Transcatheter arterial chemoembolisation combined with lenvatinib and cabozantinib in the treatment of advanced hepatocellular carcinoma.

OBJECTIVE: The objective of this study was to evaluate the effect and prognosis of transcatheter arterial chemoembolisation (TACE) combined with lenvatinib and cabozantinib in the treatment of advanced unresectable hepatocellular carcinoma (uHCC) and identify the predictors of prognosis related to cellular inflammation and body mass index (BMI). To the best of our knowledge, this is the first study to report the efficacy and prognosis of TACE combined with lenvatinib and cabozantinib in patients with uHCC and propose the neutrophil-to-lymphocyte ratio (NLR) and the platelet-to-lymphocyte ratio (PLR) as predictors of response and survival outcomes in this context. METHODS: The clinicopathologic data of 217 patients with advanced uHCC who underwent TACE combined with systemic therapy (lenvatinib mesylate + cabozantinib) in the Department of Hepatobiliary Surgery, Dazhou Central Hospital between October 2017 and February 2020 were collected retrospectively, and the relevant parameters were analysed and compared. RESULTS: Univariate and multivariate logistic regression analyses showed that BMI, NLR, PLR and prothrombin time were independent factors for the objective response rate (ORR) of transformed therapy for uHCC (OR = 0.812 vs 1,290.68 vs 1.067 vs 0.626, 95 % CI: 0.719-0.897 vs 108.081-11,541.137 vs 1.037-1.099 vs 0.414-0.946, respectively, p < 0.05). The results showed that BMI, NLR and PLR had certain predictive values for the ORR in patients with liver cancer undergoing translational therapy (p < 0.05); the combined predictive effect of the three was the best, and the area under the curve (AUC) of BMI + NLR + PLR for predicting the ORR in patients with liver cancer undergoing translational therapy was 0.951 (95 % CI: 0.921, 0.964). A total of 181 patients experienced adverse reactions at different grades, including 104 cases at grade 1, 50 cases at grade 2, 22 cases at grade 3 and 5 cases at grade 4. There was a significant difference in overall survival (OS) between low- and high-NLR groups, low- and high-PLR groups and low- and high-BMI groups (χ2 = 9.644, 8.313 and 10.314, respectively, p < 0.05). There was a significant difference in progression-free survival (PFS) between the low- and high-NLR groups, the low- and high-PLR groups and the low- and high-BMI groups (χ2 = 8.965, 9.783 and 6.343, respectively, p < 0.05). CONCLUSION: Transcatheter arterial chemoembolisation combined with lenvatinib and cabozantinib is safe and effective in the treatment of advanced uHCC, with controllable adverse reactions. High NLR and PLR and low BMI values before treatment were independent risk factors for the ORR. Body mass index, NLR and PLR predicted responses to triple switch therapy and survival outcomes in uHCC. Patients with pretreatment NLR ≥ 2.96 and PLR ≥ 184.41 had worse OS and PFS rates. Patients with pretreatment BMI ≥ 23 kg/m2 had improved OS and a reduced risk of death.

Using Normalized Carcinoembryonic Antigen and Carbohydrate Antigen 19 to Predict and Monitor the Efficacy of Neoadjuvant Chemotherapy in Locally Advanced Gastric Cancer.

Carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9) are established prognostic biomarkers for patients with gastric cancer. However, their potential as predictive markers for neoadjuvant chemotherapy (NACT) efficacy has not been fully elucidated. METHODS: We conducted a retrospective analysis to determine values of CEA and CA19-9 prior to NACT (pre-NACT) and after NACT (post-NACT) in 399 patients with locally advanced gastric cancer (LAGC) who received intended NACT and surgery. RESULTS: Among the 399 patients who underwent NACT plus surgery, 132 patients (33.1%) had elevated pre-NACT CEA/CA19-9 values. Furthermore, either pre-NACT or post-NACT CEA /CA19-9 levels were significantly associated with prognosis (p = 0.0023) compared to patients with non-elevated levels. Moreover, among the patients, a significant proportion (73/132, 55.3%) achieved normalized CEA/CA19-9 following NACT, which is a strong marker of a favorable treatment response and survival benefits. In addition, the patients with normalized CEA/CA19-9 also had a prolonged survival compared to those who underwent surgery first (p = 0.0140), which may be attributed to the clearance of micro-metastatic foci. Additionally, the magnitude of CEA/CA19-9 changes did not exhibit a statistically significant prognostic value. CONCLUSIONS: Normalization of CEA/CA19-9 is a strong biomarker for the effectiveness of treatment, and can thus be exploited to prolong the long-term survival of patients with LAGC.

Pathological α-synuclein accumulation, CSF metabolites changes and brain microstructures in cynomolgus monkeys treated with 6-hydroxydopamine.

