Taxifolin inhibits melanoma proliferation/migration impeding USP18/Rac1/JNK/ß-catenin oncogenic signaling.

BACKGROUND: Metastatic melanoma is a fatal cancer. Despite the advances in targeted therapy and immunotherapy for patients with melanoma, drug resistance and low response rates pose a considerable challenge. Taxifolin is a multifunctional natural compound with emerging antitumor potentials. However, its utility in melanoma treatment remains unclear. PURPOSE: The study aimed to investigate the effect of purified Taxifolin from Larix olgensis roots (Changbai Mountain, China) on melanoma and explore the underlying mechanism. METHODS: Purified Taxifolin from Larix olgensis roots was evaluated for its antimelanoma effects in vitro and in vivo settings. RNA-seq analysis was performed to explore the underlying mechanism. RESULTS: Purified Taxifolin (> 99 %) from Larix olgensis roots inhibited the proliferation and migration of B16F10 melanoma cells at 200 and 400 µM, and of A375 cells at 100 and 200 µM. Taxifolin administered at 60 mg/kg suppressed tumor growth and metastasis in mouse models without causing significant toxicity. Taxifolin modulated USP18/Rac1/JNK/ß-catenin axis to exert its antitumor effect. CONCLUSION: These findings indicate that Taxifolin derived from Larix olgensis roots may be a promising antimelanoma therapy.

[Clinical characteristics analysis of 22 062 patients of foot and ankle deformity from QIN Sihe Orthopaedic Surgery Database between May 25, 1978 and December 31, 2020].

Objective: Based on the clinical data of patients with foot and ankle deformities in the QIN Sihe Orthopaedic Surgery Database, to analyze the characteristics and treatment strategies of foot and ankle deformities, and provide a basis for clinical decision-making. Methods: A total of 22 062 patients with foot and ankle deformities who received orthopedic surgery between May 25, 1978 and December 31, 2020 were searched in the QIN Sihe Orthopedic Surgery Database. The gender, age at operation, regional distribution, etiology, type of deformity, operation method, postoperative fixation method, and other information were collected. Results: Among the 22 062 patients, there were 13 046 males (59.13%) and 9 016 females (40.87%); the age at operation ranged from 1 to 77 years, with a median of 17 years, and 20 026 cases (90.77%) were aged 5 to 40 years. The patients came from 32 provinces, municipalities, and autonomous regions across the China and 5 countries including India and the United States, et al. The etiology and diseases type covered 154 kinds (of which sequelae of poliomyelitis, cerebral palsy, spina bifida and tethered spinal cord, congenital equinovarus foot, post-traumatic foot and ankle deformity, and Charcot-Marie-Tooth disease accounted for the highest proportion). The types of deformities included varus foot, equinus foot, valgus foot, talipes calcaneus, equinocavus, high arched foot, claw toe, and flail foot. Surgical methods included tendon lengthening, soft tissue release, tendon transposition, osteotomy orthopedics, and ankle arthrodesis. The 36 620 operations were performed, including 11 561 cases of hip, knee, and lower leg operations to correct the foot and ankle deformities. Postoperative fixation methods included Ilizarov external fixator in 2 709 cases (12.28%), combined external fixator in 3 966 cases (17.98%), and plaster or brace fixation in 15 387 cases (69.74%). Conclusion: Male patients with foot and ankle deformities account for a large proportion, and the population distribution is mainly adolescents, with a wide distribution of regions, causes and diseases, and talipes equinovarus and varus foot are the main types of deformities. Foot and ankle deformities are often combined with deformities of other parts of the lower limb, which requires a holistic treatment concept. The application of foot soft tissue and bone surgery combined with Ilizarov external fixator and combined external fixators provides a guarantee for the correction of complex foot and ankle deformities.

Perspectives on Oncolytic Salmonella in Cancer Immunotherapy-A Promising Strategy.

Since the first reported spontaneous regression of tumors in patients with streptococcus infection, cancer biological therapy was born and it evolved into today's immunotherapy over the last century. Although the original strategy was unable to impart maximal therapeutic benefit at the beginning, it laid the foundations for the development of immune checkpoint blockade and CAR-T which are currently used for cancer treatment in the clinics. However, clinical applications have shown that current cancer immunotherapy can cause a series of adverse reactions and are captious for patients with preexisting autoimmune disorders. Salmonellae was first reported to exert antitumor effect in 1935. Until now, numerous studies have proved its potency as an antitumor agent in the near future. In this review, we summarize the currently available data on the antitumor effects of Salmonella, and discussed a possibility of integrating Salmonella into cancer immunotherapy to overcome current obstacles.

