seedlings to grow out of soil.

Efficacy and Safety of Bevacizumab Combined with Other Therapeutic Regimens for Treatment of Recurrent Glioblastoma: A Network Meta-analysis.

BACKGROUND: Despite the fact that bevacizumab (Bev) has been approved to treat recurrent glioblastoma, patients have failed to demonstrate a significant overall survival (OS) advantage. In recent years, the advent of more Bev combination regimens seems to bring new hope for patients; nevertheless, there is still a lack of intuitive comparison among these therapies. OBJECTIVE: To explore the efficacy and safety of various Bev combination regimens in patients with recurrent glioblastoma and to further explore the differences in the efficacy of each treatment in randomized controlled trials (RCTs) and nonrandomized controlled trials (non-RCTs). METHODS: We comprehensively searched the PubMed, Cochrane Library, and OVID databases for relevant RCTs and non-RCTs of Bev in combined regimens for recurrent glioblastoma. The Cochrane quality assessment method was used to assess the quality of RCTs, and the Newcastle-Ottawa scale was used to assess the quality of non-RCTs. Excel software was used to extract data from the literature, and a network meta-analysis was performed using RevMan 5.3 and Stata 16 statistical software. RESULTS: In patients with recurrent glioblastoma, the 6-month OS of patients receiving bevacizumab combination therapy was ranked from high to low as follows: Bev + rindopepimut, Bev + lomustine (CCNU), CCNU, tumor treating fields + Bev, Bev, Bev + irinotecan (Iri), Bev + temozolomide (TMZ), Bev + vorinostat, Bev + onartuzumab, Bev + dasatinib, Bev + carboplatin, Bev + trebananib, Bev + VB-111, TMZ, PCV, VB-111, and carboplatin. The 6-month progression-free survival from high to low was ranked as follows: Bev + CCNU, Bev + rindopepimut, Bev + dasatinib, Bev + vorinostat, Bev, Bev + Iri, Bev + TMZ, CCNU, Bev + carboplatin, TMZ, Bev + VB-111, PCV, Bev + trebananib, carboplatin, and VB-111. We compared the total incidence of serious adverse events (≥3) and found that Bev + vorinostat and Bev + trebananib were safer than Bev, while other regimens were not as safe as Bev. A descriptive analysis showed that Bev + rindopepimut also appeared to be safer than Bev. In subgroup analysis, among RCTs, Bev + CCNU therapy had the highest 6-month OS and 6-month progression-free survival. Among non-RCTs, Bev + Iri therapy showed the highest 6-month OS and good 6-month progression-free survival. CONCLUSIONS: Both Bev + CCNU and Bev + rindopepimut could be considered as effective therapies for treating the recurrent glioblastoma according to the network meta-analysis results. Among them, Bev + rindopepimut therapy seems to be safer and more effective. Moreover, we found that Bev + Iri also appeared to be an effective therapy in a retrospective study.

[Systematic review and Meta-analysis of efficacy and safety of acupuncture therapy on hypertensive intracerebral hemorrhage].

To systematically review the efficacy and safety of acupuncture combined with minimally invasive surgery or basic the-rapy in treating hypertensive intracerebral hemorrhage(HICH) patients compared with minimally invasive surgery or basic treatment. In this study, the four Chinese databases, the four English databases, Chinese Clinical Trial Registry and ClinicalTrail.gov, all above were systematically and comprehensively retrieved from the time of database establishment to September 10, 2020. Rando-mized controlled trials(RCTs) were screened out according to inclusion criteria and exclusion criteria established in advanced. The methodological quality of included studies was evaluated by the tool named "Cochrane bias risk assessment 6.1". Meta-analysis of the included studies was performed using RevMan 5.4, and the quality of outcome indicators was evaluated by the GRADE system. Finally, 17 studies were included, involving 1 852 patients with HICH, and the overall quality of the included studies was not high. According to Meta-analysis,(1)CSS score of the group of acupuncture combined with minimally invasive surgery or basic therapy was superior to the group of minimally invasive surgery or basic therapy(MD=-3.50,95%CI[-4.39,-2.61],P<0.000 01);(2)NIHSS score of the group of acupuncture combined with minimally invasive surgery or basic therapy was superior to the group of minimally invasive surgery or basic therapy(MD=-4.78,95%CI[-5.55,-4.00],P<0.000 01);(3)the cerebral hematoma volume of the group of acupuncture combined with minimally invasive surgery or basic therapy was superior to the group of minimally invasive surgery or basic therapy(MD=-4.44,95%CI[-5.83,-3.04],P<0.000 01);(4)ADL score of the group of acupuncture combined with minimally invasive surgery or basic therapy was superior to the group of minimally invasive surgery or basic therapy(MD=20.81,95%CI[17.25,24.37],P<0.000 01);(5)the GCS score of the group of acupuncture combined with minimally invasive surgery or basic therapy was superior to the group of minimally invasive surgery or basic therapy(MD=2.41,95%CI[1.90,2.91],P<0.000 01). The GRADE system showed an extremely low level of evidence for the above outcome indicators. Adverse reactions were mentioned only in two literatures, with no adverse reactions reported. The available evidence showed that acupuncture combined with minimally invasive surgery or basic therapy had a certain efficacy in patients of HICH compared with minimally invasive surgery or basic therapy. However, due to the high risk of bias in the included studies, its true efficacy needs to be verified by more high-quality studies in the future.

