Plasmodium immunotherapy combined with gemcitabine has a synergistic inhibitory effect on tumor growth and metastasis in murine Lewis lung cancer models.

Objective: Our previous studies have demonstrated that Plasmodium immunotherapy (infection) has antitumor effects in mice. However, as a new form of immunotherapy, this therapy has a weakness: its specific killing effect on tumor cells is relatively weak. Therefore, we tested whether Plasmodium immunotherapy combined with gemcitabine (Gem), a representative chemotherapy drug, has synergistic antitumor effects. Methods: We designed subcutaneously and intravenously implanted murine Lewis lung cancer (LLC) models to test the antitumor effect of Plasmodium chabaudi ASS (Pc) infection in combination with Gem treatment and explored its underlying mechanisms. Results: We found that both Pc infection alone and Gem treatment alone significantly inhibited tumor growth in the subcutaneous model, and combination therapy was more effective than either monotherapy. Monotherapy only tended to prolong the survival of tumor-bearing mice, while the combination therapy significantly extended the survival of mice, indicating a significant synergistic effect of the combination. In the mechanistic experiments, we found that the combination therapy significantly upregulated E-cadherin and downregulated Snail protein expression levels, thus inhibiting epithelial-mesenchymal transition (EMT) of tumor cells, which may be due to the blockade of CXCR2/TGF-ß-mediated PI3K/Akt/GSK-3ß signaling pathway. Conclusion: The combination of Pc and Gem plays a synergistic role in inhibiting tumor growth and metastasis, and prolonging mice survival in murine lung cancer models. These effects are partially attributed to the inhibition of EMT of tumor cells, which is potentially due to the blockade of CXCR2/TGF-ß-mediated PI3K/Akt/GSK-3ß/Snail signaling pathway. The clinical transformation of Plasmodium immunotherapy combined with Gem for lung cancer is worthy of expectation.

Preclinical Study of Plasmodium Immunotherapy Combined with Radiotherapy for Solid Tumors.

Immune checkpoint blockade therapy (ICB) is ineffective against cold tumors and, although it is effective against some hot tumors, drug resistance can occur. We have developed a Plasmodium immunotherapy (PI) that can overcome these shortcomings. However, the specific killing effect of PI on tumor cells is relatively weak. Radiotherapy (RT) is known to have strong specific lethality to tumor cells. Therefore, we hypothesized that PI combined with RT could produce synergistic antitumor effects. We tested our hypothesis using orthotopic and subcutaneous models of mouse glioma (GL261, a cold tumor) and a subcutaneous model of mouse non-small cell lung cancer (NSCLC, LLC, a hot tumor). Our results showed that, compared with each monotherapy, the combination therapy more significantly inhibited tumor growth and extended the life span of tumor-bearing mice. More importantly, the combination therapy could cure approximately 70 percent of glioma. By analyzing the immune profile of the tumor tissues, we found that the combination therapy was more effective in upregulating the perforin-expressing effector CD8+ T cells and downregulating the myeloid-derived suppressor cells (MDSCs), and was thus more effective in the treatment of cancer. The clinical transformation of PI combined with RT in the treatment of solid tumors, especially glioma, is worthy of expectation.

Plasmodium infection prevents recurrence and metastasis of hepatocellular carcinoma possibly via inhibition of the epithelial­mesenchymal transition.

Postoperative recurrence causes a high mortality rate among patients with hepatocellular carcinoma (HCC). The current study aimed to determine the effects of Plasmodium infection on HCC metastasis and recurrence. The antitumor effects of Plasmodium infection were determined using two murine orthotopic HCC models: The non­resection model and the resection model. Tumour tissues derived from tumour­bearing mice treated with or without Plasmodium infection were harvested 15 days post­tumour inoculation. The expression levels of biomarkers related to epithelial­mesenchymal transition (EMT) and molecules associated with CC­chemokine receptor 10 (CCR10)­mediated PI3K/Akt/GSK­3ß/Snail signalling were identified using reverse transcription­quantitative PCR and western blotting. The results demonstrated that Plasmodium infection significantly suppressed the progression, recurrence and metastasis of HCC in the two mouse models. The expression levels of E­cadherin were significantly higher in the Plasmodium­treated group compared with that in the control group, whereas the expression levels of Vimentin and Snail were significantly lower in the Plasmodium­treated group. Furthermore, Plasmodium infection inhibited the activation of Akt and GSK­3ß in the tumour tissues by downregulating the expression levels of CCR10 and subsequently suppressing the accumulation of Snail, which may contribute to the suppression of EMT and the prevention of tumour recurrence and metastasis. In conclusion, the results of the present study demonstrated that Plasmodium infection inhibited the recurrence and metastasis and improved the prognosis of HCC by suppressing CCR10­mediated PI3K/Akt/GSK­3ß/Snail signalling and preventing the EMT. These results may be important for the development of novel therapies for HCC recurrence and metastasis, especially for patients in the perioperative period.

A novel application of B-ultrasonography at various head positions in the diagnosis of untypical uveitis-glaucoma-hyphema (UGH) syndrome: A case report.