The effects of tacrolimus plus phototherapy in the treatment of vitiligo: a meta-analysis.

The objective of this meta-analysis was performed to compare the effects of tacrolimus plus phototherapy in the treatment of patients with vitiligo. Relevant studies were identified by searching PubMed, Embase, and Web of Science databases. The main outcomes of interest included excellent response (≥ 75% repigmentation), good response (50-75% repigmentation), moderate response (25%-50% repigmentation), and poor response (< 25% repigmentation). Risk ratio (RR) with 95% confidence intervals (95% CIs) was used to calculate the data. Eleven studies were included in this study. Compared with phototherapy alone, combination treatment of tacrolimus and phototherapy significantly improved excellent response rate (RR = 1.40, 95% CI 1.16, 1.69; P < 0.001) and reduced the poor response rate (RR = 0.37, 95% CI 0.22, 0.61; P = 0.001). However, the good response rate (RR = 1.00, 95% CI 0.59, 1.69, P = 1.000) and moderate response rate (RR = 0.91, 95% CI 0.60, 1.38; P = 0.653) were not significantly different between the two treatments. Subgroup analysis suggested that combination treatment had a higher excellent response rate than phototherapy alone for lesions located in the face and proximal limbs. Both NB-UVB and EL, when added to tacrolimus, resulted in a significantly higher excellent response rate than they were used alone. Meta-regression analysis showed that age was a predictive factor that influenced the effect of combination treatment on an excellent response, in which children had a high excellent response to the treatment. Other demographic and clinical variables, including gender, disease duration, family history, and type of vitiligo, did not have any impact on the treatment effect. Combination treatment with tacrolimus and phototherapy was more effective than phototherapy monotherapy for patients with vitiligo, especially in the lesions located in the face and proximal limbs. More large-scale, well-performed trials are needed to verify our findings.

Synergistic Suppression of Melanoma Growth by a Combination of Natural dsRNA and Panaxadiolsaponins.

Melanoma is one of the most lethal skin malignancies in the world. Interferons (IFNs) have been also demonstrated in response to tumor cell and IFNs such as IFN-α have been used for melanoma treatment. The long chain double-stranded RNA (dsRNA) (from a variety of nonviral sources) is a potent activator of the IFN system and an inducer of cell apoptosis. Panaxadiolsaponins (PDS) is a major Panax ginseng-derived active component with known antitumor activity and immune modulation. Here, we investigated a hypothesis that the combination of PDS and total natural dsRNA (as opposed to the synthetic dsRNA) will suppress tumor growth better than the individual agents. We have evaluated the antitumor and immunostimulatory effects of the combination of natural long chain dsRNA (derived from yeast) and PDS on melanoma cell line B16 and mice xenograft model. The underlying mechanisms of growth suppression were investigated by analyzing dsRNA-activated pathways, apoptosis, and cell cycle. Natural dsRNA and PDS exert superior anticancer effects than either agent alone. Natural dsRNA and PDS combination might be a promising strategy for treating malignancies, including melanoma.

Comparison of clinical and survival characteristics between prostate cancer patients of PSA-based screening and clinical diagnosis in China.

Prostate-specific antigen (PSA)-based mass screening remains the most controversial topic in prostate cancer. PSA-based mass screening has not been widely used in China yet. The aim of our study was to evaluate the effect of the PSA-based screening in China. The cohort consisted of 1,012 prostate cancer patients. Data were retrospectively collected and clinical characteristics of the cohorts were investigated. Survival was analyzed for prostatic carcinoma of both PSA screened and clinically diagnosed patients according to clinical characteristics and the National Comprehensive Cancer Network (NCCN) risk classification. Cox Proportional Hazards Model analysis was done for risk predictor identification. The median age was 71 years old. Five-year overall and prostate-cancer-specific survival in prostatic adenocarcinoma patients were 77.52% and 79.65%; 10-year survivals were 62.57% and 68.60%, respectively. Survival was significantly poorer in patients with metastases and non-curative management. T staging and Gleason score by NCCN classification effectively stratified prostatic adenocarcinoma patients into different risk groups. T staging was a significant predictor of survival by COX Proportional Hazard Model. PSA screened patients had a significantly higher percentage diagnosed in early stage. PSA screened prostatic adenocarcinoma patients had a better prognosis in both overall and prostate cancer-specific survivals. This Chinese cohort had a lower overall and prostate cancer survival rate than it is reported in western countries. The incidence of early-stage prostate cancer found in PSA-based mass screening was high and there were significant differences in both overall and prostate cancer-specific survival between the PSA-screened and clinically diagnosed patients.