The lack of evidence indicating the accumulation of phosphorylated α-synuclein (P-α-syn), a neuropathological hallmark of Parkinson disease (PD), limits the application of 6-OHDA animal models. In cynomolgus monkeys received unilateral 6-hydroxydopamine (6-OHDA) injection, we identified nigrostriatal dysfunction related behavioral defects, such as the increase of PD score, decrease of locomotor activities, and exhibition of typical rotations. We found the dopaminergic neurons were significantly reduced and had fragmented morphology in substantia nigra (SN). Furthermore, insoluble P-α-syn aggregates were observed. The P-α-syn aggregates were extracellular distributed and had typical morphology of inclusion. Immunofluorescence staining showed that the P-α-syn colocalized with ubiquitin (Ub) and p62. We also found there were more actived astrocytes and microglial in SN and striatum, reflecting neuroinflammations increase in nigrostriatal pathway. At last, to determine the long-term consequence of dopamine (DA) neuron loss induced by 6-OHDA injection, the changes of cerebrospinal fluid (CSF) neurotransmitters over time as well as the brain microstructure alternations were examined. The dopamine-related metabolites were decreased after 6-OHDA injection reflecting dopaminergic neuron loss. The levels of γ-aminobutyric acid (GABA) and acetylcholine (Ach) showed an increasing trend but not significant. By diffusion tensor Magnetic Resonance Imaging (MRI) image scans, the fractional anisotropy (FA) value in the ipsilateral SN and caudate was found to reduce, which indicated neural fiber injury. Therefore, these results suggested that α-syn pathology might participate in process of 6-OHDA injuring DA neurons, and may expand the application of 6-OHDA monkeys on investigations into the pathogenesis of PD.

EGF/bFGF promotes survival, migration and differentiation into neurons of GFP-labeled rhesus monkey neural stem cells xenografted into the rat brain.

Stem cell replacement therapy is considered a promising treatment for diseases of the central nervous system. Improving the ratio of surviving transplanted cells and the efficiency of differentiation into functional neuronal cells are the most important issues related to research on neuroregenerative medicine. Epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF) have been reported to promote the proliferation and differentiation of neural stem cells (NSCs) in vitro, but whether they have the same effect in vivo is unclear. In this study, NSCs derived from rhesus monkey embryonic stem cells (ESCs) were resuspended in medium with or without EGF/bFGF and xenotransplanted into the rat striatum. No behavioral abnormalities or teratoma formation were observed in the recipient engrafted rats. GFP-labeled cells exhibited a higher survival rate and longer migration in the EGF/bFGF group than control group at 2 months after transplantation. Moreover, the percentages of Tuj1+ neurons and Map2+ neurons in the EGF/bFGF group were significantly higher than those in the control group, while the percentages of astrocytes and oligodendrocytes were significantly lower in the EGF/bGFG group than control group. These findings indicated that EGF/bFGF can promote protrusion of nerve fibers and the survival and neuronal differentiation of transplanted NSCs in the recipient brain, suggesting that EGF/bFGF has a potential application for stem cell therapy.

A Novel Classification and Scoring Method Based on Immune-Related Transcription Factor Regulation Patterns in Gastric Cancer.

Background: Transcription factors (TFs) play a crucial role in tumorigenesis and anti-tumor immunity. However, the potential role of large-scale transcription factor regulation patterns in the progression in gastric cancer (GC) is unknown. Methods: We comprehensively assessed the relevance of immune-related TF (IRTF) regulation patterns in anti-tumor immunity and immunotherapy in 1,136 gastric cancer (GC) patients, and evaluated the IRTF score based on IRTF regulation patterns using random forests. Results: Two distinct IRTF regulation patterns were identified, which demonstrating the distinct characteristics in clinical phenotypes, tumor immune microenvironment (TIME), immunogenicity and prognosis in GC. Subsequently, the IRTF score was established to quantify the IRTF regulation pattern for each GC patient. Analysis of large conventional therapy cohorts showed low IRTF score was associated with a better prognosis. In addition, analysis of multiple immunotherapy cohorts showed low IRTF score was also linked to enhanced response to immunotherapy. Conclusion: TF regulation patterns were found to play an important role in the complex immune regulatory relationships in GC. Evaluation of the IRTF regulation patterns in patients will enhance our understanding of immune specificities, and thus, provide effective strategies for personalized therapy.

Altered peripheral factors affecting the absorption, distribution, metabolism, and excretion of oral medicines in Alzheimer's disease.