Pulmonary sequestration with Aspergillus infection presenting as massive hemoptysis and hemothorax with highly elevated carcinoembryonic antigen in pleural effusion that mimics advanced lung malignancy.

BACKGROUND: Pulmonary sequestration (PS) associated with massive hemoptysis, hemothorax, and elevated tumor markers or even lung malignancy has been reported in several studies. These clinical features combined with lung lesions on chest imaging are sometimes hard to differentiate from lung malignancies and often complicate the diagnostic procedure. CASE PRESENTATION: A 45-year-old man with PS presented with massive hemoptysis, hemothorax, and extremely elevated carcinoembryonic antigen (CEA) in pleural effusion was initially misdiagnosed with advanced lung carcinoma, but was ultimately diagnosed with PS with Aspergillus infection. CONCLUSIONS: PS is rarely concurrent with lung cancer; most of the time, it is misdiagnosed as a malignancy, especially when presenting with a fungal infection, which could remarkably elevate CEA in pleural effusion.

Programmed Self-Assembly of Protein-Coated AIE-Featured Nanoparticles with Dual Imaging and Targeted Therapy to Cancer Cells.

Modifying different functional moieties into one platform is a conventional strategy for constructing theranostic systems. However, this strategy usually suffers from the unsatisfied efficiency of each individual function. Herein, a programmed self-assembly strategy is presented to fabricate theranostic nanoparticles, which significantly exhibit a dual-modality imaging function involving fluorescence imaging and magnetic resource imaging (MRI), and an efficient targeted therapy to cancer cells. Fluorescent vesicles are first self-assembled by aggregation-induced emission (AIE)-active molecules. Gd3+, serving as an MRI agent, is subsequently bound to the vesicles to provide highly positive charges, which have been realized to be anticancer active. Thereafter, transferrin (Tf) protein is introduced onto the surface of Gd3+ coordinated vesicles, shielding the positive charges and making the nanoparticles nontoxic to cells. With the assistance of Tf protein, the constructed nanoparticles are specifically targeted to cancer cells. Moreover, Tf proteins further peel off from nanoparticles in lysosomes due to their charge reversion, resulting in highly positive charges and heavy toxicity of nanoparticles to kill cancer cells. In the nanoparticles, each of the functional components acts as double-sided adhesive tape to glue the next layer, so that the abilities of functional components are not compromised. This strategy holds great potential for theranostic nanomedicine.

Scientometric analysis of mTOR signaling pathway in liver disease.

BACKGROUND: The mTOR pathway is vital for homeostasis, metabolism, cancer transplantation and regeneration in the liver. The aim of this study is to use a bibliometric method to reveal current research hotspots and promising future trends in mTOR signaling in liver diseases. METHODS: Publications were searched and downloaded from the Web of Science Core Collection (WOSCC) Database. CiteSpace, Carrot2, and VOSviewer programs were utilized to analyze the contribution of various countries/regions, institutes, and authors; and to reveal research hotspots and promising future trends in this research area. RESULTS: Until May 21, 2019, a total of 2,232 papers regarding mTOR signaling pathway in liver disease were included, and each paper was cited 23.21 times on average. The most active country was the USA. 5 landmark articles with centrality and burstiness were determined by co-citation analysis. Research hotspots included "liver transplantation" "hepatic stellate cell proliferation" "NAFLD" "therapy of HCC". Moreover, six key clusters were discovered during the procedure of "clustering", including "liver transplantation" "protein synthesis" "mTOR inhibitor" "following early cyclosporine withdrawal" "srebp-1 activation", and "hepatocellular cancer". CONCLUSIONS: Various scientific methods were applied to reveal scientific productivity, collaboration, and research hotspots in the mTOR signaling pathway in liver disease. Liver transplantation, hepatic stellate cell proliferation, non-alcoholic fatty liver disease (NAFLD), therapy of hepatocellular carcinoma (HCC), cell growth and autophagy, are research hotspots and are likely to be promising in the next few years. Further studies in this field are needed.

Prognostic factors and predictors of postoperative adjuvant transcatheter arterial chemoembolization benefit in patients with resected hepatocellular carcinoma.

