[Efficacy and safety of anti-PD-1 monoclonal antibody in advanced hepatocellular carcinoma after TACE combined with TKI therapy].

Objective: To evaluate the efficacy and safety of anti-programmed cell death 1 (PD-1) receptor monoclonal antibody (MoAb) in patients with advanced hepatocellular carcinoma (HCC) after treatment of transcatheter arterial chemoembolization (TACE) combined with tyrosine kinase inhibitor (TKI). Methods: From February 2019 to February 2020, 56 HCC patients who relapsed after TACE-TKI treatment in Department of Interventional Radiology, The Second Affiliated Hospital of Guangzhou Medical University were enrolled. All patients received anti-PD-1 MoAb (sintilimab injection) and followed up every 6 weeks. According to mRECIST, the curative effect was evaluated as complete response (CR), partial response (PR), stable disease (SD) or progressive disease (PD). Objective response rate (ORR) and disease control rate (DCR), progression-free survival (PFS) and treatment-related adverse events (TRAEs) were recorded. Univariate analysis by Chi-square test and binary logistic regression model was used to determine the influencing factors of DCR. The Kaplan-Meier method and Cox proportional hazard regression model were used to analyze the survival data. Results: A total of 48 patients were enrolled in this study including 42 males and 6 females, with a median age of 55 years (29-71 years). ECOG scores comprised of 0 in 24 cases, 1-2 in 24 cases. Thirty-six patients were in Child-Pugh grade A of liver function and 12 cases were grade B. The median follow-up time was 4.5 months. There were 2 patients achieved CR, 12 patients with PR and 16 with SD. ORR was 29.2%, DCR was 62.5%. The independent influencing factors of DCR was ECOG score and AFP level (P=0.031, P=0.012). Median PFS was 4.1 months (95%CI 2.7-5.4 months), and ECOG score was the independent influencing factor of PFS (P=0.042). Treatment-related adverse events were reported in 70.8% (34/48) patients. Incidence of grade Ⅲ-Ⅳ TRAEs was 22.9% (11/48). Conclusion: In patients with HCC who relapse from TACE and TKI treatment, anti-PD-1 monoclonal antibody is efficacious safe especially in those with ECOG 0 score.

Synergistic effects of glycated chitosan with high-intensity focused ultrasound on suppression of metastases in a syngeneic breast tumor model.

Stimulation of the host immune system is crucial in cancer treatment. In particular, nonspecific immunotherapies, when combined with other traditional therapies such as radiation and chemotherapy, may induce immunity against primary and metastatic tumors. In this study, we demonstrate that a novel, non-toxic immunoadjuvant, glycated chitosan (GC), decreases the motility and invasion of mammalian breast cancer cells in vitro and in vivo. Lung metastatic ratios were reduced in 4T1 tumor-bearing mice when intratumoral GC injection was combined with local high-intensity focused ultrasound (HIFU) treatment. We postulate that this treatment modality stimulates the host immune system to combat cancer cells, as macrophage accumulation in tumor lesions was detected after GC-HIFU treatment. In addition, plasma collected from GC-HIFU-treated tumor-bearing mice exhibited tumor-specific cytotoxicity. We also investigated the effect of GC on epithelial-mesenchymal transition-related markers. Our results showed that GC decreased the expression of Twist-1 and Slug, proto-oncogenes commonly implicated in metastasis. Epithelial-cadherin, which is regulated by these genes, was also upregulated. Taken together, our current data suggest that GC alone can reduce cancer cell motility and invasion, whereas GC-HIFU treatment can induce immune responses to suppress tumor metastasis in vivo.

Remnant living cells that escape cell loss in late-stage tumors exhibit cancer stem cell-like characteristics.

A balance between cell proliferation and cell loss is essential for tumor progression. Although up to 90% of cells are lost in late-stage carcinomas, the progression and characteristics of remnant living cells in tumor mass are unclear. Here we used molecular imaging to track the progression of living cells in a syngeneic tumor model, and ex vivo investigated the properties of this population at late-stage tumor. The piggyBac transposon system was used to stably introduce the dual reporter genes, including monomeric red fluorescent protein (mRFP) and herpes simplex virus type-1 thymidine kinase (HSV1-tk) genes for fluorescence-based and radionuclide-based imaging of tumor growth in small animals, respectively. Iodine-123-labeled 5-iodo-2'-fluoro-1-beta-D-arabinofuranosyluracil was used as a radiotracer for HSV1-tk gene expression in tumors. The fluorescence- and radionuclide-based imaging using the single-photon emission computed tomography/computed tomography revealed that the number of living cells reached the maximum at 1 week after implantation of 4T1 tumors, and gradually decreased and clustered near the side of the body until 4 weeks accompanied by enlargement of tumor mass. The remnant living cells at late-stage tumor were isolated and investigated ex vivo. The results showed that these living cells could form mammospheres and express cancer stem cell (CSC)-related biomarkers, including octamer-binding transcription factor 4, SRY (sex-determining region Y)-box 2, and CD133 genes compared with those cultured in vitro. Furthermore, this HSV1-tk-expressing CSC-like population was sensitive to ganciclovir applied for the suicide therapy. Taken together, the current data suggested that cells escaping from cell loss in late-stage tumors exhibit CSC-like characteristics, and HSV1-tk may be considered a theranostic agent for targeting this population in vivo.

An initial assessment of the feasibility and effectiveness of implementing diabetes shared care system in Taiwan--some experiences from I-Lan County.