Alzheimer's disease (AD) has traditionally been considered solely a neurological condition. Therefore, numerous studies have been conducted to identify the existence of pathophysiological changes affecting the brain and the blood-brain barrier in individuals with AD. Such studies have provided invaluable insight into possible changes to the central nervous system exposure of drugs prescribed to individuals with AD. However, there is now increasing recognition that extra-neurological systems may also be affected in AD, such as the small intestine, liver, and kidneys. Examination of these peripheral pathophysiological changes is now a burgeoning area of scientific research, owing to the potential impact of these changes on the absorption, distribution, metabolism, and excretion (ADME) of drugs used for both AD and other concomitant conditions in this population. The purpose of this review is to identify and summarise available literature reporting alterations to key organs influencing the pharmacokinetics of drugs, with any changes to the small intestine, liver, kidney, and circulatory system on the ADME of drugs described. By assessing studies in both rodent models of AD and samples from humans with AD, this review highlights possible dosage adjustment requirements for both AD and non-AD drugs so as to ensure the achievement of optimum pharmacotherapy in individuals with AD.

Application of polymeric porcelain color-masking cast posts in the aesthetic repair of anterior teeth: a case report.

Many patients with large-area tooth defect need cast post-core crown restoration. However, the color defect of the cast post-core will affect the final restorative result, especially that of the anterior teeth. A new technology of color masking by applying CERAMAGE polymeric porcelain to the cast metal post-core surface improves the color of a full-ceramic restoration of anterior teeth and may provide a new alternative for the aesthetic repair of anterior teeth with a large area of defective tooth.

[Uprighting a mesially tilted mandibular second molar by using a dental implant as anchorage: a case report].

After tooth has been removed for a long time, adjacent teeth may tilt to occupy the edentulous space, leading to a break in the occlusal 3D equilibrium and a lack of restorative space. This case report presents a mandibular second molar uprighting with anchorage from a dental implant.

[Expert consensus on biomechanical research of dental implant].

Current biomechanical research of dental implants focuses on the mechanical damage and enhancement mechanism of the implant-abutment interface as well as how to obtain better mechanical strength and longer fatigue life of dental implants. The mechanical properties of implants can be comprehensively evaluated by strain gauge analysis, photo elastic stress analysis, digital image correlation, finite element analysis, implant bone bonding strength test, and measurement of mechanical properties. Finite element analysis is the most common method for evaluating stress distribution in dental implants, and static pressure and fatigue tests are commonly used in mechanical strength test. This article reviews biomechanical research methods and evaluation indices of dental implants. Results provide methodology guidelines in the field of biomechanics by introducing principles, ranges of application, advantages, and limitations, thereby benefitting researchers in selecting suitable methods. The influencing factors of the experimental results are presented and discussed to provide implant design ideas for researchers.

A unique tetranuclear Ag(i) complex emitting efficient thermally activated delayed fluorescence with a remarkably short decay time.

A novel tetranuclear Ag(i) complex, [Ag4(µ-DMPTP)2(POP)3][BF4]2 (Ag4N2P3), has been designed to achieve highly efficient thermally activated delayed fluorescence (TADF). Photophysical investigations show that the compound exhibits highly efficient TADF (Φ = 76%) and has a very short ambient-temperature TADF decay time of only 0.65 µs, corresponding to a radiative decay rate of k = Φ/τ = 1.2 × 106 s-1, a value belonging to the fast radiative rates in TADF materials.

Microwatts continuous-wave pumped second harmonic generation in few- and mono-layer GaSe.

We demonstrate the first achievement of continuous-wave (CW) pumped second harmonic generation (SHG) in few- and mono-layer gallium selenide (GaSe) flakes, which are coated on silicon photonic crystal (PC) cavities. Because of ultrahigh second order nonlinearity of the two-dimensional (2D) GaSe and localized resonant mode in the PC cavity, SHG's pump power is greatly reduced to microwatts. In a nine-layer GaSe coated PC cavity, while the optical power inside the GaSe flake is only 1.5% of that in the silicon PC slab, the SHG in GaSe is more than 650 times stronger than the third harmonic generation in silicon slab, indicating 2D GaSe's great potentials to strengthen nonlinear processes in silicon photonics. Our study opens up a new view to expand 2D materials' optoelectronic applications in nonlinear regime and chip-integrated active devices.

Celastrol protects TGF-ß1-induced endothelial-mesenchymal transition.

