Mechanism Research of PZD Inhibiting Lung Cancer Cell Proliferation, Invasion, and Migration based on Network Pharmacology.

BACKGROUND: A classic Chinese medicine decoction, Pinellia ternata (Thunb.) Breit.-Zingiber officinale Roscoe (Ban-Xia and Sheng-Jiang in Chinese) decoction (PZD), has shown significant therapeutic effects on lung cancer. OBJECTIVE: This study aimed to explore and elucidate the mechanism of action of PZD on lung cancer using network pharmacology methods. METHODS: Active compounds were selected according to the ADME parameters recorded in the TCMSP database. Potential pathways related to genes were identified through GO and KEGG analysis. The compoundtarget network was constructed by using Cytoscape 3.7.1 software, and the core common targets were obtained by protein-protein interaction (PPI) network analysis. Batch molecular docking of small molecule compounds and target proteins was carried out by using the AutoDock Vina program. Different concentrations of PZD water extracts (10, 20, 40, 80, and 160 µg/mL) were used on lung cancer cells. Moreover, MTT and Transwell experiments were conducted to validate the prominent therapeutic effects of PZD on lung cancer cell H1299. RESULTS: A total of 381 components in PZD were screened, of which 16 were selected as bioactive compounds. The compound-target network consisting of 16 compounds and 79 common core targets was constructed. MTT experiment showed that the PZD extract could inhibit the cell proliferation of NCI-H1299 cells, and the IC50 was calculated as 97.34 ± 6.14 µg/mL. Transwell and wound-healing experiments showed that the PZD could significantly decrease cell migration and invasion at concentrations of 80 and 160 µg/mL, respectively. The in vitro experiments confirmed that PZD had significant therapeutic effects on lung cancer cells, mainly through the PI3K/AKT signaling pathway. CONCLUSION: PZD could inhibit the cell proliferation, migration, and invasion of NCI-H1299 cells partially through the PI3K/AKT signaling pathway. These findings suggested that PZD might be a potential treatment strategy for lung cancer patients.

A systematic review and meta-analysis of intraarterial chemotherapy for non muscle invasive bladder cancer: Promising alternative therapy in high tuberculosis burden countries.

INTRODUCTION: Local therapies for high risk non-muscle-invasive bladder cancer (NMIBC) such as intravesical chemotherapy (IVC) have shown a high rate of progression and recurrence. Intravesical Bacillus Calmette-Guérin (BCG) for local therapies has been shown to reduce progression and recurrence in patient with NMIBC. However, its potential role is limited in high burden countries for tuberculosis (TB) due to its low specificity that can cause wrong diagnosis or false positive in patients with clinically diagnosed tuberculosis. BCG vaccine that has to be given for most people in tuberculosis endemic countries will induce trained immunity that could reduce the effectivity of intravesical BCG for NMIBC. Moreover, intravesical BCG is contraindicated in patient with or previous tuberculosis. The potential clinical benefit of intraarterial chemotherapy (IAC) in delaying the recurrence and progression of high-risk NMIBC have been investigated with promising results. We aimed to conduct a meta-analysis to evaluate the potential anti-tumor effect of IAC in NMIBC. METHODS: We conducted a comprehensive search of published articles in Cochrane Library, Pubmed, and Science-Direct to identify relevant randomized controlled trials (RCTs) and observational studies comparing IAC alone or combined with IVC versus IVC/BCG alone in NMIBC. The protocol of preferred reporting items for systematic review and meta-analysis (PRISMA) was applied to this study. RESULTS: Four RCTs and 4 cohort observational studies were eligible in this study and 5 studies were included in meta-analysis. The risk ratio of tumor recurrence was reduced by 35% (RR = 0.65; 95% CI 0.49-0.87; p = 0.004) in IAC plus IVC, while recurrence-free survival (RFS) was prolonged by 45% (HR: 0.55; 95% CI, 0.44-0.69; p < 0.001). The risk of tumor progression was reduced by 45% (RR = 0.55; 95% CI 0.41-0.75; p = 0.002) and tumor progression-free survival (PFS) was also prolonged by 53% (HR: 0.47; 95% CI, 0.34-0.65; p<0.001). Some RCT's had high or unclear risk of bias, meanwhile 4 included cohort studies had overall low risk of bias, therefore the pooled results need to be interpreted cautiously. Subgroup analysis revealed that the heterogeneity outcome of tumour recurrence might be attributed to the difference in NMIBC stages and grades. CONCLUSIONS: The IAC alone or combined with IVC following bladder tumor resection may lower the risk of tumor recurrence and progression. These findings highlight the importance of further multi institutional randomized controlled trials with bigger sample size using a standardized IAC protocol to validate the current results.

Prevention of Bladder Cancer Recurrence With the Botanical Formula LCS103: A Case Series Study.