RATIONALE: Uveitis-glaucoma-hyphema (UGH) syndrome could be identified by conventional ultrasound biomicroscopy (UBM) and B-ultrasonography, but failed in some untypical cases. We introduced a novel application of B-ultrasonography in diagnosis of UGH syndrome in a rare case. PATIENT CONCERNS: A 60-year-old woman was referred for distending pain with blurred vision for more than 1 month in the right eye after cataract surgery. DIAGNOSES: B-ultrasound scanner and UBM demonstrated the Intraocular Lens (IOL) was centered in the bag. No chafing in all directions was detected between IOL and iris/ciliary body. The proposed diagnoses were iridocyclitis and secondary glaucoma of the right eye. INTERVENTIONS: The symptoms were not improved after antiinflammation and intraocular pressure (IOP) lowering treatment for 1 month. B-ultrasonography was applied in horizontal, sitting, and head-down positions. The results demonstrated movements of IOLs when position changed. The IOLs were in contact with the iris pigment epithelium in sitting position and head-down positions but not in horizontal position. The dynamic interactions between IOLs and iris/ciliary body implied a diagnosis of UGH syndrome. The IOLs were then extracted. OUTCOMES: Two weeks after the IOLs explantation, the IOP significantly reduced to a normal level in both eyes. Ten-month follow-up showed that the IOP was maintained at a normal level. LESSONS: The chronically intermittent chafing between IOL and iris in specific head positions would also lead to UGH syndrome. Dynamic application of B-ultrasonography in various head positions could be useful in the diagnosis of an untypical UGH syndrome.

Bilateral Same-Session Ureteroscopy for Treatment of Ureteral Calculi: A Systematic Review and Meta-Analysis.

INTRODUCTION: The traditional procedure for the management of bilateral ureteral stones is staged ureteroscopic lithotripsy (URS). However, in recent years particularly, some urologists advocate same-session bilateral URS on the ground of success rates and minimal morbidity. This systematic review is to evaluate the efficacy and safety of same-session bilateral ureteroscopy for the treatment of ureteral calculi. MATERIALS AND METHODS: We conducted a bibliographic search using MEDLINE (1980 to August 2015) and EMBASE (1980 to August 2015). Review articles and abstract data were excluded and only studies in English reporting on outcomes of bilateral URS were included in this meta-analysis. Two reviewers independently assessed the quality of each included studies and extracted data. STATA 12.0 was used for meta-analysis. RESULTS: In 11 studies, 431 patients were reportedly treated with bilateral URS. Most of the stone sizes were not larger than 20 mm. The mean stone-free rate is 96% for the distal ureter, 85% for the middle ureter, and 72% for the proximal ureter. The mean operative time ranged from 45 to 100 minutes with an average hospital stay from 2 to 4 days. The overall complications rates were 17%, with the incidence of postoperative fever 4%, postoperative pain 20%, and gross hematuria 4%. Other complications, including urosepsis, urinary tract infection, small mucosal laceration, stone migration, and ureteral perforation, accounted for 6% of overall complications. CONCLUSIONS: This meta-analysis found that bilateral same-session ureteroscopy could achieve a high overall stone-free rate. There might be a relatively higher complication incidence, but most of the complications are minor. For selected cases, bilateral URS could be safe and effective.

Buyang Huanwu decoction increases the expression of glutamate transporter-1 and glutamate synthetase in association with PACAP-38 following focal ischemia.

The neuroprotective role of Buyang Huanwu decoction (BYHWD) in focal ischemia is associated with decreasing glutamate concentration. However, the mechanisms are not fully understood. The present study aimed to explore whether glutamate transporter-1 (GLT-1) and glutamine synthetase (GS) participated in the decreased level of glutamate and whether pituitary adenylate cyclase-activating polypeptide-38 (PACAP-38) was involved in this process. BYHWD was found to significantly upregulate the expression of GLT-1 and GS in the hippocampal CA1 area compared to the ischemia group, with the difference on day 3 being most significant. BYHWD increased the level of PACAP-38, and PACAP-(6-38) (PACAP receptor antagonist) significantly attenuated the effect of BYHWD on GLT-1 and GS, suggesting that PACAP-38 was involved in the upregulation of GLT-1 and GS induced by BYHWD. In addition, as GLT-1 and GS are mainly located in astrocytes, the changes of astrocytes were detected by glial fibrillary acidic protein (GFAP; an astrocytic marker) immunostaining. The results showed that BYHWD inhibited the expression of GFAP compared with the ischemia group, however, co-administration with PACAP-(6-38), which inhibited the effect of BYHWD on GLT-1 and GS in astrocytes, attenuated this effect, indicating that astrocytes participated in the protective role of BYHWD following focal ischemia. These results provided the evidence for the first time that not only neurons but also astrocytes contribute to the protective role of BYHWD, which opposes previous studies and may be a starting point for traditional medicine.

Opposite effects of the gap junction blocker octanol on focal cerebral ischemia occluded for different durations.

Protectants and executioners have been demonstrated to be used by gap junctions in focal cerebral ischemia. Certain researchers hypothesized that the opposite role of gap junctions may be associated with the injury extent, which has been demonstrated to be highly correlated with occlusion duration. In order to examine this hypothesis directly, the effects of octanol, a frequently used drug, were examined to investigate the role of gap junctions, in rats following middle cerebral artery occlusion (MCAO) for 30 min/2 h and 24 h reperfusion, respectively. Octanol significantly reduced the infarct volume following 2 h of occlusion concomitant with lower neurological deficits, whereas it enlarged the infarct volume following 30 min of occlusion. Consistently, octanol attenuated the number of transferase dUTP nick-end labeling (TUNEL) positive neurons in the hippocampal CA1 region following 2 h of occlusion, while opposite effects were observed for 30 min of occlusion. Further immunohistochemical studies demonstrated that the expression of B-cell leukemia-2 (Bcl-2, anti-apoptotic protein) was upregulated and that Bcl-2-associated X (Bax, proapoptotic protein) was downregulated following 2 h of occlusion in the octanol group compared with the ischemic group. Conversely, octanol downregulated the expression of the Bcl-2 protein concomitant with increased Bax protein following 30 min of occlusion. These results indicated that the gap junction blocker octanol can protect against ischemic injury following long-term occlusion, however, can aggravate ischemic injury following short-term occlusion.