Diabetes is the fifth leading cause of death in Taiwan and the burden of suffering is still increasing. Building a comprehensive and efficient health care system is crucial to improve the outcome of the diabetics. We implemented the first diabetes shared care system of Taiwan in I-Lan County since August 1996 under the support of Department of Health, the Executive Yuan. This county-wide system was named 'Lan-Yang Diabetes Shared Care System' by the regional steering committee. Regional guidelines for diabetes management were developed after extensive discussion. A multidisciplinary diabetes care team was organized through a training and certification process. Registered patients held diabetes passports to keep clinical record. Physicians of the system use shared referral protocols and sheets. By the end of June 1999, 99 medical professionals had completed their training for diabetes shared care and been certified. The shared care system awarded 26 clinics to hang the lamp signs with the system logo to make them distinguishable. Such clinics have now been available throughout 12 townships in I-Lan County. The number of registered patients carrying diabetes passport increased to 3484 and there was a community-based patient group in every township of I-Lan County. The amount of continuing diabetes clinical training delivered by the specialists to the primary care physicians and non-physician professionals increased to 1681 person-hours per year. The proportion of registered patients undertaking fundus examination within 1 year increased to 30.9%, checking urine micro-albumin to 28.0% and checking HbA(1c) 72.8%, respectively. Mean HbA(1c) value decreased from 8.7% in the first year to 7.9% in the third year. Our study showed that under the co-ordination by regional health bureau with integration of different levels of medical facilities, governmental sectors and non-governmental community resources, the diabetes shared care model is feasible in Taiwan. Through its implementation, quality of regional diabetes care has achieved preliminary improvement.

Electrophysiological basis for antiarrhythmic efficacy, positive inotropy and low proarrhythmic potential of (-)-caryachine.

1. (-)-Caryachine, isolated from the plant (Cryptocarya chinensis), increased the contractility of atrial and right ventricular strips and significantly suppressed the reperfusion arrhythmias in adult rabbit heart (ED50 = 1.27 microM). 2. Data obtained by the whole-cell voltage clamp technique has shown that (-)-caryachine causes a negative shift of the steady-state Na channel inactivation and a slower rate of recovery from inactivation. The maximal Na current amplitude decreased to 67 +/- 7%, 29 +/- 8% and 12 +/- 5% after 0.5, 1.5 and 4.5 microM (-)-caryachine, respectively. 3. This agent also had effects on the time- and voltage-dependent K currents. (-)-Caryachine markedly suppressed the 4-AP-sensitive transient outward current (I10). However, it produced very little voltage-dependent shift in inactivation. After 0.5, 1.5 and 4.5 microM of the compound, the respective value of I10 elicited at +60 mV was 80 +/- 7%, 45 +/- 8% and 15 +/- 3%. At higher concentrations, the inward rectifier K current (IK1) was also inhibited but to a much smaller extent. Its slope conductance after 0.5, 1.5 and 4.5 microM (-)-caryachine was reduced to 71 +/- 9%, 51 +/- 12% and 42 +/- 11%, respectively. The outward hump of inward rectification was not changed. 4. In contrast, the L-type Ca current was not significantly changed by (-)-caryachine. 5. Electrophysiological studies in perfused whole heart preparations revealed that (-)-caryachine increased the intra-atrial conduction interval and also prolonged the atrial refractory period. No proarrhythmic effects were induced during the infusion of this compound (up to 13.5 microM). 6. We conclude that (-)-caryachine predominantly blocks the Na and I10 currents. These changes alter the electrophysiological properties of the heart and terminate the induced ventricular arrhythmias. The relatively selective I10 inhibition, safety margin of Ik1 suppression and lack of effect on Ica-L will provide an opportunity to develop an effective antiarrhythmic agent with positive inotropy as well as low proarrhythmic potential.

Effect of pentoxifylline on intraperitoneal adhesions after intestinal resection in rats.

Pentoxifylline, an analogue of the methylxanthine theobromine, inhibits glycosaminoglycan and collagen synthesis by dermal fibroblasts in vitro and also inhibits the proliferation of dermal fibroblasts. It may have the same effect on fibroblasts derived from postoperative adhesion bands, thus preventing postoperative adhesion formation. An animal model was developed to evaluate the effect of pentoxifylline. Twenty-four male Wistar rats were divided into four groups, and all underwent laparotomy with a 15 cm intestinal resection and reanastomosis. The intestinal serosa was scratched to induce adhesion formation. No medication was given in group 1 rats, group 2 rats received 6 mL normal saline by intraoperative peritoneal irrigation, group 3 rats received 6 mL pentoxifylline solution (1 mg/mL) by intraperitoneal irrigation and group 4 rats received both 6 mL intraoperative pentoxifylline solution (1 mg/mL) irrigation and 50 mg/kg pentoxifylline by intramuscular injection, twice a day for 14 days. All rats were sacrificed 2 weeks later. The numbers of fibrous bands at and away from the anastomotic site were recorded and scored. The score for each rat was calculated as the sum of the scores for each band. The strength and the extent of the fibrous bands were also measured and compared. The scores of adhesion bands at the anastomotic site were significantly reduced in group 3 and group 4 rats when compared with group 1 rats. However, there were no significant differences among the 4 groups in the extent and strength of adhesions at sites other than the anastomosis site.

Nuclear transplantation in teleosts. Hybrid fish from the nucleus of crucian and the cytoplasm of carp.

Hybrid fish are obtained from the combination of nucleus and cytoplasm from two genera of fresh-water teleosts using the technique of nuclear transplantation (i.e. the combination of the nucleus of crucian (Carassius auratus) and the cytoplasm of carp (Cyprinus carpio]. Morphological characteristics of these hybrid fish that have been examined so far indicate that some features such as barbs, pharyngeal teeth, the number of scales along the lateral line, and the number of vertebrae are similar to those of crucian. Some of the hybrid fish grow to normal adult fish.