A cortico-collicular circuit for orienting to shelter during escape.

When faced with predatory threats, escape towards shelter is an adaptive action that offers long-term protection against the attacker. Animals rely on knowledge of safe locations in the environment to instinctively execute rapid shelter-directed escape actions1,2. Although previous work has identified neural mechanisms of escape initiation3,4, it is not known how the escape circuit incorporates spatial information to execute rapid flights along the most efficient route to shelter. Here we show that the mouse retrosplenial cortex (RSP) and superior colliculus (SC) form a circuit that encodes the shelter-direction vector and is specifically required for accurately orienting to shelter during escape. Shelter direction is encoded in RSP and SC neurons in egocentric coordinates and SC shelter-direction tuning depends on RSP activity. Inactivation of the RSP-SC pathway disrupts the orientation to shelter and causes escapes away from the optimal shelter-directed route, but does not lead to generic deficits in orientation or spatial navigation. We find that the RSP and SC are monosynaptically connected and form a feedforward lateral inhibition microcircuit that strongly drives the inhibitory collicular network because of higher RSP input convergence and synaptic integration efficiency in inhibitory SC neurons. This results in broad shelter-direction tuning in inhibitory SC neurons and sharply tuned excitatory SC neurons. These findings are recapitulated by a biologically constrained spiking network model in which RSP input to the local SC recurrent ring architecture generates a circular shelter-direction map. We propose that this RSP-SC circuit might be specialized for generating collicular representations of memorized spatial goals that are readily accessible to the motor system during escape, or more broadly, during navigation when the goal must be reached as fast as possible.

Single medium-sized hepatocellular carcinoma treated with sequential conventional transarterial chemoembolization (cTACE) and microwave ablation at 4 weeks versus cTACE alone: a propensity score.

BACKGROUND: Microwave ablation (MWA) is a potentially curative treatment for unresectable patients with hepatocellular carcinoma (HCC) ≤ 3 cm, while its therapeutic efficacy decreases significantly for HCC > 3cm. Previous studies have demonstrated that conventional transarterial chemoembolization (cTACE) combined with MWA (cTACE-MWA) may improve local tumor control rate and reduce the recurrence rate for HCC > 3cm. However, there have been few study designs to analyze the clinical efficacy of cTACE-MWA for medium-sized HCC (3-5cm). Therefore, this study aims to compare the clinical efficacy and safety of cTACE-MWA with cTACE alone for a single medium-sized HCC of 3-5 cm in diameter. METHODS: We retrospectively investigate the data of 90 patients with a single medium-sized HCC who were referred to our hospital and underwent cTACE-MWA or cTACE alone from December 2017 to March 2020. Then, patients were identified with propensity score-matched (1:1). The local tumor response to treatment and time to progression (TTP) were compared using mRECIST criteria between the cTACE-MWA group and the cTACE group. RESULTS: A total of 42 patients were included after matching (cTACE-MWA: 21; cTACE: 21). Comparing with cTACE, cTACE-MWA demonstrate significantly better local tumor control (ORR: 95.2% vs 61.9%, p = 0.02; DCR: 95.2% vs 66.7%, p = 0.045) and TTP (median 19.8 months vs 6.8 months, p < 0.001). The 1- and 2-year cumulative probabilities of OS were 100% and 95% in the cTACE-MWA group, which were significantly higher than those in the cTACE group (95% and 76%) (p = 0.032). Multivariate Cox regression analysis illustrates that cTACE-MWA was associated with better TTP (hazard ratio, 0.28; 95% CI: 0.1, 0.76; p = 0.012), but tumor size was associated with worse TTP (hazard ratio, 1.71; 95% CI: 1.01, 2.89; p = 0.045). CONCLUSIONS: cTACE followed by MWA improved TTP and OS in patients with a single medium-sized HCC, and no major complication was observed in this study.

Parvalbumin and Somatostatin Interneurons Contribute to the Generation of Hippocampal Gamma Oscillations.