BACKGROUND: Postoperative adjuvant transcatheter arterial chemoembolization (PA-TACE) has improved overall survival (OS) in patients with hepatocellular carcinoma (HCC). However, the prognostic and predictive factors remain unclear. AIM: To assess the prognostic factors and the predictors of PA-TACE benefit for OS in patients with resected HCC. METHODS: Univariate and multivariate analyses were performed to identify the potential prognostic factors for OS. In order to assess the predictive factors of PA-TACE benefit, the interaction variables between treatments for each subgroup were evaluated using the Cox proportional hazards regression model. RESULTS: A total of 378 patients (PA-TACE vs surgery alone, 189:189) from three centers were included after a propensity-score 1:1 matching analysis. Compared to the group receiving surgery alone, PA-TACE prolonged the OS rate in patients with resected HCC (P < 0.001). The Barcelona Clinic Liver Cancer system and ferritin-to-hemoglobin ratio (FHR) were used as the prognostic factors for OS in both groups. Age (P = 0.023) and microscopic vascular invasion (MVI) (P = 0.002) were also identified in the PA-TACE group, while gender (P = 0.027), hepatitis B virus (P = 0.034) and albumin-bilirubin grade (P = 0.027) were also selected in the surgery alone group. In addition, PA-TACE resulted in longer OS than surgery alone across subgroups [all hazard ratios (PA-TACE-to-surgery alone) < 1]. Notably, a significantly prolonged OS following PA-TACE was observed in patients with high FHR (P = 0.038) and without MVI (P = 0.048). CONCLUSION: FHR and Barcelona Clinic Liver Cancer stages were regarded as prognostic factors for OS. Moreover, high FHR and the absence of MVI were important predictive factors, which can be used to assist clinicians in selecting which patients could achieve a better OS with PA-TACE.

Exploration of Efficacy and Safety of Interventions for Intraventricular Hemorrhage: A Network Meta-Analysis.

OBJECTIVE: To explore whether endoscopy surgery (ES) and extraventricular drainage (EVD) combined with intraventricular fibrinolytic (IVF) are superior to EVD alone in patients with intraventricular hemorrhage (IVH) and to determine which procedure is more suitable in such patients. METHODS: We searched the following databases: PubMed, MEDLINE, Ovid, Embase, and Cochrane Library. Randomized controlled trials and nonrandomized studies comparing ≥2 different interventions in patients with IVH were included. The quality of the included studies was assessed. Pairwise and network meta-analysis were performed using software Stata 13.0 and Revman 5.3. RESULTS: Compared with the EVD-alone intervention, the ES regimen, EVD combined with urokinase (UK), and EVD combined with recombinant tissue plasminogen activator (rt-PA) regimens all resulted in better survival and prognosis in patients with IVH. For both survival rate and prognosis, the order from best to worst was ES, EVD combined with UK, EVD combined with rt-PA, and EVD-alone. However, EVD combined with IVF had a high risk of intracranial rebleeding; the order of intracranial rebleeding risk from lowest to highest was ES, EVD-alone, EVD combined with rt-PA, and EVD combined with UK. The risk of intracranial infection in EVD combined with rt-PA was lower than that of EVD-alone, but EVD combined with UK also had a higher risk than did EVD-alone. The risk of intracranial infection from lowest to the highest was ES, EVD combined with rt-PA, EVD-alone, and EVD combined with UK. CONCLUSIONS: Our analysis showed that ES is more suitable for patients with IVH. ES not only improved the survival and prognosis but also had the lowest risk of ventriculoperitoneal shunt and intracranial rebleeding or infection.

Complete duodenal obstruction induced by groove pancreatitis: A case report.

BACKGROUND: Groove pancreatitis (GP) is a type of chronic pancreatitis occurring in an anatomic area between the duodenum, head of the pancreas, and common bile duct. Duodenal obstruction is always caused by malignant pancreatic diseases, such as pancreatic head carcinoma, while is rarely induced by benign pancreatic diseases, such as pancreatitis. CASE SUMMARY: A 39-year-old man presented with a 1-mo history of upper abdominal discomfort. His concomitant symptoms were abdominal distension, postprandial nausea, and vomiting. Contrast-enhanced computed tomography of the abdomen showed thickening of the intestinal wall with enhancement of the descending segment of the duodenum, which could not be clearly differentiated from the head of the pancreas. Upper gastrointestinal radiographs and gastrointestinal endoscopy showed a complete obstruction of the descending duodenum. An operation found that a 3-cm mass was located in the "groove part" of the pancreas and oppressing the descending duodenum. Pancreaticoduodenectomy was performed to relieve the obstruction and thoroughly remove the pancreatic lesions. The pathologic diagnosis was pancreatitis. The patient had an uneventful recovery with no complications. CONCLUSION: Because of the special location and the contracture induced by long-term chronic inflammation, our case reminds surgeons that some benign pancreatic diseases, such as GP, can also present with symptoms similar to those of pancreatic cancer. This knowledge can help to avoid an unnecessary radical operation.