[Effects of platycodin D in combination with different active ingredients of Chinese herbs on proliferation and invasion of 4T1 and MDA-MB-231 breast cancer cell lines].

OBJECTIVE: To investigate the effects of platycodin D in combination with different active ingredients of Chinese herbs under different therapeutic principles on proliferation and invasion of 4T1 and MDA-MB-231 breast cancer cell lines. METHODS: The effective doses of platycodin D, Ophiopogon total saponins, curcumenol and osthole in inhibiting proliferation of breast cancer cell lines 4T1 and MDA-MB-231 were detected by methyl thiazolyl tetrazolium (MTT) assay, respectively. Optimized combinations of platycodin D with Ophiopogon total saponins, curcumenol, or osthole were determined by uniform design method. Effects of the optimized combinations of platycodin D with the three ingredients on proliferation and invasion of 4T1 and MDA-MB-231 cells were verified and evaluated by MTT assay and Transwell chamber test, respectively. RESULTS: Verifying study showed that the inhibitory effects of platycodin D in combination with curcumenol or osthole on proliferation of 4T1 and MDA-MB-231 cells were better than those of platycodin D in combination with Ophiopogon total saponins and each ingredient used alone (P<0.05 or P<0.01). The inhibitory effect of platycodin D in combination with Ophiopogon total saponins or osthole on invasion of 4T1 cells was significantly better than those of platycodin D in combination with curcumenol and each ingredient used alone (P<0.05 or P<0.01). Moreover, the inhibitory effect of platycodin D in combination with curcumenol or osthole on invasion of MDA-MB-231 cells was significantly better than that of platycodin D in combination with Ophiopogon total saponins (P<0.01). CONCLUSION: The optimized combinations of platycodin D with three different active ingredients of Chinese herbs under different therapeutic principles can significantly inhibit the proliferation and decrease the invasion of 4T1 and MDA-MB-231 cells. Different platycodin D combinations have different potency in suppressing breast cancer cell proliferation and invasion.

[Inhibitory effects of osthole, psoralen and aconitine on invasive activities of breast cancer MDA-MB-231BO cell line and the mechanisms].

OBJECTIVE: To explore the inhibitory effects and to investigate the mechanisms of combined treatment of osthole, psoralen with aconitine on human breast cancer cell line MDA-MB-231BO. METHODS: The best inhibitory concentration of osthole, psoralen combined with aconitine on MDA-MB-231BO cells was obtained by stepwise regression analysis after adopting a uniform experiment design. The invasive activities were observed by transwell assays, and expressions of transforming growth factor-ß1 (TGF-ß1), Smad2, Smad3, Smad4, Smad7, nuclear factor-κB (NF-κB) and receptor activator of NF-κB ligand (RANK) mRNAs were analyzed by real-time quantitative polymerase chain reaction. RESULTS: The optimal combination concentrations of osthol, psoralen and aconitine were 6.44, 8.89 and 9.44 µg/mL, respectively. Cell invasion was significantly inhibited after 24 hours of treatment using the combination drugs and zoledronic acid. TGF-ß1, Smad2, Smad3, Smad4, Smad7, NF-κB and RANK mRNA expressions of the optimal combination group and zoledronic acid group were significantly reduced compared with the control group (P<0.01). Furthermore, TGF-ß1, Smad2, Smad3, Smad4, Smad7, NF-κB and RANK mRNA expressions of the optimal combination group were significantly lower than those of the weak combination group (P<0.01). CONCLUSION: Combination treatment of osthole, psoralen with aconitine can inhibit cancer cell invasion, which is a result of alteration of the TGF-ß/Smad signaling pathway and down-regulation of NF-κB and RANK expressions.