γ-frequency oscillations (30-120 Hz) in cortical networks influence neuronal encoding and information transfer, and are disrupted in multiple brain disorders. While synaptic inhibition is important for synchronization across the γ-frequency range, the role of distinct interneuronal subtypes in slow (<60 Hz) and fast γ states remains unclear. Here, we used optogenetics to examine the involvement of parvalbumin-expressing (PV+) and somatostatin-expressing (SST+) interneurons in γ oscillations in the mouse hippocampal CA3 ex vivo, using animals of either sex. Disrupting either PV+ or SST+ interneuron activity, via either photoinhibition or photoexcitation, led to a decrease in the power of cholinergically induced slow γ oscillations. Furthermore, photoexcitation of SST+ interneurons induced fast γ oscillations, which depended on both synaptic excitation and inhibition. Our findings support a critical role for both PV+ and SST+ interneurons in slow hippocampal γ oscillations, and further suggest that intense activation of SST+ interneurons can enable the CA3 circuit to generate fast γ oscillations.SIGNIFICANCE STATEMENT The generation of hippocampal γ oscillations depends on synchronized inhibition provided by GABAergic interneurons. Parvalbumin-expressing (PV+) interneurons are thought to play the key role in coordinating the spike timing of excitatory pyramidal neurons, but the role distinct inhibitory circuits in network synchronization remains unresolved. Here, we show, for the first time, that causal disruption of either PV+ or somatostatin-expressing (SST+) interneuron activity impairs the generation of slow γ oscillations in the ventral hippocampus ex vivo We further show that SST+ interneuron activation along with general network excitation is sufficient to generate high-frequency γ oscillations in the same preparation. These results affirm a crucial role for both PV+ and SST+ interneurons in hippocampal γ oscillation generation.

miR-23b Attenuates LPS-Induced Inflammatory Responses in Acute Lung Injury via Inhibition of HDAC2.

Inflammatory responses play significant role in infectious etiology-induced acute lung injury (ALI). Histone deacetylase 2 is found to be essential and stimulated in lipopolysaccharide (LPS)-induced ALI by regulating proinflammatory cytokines. miR-23b has been demonstrated to be downregulated in LPS-induced inflammatory injury. In this study, we aimed to explore the interaction between miR-23b and HDAC2 and their function in LPS-induced ALI. LPS treatment was induced on murine alveolar macrophage cell line MH-S. Level of miR-23b and HDAC2 were determined by real-time PCR or Western blot. Proinflammatory cytokines expression and secretion were detected by real-time PCR and ELISA assay. The levels of miR-23b and HDAC2 were manipulated by transient transfection of miRNA mimics, shRNA or overexpression vector. The interaction between miR-23b and HDAC2 were tested by Luciferase reporter assay. LPS treatment inhibited miR-23b expression, while increased HDAC2 level in MH-S cells. Proinflammatory cytokines were stimulated by LPS treatment. Knockdown of HDAC2 or overexpression of miR-23b significantly repressed the expression of proinflammatory cytokines induced by LPS. miR-23b could suppress HDAC2 expression by directly targeting to its mRNA. LPS treatment stimulated the inflammatory responses in macrophages through inhibition of miR-23b, enhanced HDAC2 expression and inducing the expression of its downstream targets TNF-α, IL-6, and IL-1ß. Overexpression of miR-23b was sufficient to suppress inflammatory responses by targeting HDAC2, making it a promising therapeutic target to ALI treatment.

MicroRNA-182 Promotes Lipoprotein Lipase Expression and Atherogenesisby Targeting Histone Deacetylase 9 in Apolipoprotein E-Knockout Mice.

BACKGROUND: Lipoprotein lipase (LPL) expressed in macrophages plays an important role in promoting the development of atherosclerosis or atherogenesis. MicroRNA-182 (miR-182) is involved in the regulation of lipid metabolism and inflammation. However, it remains unclear how miR-182 regulates LPL and atherogenesis.Methods and Results:Using bioinformatics analyses and a dual-luciferase reporter assay, we identified histone deacetylase 9 (HDAC9) as a target gene of miR-182. Moreover, miR-182 upregulated LPL expression by directly targetingHDAC9in THP-1 macrophages. Hematoxylin-eosin (H&E), Oil Red O and Masson's trichrome staining showed that apolipoprotein E (ApoE)-knockout (KO) mice treated with miR-182 exhibited more severe atherosclerotic plaques. Treatment with miR-182 increased CD68 and LPL expression in atherosclerotic lesions in ApoE-KO mice, as indicated by double immunofluorescence staining in the aortic sinus. Increased miR-182-induced increases in LPL expression in ApoE-KO mice was confirmed by real-time quantitative polymerase chain reaction and western blotting analyses. Treatment with miR-182 also increased plasma concentrations of proinflammatory cytokines and lipids in ApoE-KO mice. CONCLUSIONS: The results of the present study suggest that miR-182 upregulates LPL expression, promotes lipid accumulation in atherosclerotic lesions, and increases proinflammatory cytokine secretion, likely through targetingHDAC9, leading to an acceleration of atherogenesis in ApoE-KO mice.