Despite effective chemotherapy and other available oncology treatments, recurrence rates for non-muscle invasive bladder cancer (NMIBC) remain high, with as many as 60% of patients requiring repeat intravesical treatments with BCG or other agents within a 24-month period. The botanical formula LCS103 has displayed anti-cancer activity on bladder cancer cells, though its clinical efficacy remains to be proven. A consecutive series of 30 patients with bladder cancer was examined retrospectively, of which a cohort of 20 patients (18 with NMIBC, 2 with metastatic disease) was treated with LCS103 for between 14 months and 16 years, in addition to their conventional oncology care. Only 3 patients (15%) had a single tumor recurrence after initiation of the botanical treatment, as opposed to pre-treatment recurrence reported among 11 patients (55%; range, 1-5). The majority of LCS103-treated patients reported reduced severity for urological symptoms (pain, frequency, and urgency on urination; and nocturia), as well as for weakness and fatigue, and for general wellbeing. No adverse events were associated with use of the botanical formula. Further prospective randomized trials are needed to confirm and better understand these initial findings.

[Trametenolic acid inhibits migration and invasion of hepatocellular carcinoma HepG2.2.15 cells via RhoC/ROCK1 pathway].

This study investigated the effect of trametenolic acid(TA) on the migration and invasion of human hepatocellular carcinoma HepG2.2.15 cells by using Ras homolog gene family member C(RhoC) as the target and probed into the mechanism, aiming to provide a basis for the utilization of TA. The methyl thiazolyl tetrazolium(MTT) assay was employed to examine the proliferation of HepG2.2.15 cells exposed to TA, and scratch and Transwell assays to examine the cell migration and invasion. The pull down assay was employed to determine the impact of TA on RhoC GTPase activity. Western blot was employed to measure the effect of TA on the transport of RhoC from cytoplasm to cell membrane and the expression of RhoC/Rho-associated kinase 1(ROCK1)/myosin light chain(MLC)/matrix metalloprotease 2(MMP2)/MMP9 pathway-related proteins. RhoC was over-expressed by transient transfection of pcDNA3.1-RhoC. The changes of F-actin in the cytoskeleton were detected by Laser confocal microscopy. In addition, the changes of cell migration and invasion, expression of proteins in the RhoC/ROCK1/MLC/MMP2/MMP9 pathway, and RhoC GTPase activity were detected. The subcutaneously transplanted tumor model of BALB/c nude mice and the low-, medium-, and high-dose(40, 80, and 120 mg·kg~(-1), respectively) TA groups were established and sorafenib(20 mg·kg~(-1)) was used as the positive control. The tumor volume and weight in each group were measured, and the expression of related proteins in the tumor tissue was determined by Western blot. The results showed that TA inhibited the proliferation of HepG2.2.15 cells in a concentration-dependent manner, with the IC_(50) of 66.65 and 23.09 µmol·L~(-1) at the time points of 24 and 48 h, respectively. The drug administration groups had small tumors with low mass. The tumor inhibition rates of sorafenib and low-, medium-and high-dose TA were 62.23%, 26.48%, 55.45%, and 62.36%, respectively. TA reduced migrating and invading cells and inhibited RhoC protein expression and RhoC GTPase activity in a concentration-dependent manner, dramatically reducing RhoC and membrane-bound RhoC GTPase. The expression of ROCK1, MLC, p-MLC, MMP2, and MMP9 downstream of RhoC can be significantly inhibited by TA, as confirmed in both in vitro and in vivo experiments. After HepG2.2.15 cells were transfected with pcDNA3.1-RhoC to overexpress RhoC, TA down-regulated the protein levels of RhoC, ROCK1, MLC, p-MLC, MMP2, and MMP9 and decreased the activity of RhoC GTPase, with the inhibition level comparable to that before overexpression. In summary, TA can inhibit the migration and invasion of HepG2.2.15 cells. It can inhibit the RhoC/ROCK1/MLC/MMP2/MMP9 signaling pathway by suppressing RhoC GTPase activity and down-regulating RhoC expression. This study provides a new idea for the development of autophagy modulators targeting HSP90α to block the proliferation and inhibit the invasion and migration of hepatocellular carcinoma cells via multiple targets of active components in traditional Chinese medicines.

miR-30d-5p inhibits proliferation, invasion and migration of breast cancer cells by targeting SERPINE1 and promoting fatty acid ß-oxidation.

Breast cancer (BC) is among the top three most prevalent cancers across the world, especially in women, and its pathogenesis is still unknown. Fatty acid ß-oxidation is highly associated with breast cancer. Serpin family E member 1 (SERPINE1)-induced down-regulation of fatty acid ß-oxidation can facilitate BC cell proliferation, invasion, and metastasis. In this paper, the difference of miR-30d-5p expressions in both cancerous tissues and para-carcinoma tissues was first detected. Next, the expressions of SERPINE1, long-chain acyl-CoA dehydrogenase (LCAD) and medium-chain acyl-CoA dehydrogenase (MCAD) in the aforementioned tissues were analyzed. Finally, miR-30d-5p mimics were supplemented to breast cancer cells to observe the miR-30d-5p effect upon breast cancer cells. Via immunofluorescence assay and Western blotting, it was found that cancerous tissues had lower expressions of miR-30d-5p, MCAD and LCAD and a higher expression of SERPINE1 than para-carcinoma tissues. The miR-30d-5p mimic group had a decreased SERPINE1 expression and increased MCAD and LCAD expressions compared with the NC group, thus inhibiting BC cell proliferation, invasion, and metastasis. To sum up, miR-30d-5p blocks the cell proliferation, invasion and metastasis by targeting SERPINE1 and promoting fatty acid ß-oxidation. Preclinical studies are further required to establish a fatty acid ß-oxidation-targeting therapy for breast cancer.