The endothelial-to-mesenchymal transition (EndMT) in endothelial cells contributes to the development of cardiac fibrosis, ultimately leading to cardiac remodeling. In this study, the effects and molecular mechanisms of celastrol (CEL) on transforming growth factor-ß1 (TGF-ß1)-induced EndMT in human umbilical vein endothelial (HUVEC-12) cells were investigated. The presented data demonstrated that CEL significantly blocked the morphology change of HUVEC-12 cells induced by TGF-ß1 without cell cytotoxicity. In accordance with these findings, CEL blocked TGF-ß1-induced EndMT as evidenced by the inhibition of the mesenchymal markers, including collagen I, III, α-SMA, fibronectin mRNA expression, and the increase in the mRNA expression of endothelial cell marker CD31. These changes were also confirmed by double immunofluorescence staining of CD31 and vimentin. The in vitro scratch assay showed that CEL inhibited the migration capacity of the transitioned endothelial cells induced by TGF-ß1. Further experiments showed that the beneficial effect of CEL on blocking the EndMT in HUVEC-12 cells was associated with the suppression of the TGF-ß1/Smads signalling pathway, which was also confirmed by the inhibition of its downstream transcription factor snail1, twist1, twist2, ZEB1 and ZEB2. These results indicate that CEL blocks TGF-ß1-induced EndMT through TGF-ß1/Smads signalling pathway and suggest that it may be a feasible therapy for cardiac fibrosis diseases.

Efficacy and safety analysis of new P2Y12 inhibitors versus clopidogrel in patients with percutaneous coronary intervention: a meta-analysis.

OBJECTIVE: New P2Y12 inhibitors, classified as oral (prasugrel and ticagrelor) and intravenous (cangrelor and elinogrel) drugs, have shown improved antithrombotic effects compared with clopidogrel in patients with acute coronary syndrome (ACS) or patients undergoing percutaneous coronary intervention (PCI) in landmark trials. The purpose of this study was to perform a meta-analysis of randomized trials that compared new P2Y12 inhibitors with clopidogrel to determine their efficacy and safety in patients undergoing PCI. METHODS: Randomized controlled trials of at least 4 weeks, comparing new P2Y12 inhibitors with clopidogrel in PCI, were identified using the electronic databases Cochrane Central Register of Controlled Trials, Medline, PubMed, Web of Science, and Google Scholar from January 1, 1980, to July 31, 2014. MAIN OUTCOME MEASURES: The primary efficacy endpoints were all-cause death and major adverse cardiovascular events (MACEs). The primary safety endpoint was thrombolysis in myocardial infarction (TIMI) major bleeding. RESULTS: Twelve studies including 71,097 patients met the inclusion criteria. New P2Y12 inhibitors significantly reduced all-cause death (odds ratio [OR]: 0.81; 95% confidence interval [CI] 0.73-0.90, p < 0.0001), MACEs (OR 0.81; 95% CI 0.73-0.90, p < 0.0001), stent thrombosis (OR 0.58; 95% CI 0.49-0.69, p < 0.00001), myocardial infarctions (OR 0.87; 95% CI 0.76-0.99, p = 0.03) and cardiovascular death (OR 0.82; 95% CI 0.73-0.92, p = 0.001) compared with clopidogrel. There were no significant differences between stroke (OR 0.87; 95% CI 0.72-1.05, p = 0.14) and major bleeding events (OR 1.22; 95% CI 0.99-1.52, p = 0.06) between the new P2Y12 inhibitor and clopidogrel groups. CONCLUSION: New P2Y12 inhibitors decreased death in patients undergoing PCI compared with clopidogrel with a considerable safety and tolerability profile; however, the risk/benefit ratio of ischemic and bleeding events should be further investigated.

A new scheme with infusion of hepatitis B immunoglobulin combined with entecavir for prophylaxis of hepatitis B virus recurrence among liver transplant recipients.

OBJECTIVE: Liver transplantation significantly increases recurrence of hepatitis B virus (HBV) among high-risk patients. Hepatitis B immunoglobulin (HBIG) and antiviral nucleotide analogues are effective prophylaxis reagents in preventing HBV recurrence. However, HBV recurrence still occurs with these treatments. METHODS: To explore a more cost-effective prophylaxis protocol in patients after liver transplantation, we treated patients with an initial high dose of 10 000 IU HBIG during the anhepatic phase and a second high dose of HBIG at an optimal time point during surgery. The patients were treated with the traditional European protocol as a control, in which one dose of 10 000 IU HBIG was infused during the anhepatic phase and multiple doses of 10 000 IU HBIG were administered daily for 1 week after liver transplantation. RESULTS: There were two mortalities among 50 patients treated with the new protocol and nine mortalities among 52 patients treated with the European protocol within 3 years after liver transplantation. The new prophylaxis method markedly improved the 3-year survival without HBV recurrence in 50 treated patients. However, there were five recurrences in 52 patients treated with the European protocol. High-risk factors such as HBV DNA+, positive hepatitis B e antigen, and hepatocellular carcinoma were all detected among five patients with HBV recurrence. The suppressed HBV recurrence was associated with significantly lower serum alanine aminotransferase and aspartate aminotransferase in the new protocol-treated patients tested at 1 month and 1 week after liver surgery compared with those treated with the European protocol. CONCLUSION: Infusion of two high doses of HBIG during surgery in combination with entecavir significantly prevented HBV recurrence and improved the 3-year survival after liver transplantation.