MicroRNA-134 actives lipoprotein lipase-mediated lipid accumulation and inflammatory response by targeting angiopoietin-like 4 in THP-1 macrophages.

Angiopoietin-like 4 (Angptl4), a secreted protein, is an important regulator to irreversibly inhibit lipoprotein lipase (LPL) activity. Macrophage LPL contributes to foam cell formation via a so-called"molecular bridge" between lipoproteins and receptors on cell surface. It has been reported that macrophage ANGPTL4 suppresses LPL activity, foam cell formation and inflammatory gene expression to reduce atherosclerosis development. Recently, some studies demonstrated that microRNA-134 is upregulated in atherosclerotic macrophages. Here we demonstrate that miR-134 directly binds to 3'UTR of ANGPTL4 mRNA to suppression the expression of ANGPTL4. To investigate the potential roles of macrophage miR-134, THP-1 macrophages were transfected with miR-134 mimics or inhibitors. Our results showed that LPL activity and protein were dramatically increased. We also found that miR-134 activated LPL-mediated lipid accumulation. Collectively, our findings indicate that miR-134 may regulate lipid accumulation and proinfiammatory cytokine secretion in macrophages by targeting the ANGPTL4 gene. Our results have also suggested a promising and potential therapeutic target for atherosclerosis.

MiR-486 regulates cholesterol efflux by targeting HAT1.

RATIONALE: Excessive cholesterol accumulation in macrophages is a major factor of foam cell formation and development of atherosclerosis. Previous studies suggested that miR-486 plays an important role in cardiovascular diseases, but the underlying mechanism is still unknown. OBJECTIVE: The purpose of this study is to determine whether miR-486 regulates ATP-binding cassette transporter A1 (ABCA1) mediated cholesterol efflux, and also explore the underlying mechanism. METHODS AND RESULTS: Based on bioinformatics analysis and luciferase reporter assay, we transfected miR-486 mimic and miR-486 inhibitor into THP-1 macrophage-derived foam cells, and found that miR-486 directly bound to histone acetyltransferase-1 (HAT1) 3'UTR, and downregulated its mRNA and protein expression. In addition, our studies through transfection with wildtype HAT1 or shHAT1 (short hairpin HAT1) revealed that HAT1 could promote the expression of ABCA1 at both mRNA and protein levels. At the same time, the acetylation levels of the lysines 5 and 12 of histone H4 were upregulated after overexpression with HAT1. Meanwhile, the results of liquid scintillation counter and high performance liquid chromatography (HPLC) showed that miR-486 promoted cholesterol accumulation in THP-1 macrophages. CONCLUSION: These data indicated that miR-486 aggravate the cholesterol accumulation in THP-1 cells by targeting HAT1.

Cystathionine γ-lyase(CSE)/hydrogen sulfide system is regulated by miR-216a and influences cholesterol efflux in macrophages via the PI3K/AKT/ABCA1 pathway.

This study was designed to evaluate whether CSE/H2S system, which is regulated by miR-216a, regulated ABCA1-mediated cholesterol efflux and cholesterol contents in THP-1 macrophages-derived foam cells. Our qPCR and western blotting results showed that CSE/H2S significantly up-regulated the expression of ATP-binding cassette transporter A1 (ABCA1) mRNA and protein via PI3K/AKT pathway in foam cells derived from human THP-1 macrophages. The miR-216a directly targeted 3' untranslated region of CSE. It significantly reduced CSE and ABCA1 expression, and also decreased the phosphorylation of PI3K and AKT. Additionally, cholesterol efflux decreased, and cholesterol levels increased in THP-1 macrophage-derived foam cells in response to treatment with miR-216a. Our study demonstrates that CSE/H2S system is regulated by miR-216a, and regulates ABCA1-mediated cholesterol efflux and cholesterol levels through the PI3K/AKT pathway.

