A novel therapeutic strategy of combined camrelizumab and apatinib for the treatment of advanced hepatocellular carcinoma.

Methods: 83 patients with hepatocellular carcinoma (HCC) admitted to the interventional oncology department were randomly divided into two groups. Apatinib and camrelizumab were administered to 42 patients in group A, whereas sorafenib was administered to 41 patients in group B for three months. The clinical efficacy was evaluated in terms of objective response rate (ORR), and disease control rate (DCR). Certain tumor markers like alpha-fetoprotein (AFP), carbohydrate antigen 199 (CA199), carcinoembryonic antigen (CEA), hypoxia-inducible factor (HIF-1), immune function T lymphocyte subsets (CD3+, CD4+, CD8+, CD4+/CD8+) were determined before and after treatment. The serum levels of vascular endothelial growth factor (VEGF), osteopontin (OPN), aspartate aminotransferase (AST), and epidermal growth factor 7 (EGF7)] were observed. The survival time between the two groups was compared, such as progression-free survival (PFS) and median survival (MS). Finally, the toxicity and side effects data were also obtained. Results: The ORR and DCR of group A were 69.05% and 88.10%, respectively, which were significantly higher (P<0.05) than group B (ORR=53.66% and DCR=70.73%). After treatment, the AFP, CA199, CEA, and HIF-1 levels of both groups decreased significantly (P<0.05), and the respective biomarker levels of group A were lower than those of group B (P<0.05). Following treatment, CD3+, CD4+, CD4+/CD8+ index in group A significantly increased (P<0.05) while CD8+ level was significantly decreased (P<0.05). Compared to group B, a significant increase was observed in group A's CD3+, CD4+, and CD4+/CD8+ index. There were no significant changes in CD3+, CD4+, CD8+, CD4+/CD8+ indexes before and after treatment in group B (P>0.05). The serum level of VEGF, OPN, EGF-7 and AST indexes of group A&B were decreased significantly (P<0.05). Compared with group B, the VEGF, OPN, EGF7 and AST indexes of group A were significantly reduced (P<0.05). PFS and MS in group A were significantly higher than in group B (P<0.05). There was no significant difference between groups A and B in terms of toxicity and adverse effects (P>0.05). Conclusion: In treating HCC, combining apatinib and camrelizumab can reduce tumor markers, enhance the immune system and curative effect, and prolong patient survival. The underline mechanism is related to the down-regulation of VEGF, OPN and HIF-1 indexes.

HCN1 channels reduce the rate of exocytosis from a subset of cortical synaptic terminals.

The hyperpolarization-activated cyclic nucleotide-gated (HCN1) channels are predominantly located in pyramidal cell dendrites within the cortex. Recent evidence suggests these channels also exist pre-synaptically in a subset of synaptic terminals within the mature entorhinal cortex (EC). Inhibition of pre-synaptic HCN channels enhances miniature excitatory post-synaptic currents (mEPSCs) onto EC layer III pyramidal neurons, suggesting that these channels decrease the release of the neurotransmitter, glutamate. Thus, do pre-synaptic HCN channels alter the rate of synaptic vesicle exocytosis and thereby enhance neurotransmitter release? To address this, we imaged the release of FM1-43, a dye that is incorporated into synaptic vesicles, from EC synaptic terminals using two photon microscopy in slices obtained from forebrain specific HCN1 deficient mice, global HCN1 knockouts and their wildtype littermates. This coupled with electrophysiology and pharmacology showed that HCN1 channels restrict the rate of exocytosis from a subset of cortical synaptic terminals within the EC and in this way, constrain non-action potential-dependent and action potential-dependent spontaneous release as well as synchronous, evoked release. Since HCN1 channels also affect post-synaptic potential kinetics and integration, our results indicate that there are diverse ways by which HCN1 channels influence synaptic strength and plasticity.

Firing of hippocampal neurogliaform cells induces suppression of synaptic inhibition.

Little is known about how neuron firing recorded in vivo retrogradely influences synaptic strength. We injected the firing of a rat hippocampal neurogliaform cell (NGFC), a widely expressed GABAergic neuron type, detected in vivo during theta rhythm, into NGFCs of rat or neuronal nitric oxide synthase (nNOS)-Cre-tdTomato mouse recorded in vitro. We found that the "in vivo firing pattern" produced a transient firing-induced suppression of synaptic inhibition (FSI) evoked by a presynaptic NGFC. Imaging experiments demonstrate that FSI was associated with action potential backpropagation (bAP) and a supralinear increase in dendritic Ca(2+). The application of the L-type Ca(2+) channel antagonist nimodipine blocked FSI. Further pharmacological experiments, such as the application of a nitric oxide-sensitive guanylyl cyclase (NO-sGC) receptor antagonist, a NOS inhibitor, and NO donors, suggested that NO released from postsynaptic cells mediated FSI and likely activated presynaptic receptors to inhibit GABA release. The in vivo firing pattern modulated the size of unitary EPSPs impinging on NGFCs through FSI and not via a direct effect on excitatory synaptic transmission. Our data demonstrate: (1) retrograde signaling initiated by in vivo firing pattern, (2) interneuron bAPs detected with fast temporal resolution, and (3) a novel role for NO expressed by specific interneuron types.