Apelin-13 impedes foam cell formation by activating Class III PI3K/Beclin-1-mediated autophagic pathway.

Apelin-13, an adipokine, promotes cholesterol efflux in macrophages with antiatherosclerotic effect. Autophagy, an evolutionarily ancient response to cellular stress, has been involved in atherosclerosis. Therefore, the purpose of this study was to investigate whether apelin-13 regulates macrophage foam cell cholesterol metabolism through autophagy, and also explore the underlying mechanisms. Here, we revealed that apelin-13 decreased lipid accumulation in THP-1 derived macrophages through markedly enhancing cholesterol efflux. Our study further demonstrated that apelin-13 induced autophagy via activation of Class III phosphoinositide 3-kinase (PI3K) and Beclin-1. Inhibition of Class III PI3K and Beclin-1 suppressed the stimulatory effects of apelin-13 on autophagy activity. The present study concluded that apelin-13 reduces lipid accumulation of foam cells by activating autophagy via Class III PI3K/Beclin-1 pathway. Therefore, our results provide brand new insight about apelin-13 inhibiting foam cell formation and highlight autophagy as a promising therapeutic target in atherosclerosis.

Growth differentiation factor-15 induces expression of ATP-binding cassette transporter A1 through PI3-K/PKCζ/SP1 pathway in THP-1 macrophages.

OBJECTIVE: The aim of this study was to determine whether ATP-binding cassette transporter A1 (ABCA1) was up-regulated by growth differentiation factor-15 (GDF-15) via the phosphoinositide 3-kinase (PI3K)/protein kinase Cζ (PKCζ)/specificity protein 1 (SP1) pathway in THP-1 macrophages. METHODS AND RESULTS: We investigated the effects of different concentrations of GDF-15 on ABCA1 expression in THP-1 macrophages. The results showed that GDF-15 dramatically increased cholesterol efflux and decreased cellular cholesterol levels. In addition, GDF15 increased ABCA1 mRNA and protein levels. The effects of GDF-15 on ABCA1 protein expression and cellular cholesterol efflux were abolished by wither inhibition or depletion of PI3K, PKCζ and SP1, respectively, suggesting the potential roles of PI3K, PKCζ and SP1 in ABCA1 expression. Taken together, GDF-15 appears to activate PI3K, PKCζ and SP1 cascade, and then increase ABCA1 expression, thereby promoting cholesterol efflux and reducing foam cell formation. CONCLUSION: Our results suggest that GDF-15 has an overall protective effect on the progression of atherosclerosis, likely through inducing ABCA1 expression via the PI3K/PKCζ/SP1 signaling pathway and enhancing cholesterol efflux.

Interleukin-27 inhibits foam cell formation by promoting macrophage ABCA1 expression through JAK2/STAT3 pathway.

The purpose of this study is to determine whether IL-27 regulates macrophage ABCA1 expression, foam cell formation, and also explore the underlying mechanisms. Here, we revealed that IL-27 decreased lipid accumulation in THP-1 derived macrophages through markedly enhancing cholesterol efflux and increasing ABCA1 expression at both protein and mRNA levels. Our study further demonstrated that IL-27 increased ABCA1 level via activation of signal transducer and activator of transcription 3 (STAT3). Inhibition of Janus kinase 2, (JAK2)/STAT3 suppressed the stimulatory effects of IL-27 on ABCA1 expression. The present study concluded that IL-27 reduces lipid accumulation of foam cell by upregulating ABCA1 expression via JAK2/STAT3. Therefore, targeting IL-27 may offer a promising strategy to treat atherosclerotic vascular disease.

Advanced oxidation protein products exacerbates lipid accumulation and atherosclerosis through downregulation of ATP-binding cassette transporter A1 and G1 expression in apolipoprotein E knockout mice.

BACKGROUND: Both clinical data and basic science studies suggest that advanced oxidation protein products (AOPPs) may contribute to the progression of atherosclerosis. The aim of this study was to investigate the effects of AOPPs on ATP-binding cassette transporter (ABC) A1 and ABCG1 expression, lipid accumulation and atherosclerotic lesions in apolipoprotein E knockout (apoE-KO) mice. METHODS AND RESULTS: Male 8-week-old apoE-KO mice were fed a high-fat/high-cholesterol diet. Mice received intraperitoneal injections of AOPPs (5 mg/kg) and/or Janus Kinase (JAK) inhibitor AG-490 (5 mg/kg) once every other day for 8 weeks. As shown in our data, AOPPs increased lipid levels of plasma, and promoted advanced lesions in the aortic regions in apoE-KO mice. The ABCA1, ABCG1 and liver X receptor alpha (LXRα) expression were downregulated in apoE-KO mice treated with AOPPs, whereas the lesions in the aortas were decreased, and the ABCA1, ABCG1 and LXRα expression were upregulated in mice treated with AOPPs plus AG-490, compared to the mice treated with AOPPs only. The ABCA1 and LXRα expressions of aortas, liver and intestine were downregulated in the AOPPs group, while the expressions were upregulated in the AOPPs-plus-AG-490 group when compared to the AOPPs group. The same results can be also observed in peritoneal macrophages. CONCLUSIONS: AOPPs increase accumulation of lipids and exacerbate atherosclerosis through downregulation of ABCA1 and ABCG1 expression, and the JAK-LXRα signaling pathway in apoE-KO mice.

Immune-related long noncoding RNA zinc finger protein 710-AS1-201 promotes the metastasis and invasion of gastric cancer cells.

BACKGROUND: Gastric cancer (GC) is a prevalent malignant tumor of the gastrointestinal system. ZNF710 is a transcription factor (TF), and zinc finger protein 710 (ZNF710)-AS1-201 is an immune-related long noncoding RNA (lncRNA) that is upregulated in GC cells. AIM: To assess the correlation between ZNF710-AS1-201 and immune microenvironment features and to investigate the roles of ZNF710-AS1-201 in the invasion and metastasis processes of GC cells. METHODS: We obtained data from The Cancer Genome Atlas and Wujin Hospital. We assessed cell growth, migration, invasion, and programmed cell death using cell counting kit-8, EdU, scratch, Transwell, and flow cytometry assays. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to identify the potential downstream targets of ZNF710-AS1-201. RESULTS: In GC tissues with low ZNF710-AS1-201 expression, immunoassays detected significant infiltration of various antitumor immune cells, such as memory CD8 T cells and activated CD4 T cells. In the low-expression group, the half-maximal inhibitory concentrations (IC50s) of 5-fluorouracil, cisplatin, gemcitabine, and trametinib were lower, whereas the IC50s of dasatinib and vorinostat were higher. The malignant degree of GC was higher and the stage was later in the high-expression group. Additionally, patients with high expression of ZNF710-AS1-201 had lower overall survival and disease-free survival rates. In vitro, the overexpression of ZNF710-AS1-201 greatly enhanced growth, metastasis, and infiltration while suppressing cell death in HGC-27 cells. In contrast, the reduced expression of ZNF710-AS1-201 greatly hindered cell growth, enhanced apoptosis, and suppressed the metastasis and invasion of MKN-45 cells. The expression changes in ZNF710 were significant, but the corresponding changes in isocitrate dehydrogenase-2, Semaphorin 4B, ARHGAP10, RGMB, hsa-miR-93-5p, and ZNF710-AS1-202 were not consistent or statistically significant after overexpression or knockdown of ZNF710-AS1-201, as determined by qRT-PCR. CONCLUSION: Immune-related lncRNA ZNF710-AS1-201 facilitates the metastasis and invasion of GC cells. It appears that ZNF710-AS1-201 and ZNF710 have potential as effective targets for therapeutic intervention in GC. Nevertheless, it is still necessary to determine the specific targets of the ZNF710 TF.

Comparing the effectiveness and safety of Sorafenib plus TACE with Apatinib plus TACE for treating patients with unresectable hepatocellular carcinoma: a multicentre propensity score matching study.

OBJECTIVE: Local combined systemic therapy has been an important method for the treatment of unresectable hepatocellular carcinoma (HCC).The purpose of this study was to compare the effectiveness and safety of transarterial chemoembolization (TACE) plus Sorafenib versus TACE plus Apatinib for treating patients with unresectable HCC. METHODS: The clinical data of patients with unresectable HCC who were treated with TACE plus Sorafenib or TACE plus Apatinib at 5 Chinese medical centers between January 2016 and December 2020 were retrospectively analyzed. Propensity score matching (PSM) was applied to reduce the bias from confounding factors. RESULTS: A total of 380 patients were enrolled, of whom 129 cases were treated with TACE plus Sorafenib and 251 cases with TACE plus Apatinib. After the 1:1 PSM, 116 pairs of patients were involved in this study. The results showed that the PFS and OS in the TACE-Sorafenib group were significantly longer than those in the TACE-Apatinib group (PFS: 16.79 ± 6.45 vs. 14.76 ± 6.98 months, P = 0.049; OS: 20.66 ± 6.98 vs. 17.69 ± 6.72 months, P = 0.013). However, the ORR in the TACE-Apatinib group was markedly higher than that in the TACE-Sorafenib group (70.69% vs. 56.03%, P = 0.021). There were more patients with adverse events (AEs) in the TACE-Apatinib group than those in the TACE-Sorafenib group before dose adjustment (87 vs. 63, P = 0.001); however, the number of patients who suffered from AEs was not significantly different between the two groups after the dose adjustment (62 vs. 55, P = 0.148). No treatment-related death was found in the two groups. Subgroup analysis revealed that patients with unresectable HCC could better benefit from regular doses than reduced doses (Sorafenib, 22.59 vs. 18.02, P < 0.001; Apatinib, 19.75 vs. 16.86, P = 0.005). CONCLUSION: TACE plus either Sorafenib or Apatinib could effectively treat patients with unresectable HCC, the safety of TACE plus Sorafenib was better. and the ORR of TACE plus Apatinib was higher.

[Enoxaparin for the prevention of post surgical pulmonary embolism].

OBJECTIVE: To evaluate the efficacy and safety of the administration of enoxaparin, a low molecular weight heparin (LMWH), in the prevention of post surgical deep vein thrombosis (DVT) and pulmonary embolism (PE). METHODS: 1928 patients hospitalized for general surgery were randomly divided into: (1) test group (n = 960) to receive enoxaparin (40 mg, s.c., 12 hours before and after surgery, then once daily for 7 consecutive days); (2) control group (n = 968) without intervention. The incidence of DVT,PE and bleeding were recorded for statistical analysis during hospitalization and a 2 months follow-up after discharge. RESULTS: (1) No significant difference was found between the two groups in age, sex, average body mass index, type of surgery, and DVT / PE risk factors (obesity, varicose veins, and history of: venous thrombosis, chronic obstructive pulmonary disease, chronic heart failure, and hormone therapy). The percentage of non-malignant / malignant tumor surgery were 36.5% / 63.5% (average operation time 2.3 hours) in control group and 35.6% / 64.4% (2.2 hours) in test group (both P > 0.05). (2) During the hospitalization period, 59 cases (incidence=6.1%) of DVT and 14 cases (incidence=1.4%) of PE (among them 6 were fetal, 42.8% of all PE cases) were found in the control group, while 28 cases of DVT (2.9%) and 3 cases (0.3%) of PE (1 fetal, 33.3% of all PE cases) were found in test group. The incidence of DVT, PE (total), and PE (fetal) were significant lower in test group (P < 0.05 or P < 0.01). During the follow up, 14 more cases of DVT (1.4%) and 1 more case (0.1%) of PE (a fetal) were found in the control group, and 2 more DVT cases (0.2%) in test group, with the DVT incidence in test group significantly lower (P < 0.01). (3) During the enoxaparin administration, 30 cases (3.1%) minor bleeding and 8 cases (0.8%) major bleeding were found in the control group, while 33 cases (3.4%) minor bleeding events and 9 cases (0.9%) major bleeding events were found in the test group. THE RESULTS: in the two groups were not significantly different in either type of bleeding events (both P > 0.05). Also no significant difference was found in the bleeding events after the ending of enoxaparin administration and during the follow up. CONCLUSION: Enoxaparin may reduce the incidence of DVT and PE in patients undergoing general surgery without increased risk of bleeding.

The Efficacy and Prognostic Factors of the Combination of TACE and Apatinib for the Treatment of BCLC Stage C Hepatocellular Carcinoma.

Objective: Apatinib is a inhibitor of vascular endothelial growth factor receptor-2. To explore the efficacy and prognostic factors of transarterial chemoembolization (TACE) combined with apatinib in the treatment of Barcelona Clinic Liver Cancer stage C (BCLC C) hepatocellular carcinoma (HCC). Methods: Clinical data of 146 HCC patients with BCLC stage C admitted to our hospital were collected and analyzed retrospectively, of which 76 cases were treated with TACE combined with apatinib (TACE-apatinib) and 70 with TACE alone. The tumor response, survival time, and adverse events were compared between the two groups, and the factors affecting the prognosis were analyzed. Results: The objective response rate (ORR) and disease control rate (DCR) in the TACE-apatinib group were higher than in the TACE-alone group (ORR: 42.10 vs. 25.71%, P = 0.03; DCR: 84.21 vs. 55.71%, P = 0.001). The median time to progression (TTP) and overall survival (OS) in the TACE-apatinib group were longer than in the TACE-alone group (TTP: 5.5 vs. 3.7 months, P = 0.02; OS: 10.0 vs. 6.2 months, P = 0.01). Univariate and multivariate Cox regression analysis showed that tumor size, Child-Pugh class, and the presence of the portal vein tumor thrombus affect the prognosis of patients. Subgroup analysis revealed that TACE-apatinib therapy resulted in a higher OS in patients with tumor size <10 cm, without portal vein tumor thrombus, and with Child-Pugh class A (P < 0.05). The likelihood of adverse events (hand-foot syndrome, hypertension, oral ulcer) was significantly higher in the increased in the TACE-apatinib group than in the TACE alone group (P < 0.05). Conclusion: TACE-apatinib is an effective and safe method for the treatment of BCLC stage C HCC. Tumor size, Child-Pugh class, and portal vein tumor thrombus affect survival time in HCC patients with BCLC stage C.

Flexible inhibitory control of visually evoked defensive behavior by the ventral lateral geniculate nucleus.

Animals can choose to act upon, or to ignore, sensory stimuli, depending on circumstance and prior knowledge. This flexibility is thought to depend on neural inhibition, through suppression of inappropriate and disinhibition of appropriate actions. Here, we identified the ventral lateral geniculate nucleus (vLGN), an inhibitory prethalamic area, as a critical node for control of visually evoked defensive responses in mice. The activity of vLGN projections to the medial superior colliculus (mSC) is modulated by previous experience of threatening stimuli, tracks the perceived threat level in the environment, and is low prior to escape from a visual threat. Optogenetic stimulation of the vLGN abolishes escape responses, and suppressing its activity lowers the threshold for escape and increases risk-avoidance behavior. The vLGN most strongly affects visual threat responses, potentially via modality-specific inhibition of mSC circuits. Thus, inhibitory vLGN circuits control defensive behavior, depending on an animal's prior experience and its anticipation of danger in the environment.

An mPOA-ARCAgRP pathway modulates cold-evoked eating behavior.

Enhanced appetite occurs as a means of behavioral thermoregulation at low temperature. Neural circuitry mediating this crosstalk between behavioral thermoregulation and energy homeostasis remains to be elucidated. We find that the hypothalamic orexigenic agouti-related neuropeptide (AgRP) neurons in the arcuate nucleus (ARC) are profoundly activated by cold exposure. The calcium signals in ARCAgRP neurons display an immediate-response pattern in response to cold stimulation. Cold-responsive neurons in the medial preoptic area (mPOA) make excitatory synapses onto ARCAgRP neurons. Inhibition of either ARCAgRP neurons or ARC-projecting mPOA neurons attenuates cold-evoked feeding, while activation of the mPOA-to-ARC projection increases food intake. These findings reveal an mPOA-ARCAgRP neural pathway that modulates cold-evoked feeding behavior.