Paris polyphylla saponins II inhibits invasive, migration and epithelial-mesenchymal transition of melanoma cells through activation of autophagy.

Malignant melanoma is a kind of malignant tumor derived from normal epidermal melanocytes or original nevus cells. It has a high degree of malignancy, rapid progress, dangerous condition, and poor prognosis. In recent years, the innovation of traditional Chinese medicine has broadened the scope and effect of tumor treatment. It is a hotspot and breakthrough to find new anti-tumor invasion and migration drugs from natural plants or traditional Chinese medicine. This study explored the role of PPII in promoting autophagy to inhibit EMT of melanoma cells, the role of the PI3K/Akt signaling pathway in the invasion and migration of melanoma cells induced by PPII. We found that PPII effectively inhibited the proliferation, invasion and migration of melanoma B16 and B16F10 in vitro, and induced autophagy. We also established the xenograft tumor and metastatic tumor model of C57BL/6 mice with B16F10 cells. Results showed that PPII effectively inhibited the growth of transplanted tumors, induced autophagy and inhibited the expression level of EMT related protein; Metastasis experiment showed that PPII inhibited the invasion and migration of B16F10, the effect of inhibiting lung metastasis is the most significant. Further mechanism studies showed that the inhibition of PPII on melanoma invasion and migration is related to its induction of autophagy and then inhibition of EMT.

Comparison of hyperthermic intravesical chemotherapy and Bacillus Calmette-Guerin therapy in high-risk non-muscle invasive bladder cancer: a matched-pair analysis.

PURPOSE: To compare adjuvant hyperthermic intravesical chemotherapy (HIVEC) with mitomycin C and standard Bacillus Calmette-Guerin (BCG) therapy in terms of oncological outcomes and adverse events in patients with high-risk non-muscle-invasive bladder cancer (NMIBC). MATERIALS AND METHODS: The data of patients with high-risk papillary NMIBC treated with adjuvant intravesical BCG instillations or HIVEC in our institution between June 2017 and August 2022 were analyzed retrospectively. Twenty-four patients who received HIVEC were matched 1:1 with patients receiving BCG therapy based on tumor characteristics (tumor stage and grade), age, gender, smoking status, and the number of tumors (single or multiple). HIVEC and standard BCG treatments were compared in terms of recurrence-free survival (RFS), progression-free survival (PFS), and adverse events. RESULTS: Forty-eight patients (24 in the BCG group and 24 in the HIVEC group) were included in the study. The median follow-up times of the BCG and HIVEC groups were 32 [interquartile range (IQR): 28.0-47.8] and 28 (IQR: 16.7-41.8) months, respectively (p = 0.11). There was no significant difference between the groups in terms of the 24-month RFS (BCG 83% vs HIVEC 88%, p = 0.64) and the 24-month PFS (BCG 100% vs HIVEC 94%, p = 0.61). Regarding the safety profile, at least one adverse event occurred in 13 (54%) of the patients in the BCG group and 12 (50.0%) of those in the HIVEC group (p = 0.77). CONCLUSION: This study demonstrated that HIVEC with mitomycin C has a similar oncological efficacy and safety profile to standard BCG therapy in high-risk NMIBC.

Device-assisted intravesical chemotherapy versus bacillus Calmette-Guerin for intermediate or high-risk non-muscle invasive bladder cancer: a systematic reviewer and meta-analysis.

PURPOSE: To investigate the effectiveness and safety of device-assisted intravesical chemotherapy compared to Bacillus Calmette-Guerin (BCG) in the treatment of patients with intermediate- and high-risk non-muscle-invasive bladder cancer (NMIBC). METHODS: In February 2023, a systematic search was conducted on the PubMed, Cochrane, and Embase databases. Following the PRISMA guidelines, a systematic review and meta-analysis of the primary outcomes of interest were performed. The review was prospectively registered on PROSPERO under the registration number CRD42023398559. RESULTS: A total of 10 studies involving 1160 patients were included. The results of the meta-analysis showed that compared to BCG, device-assisted chemotherapy had a lower recurrence rate (OR: 0.63, 95% CI: 0.48-0.84, p = 0.001), longer recurrence-free survival (OR: 0.64, 95% CI: 0.47-0.88, p = 0.006), and lower incidence of fever (OR: 0.18, 95% CI: 0.08-0.44, p = 0.0002). However, no significant differences were observed between the two groups in terms of progression, overall survival, progression-free survival, disease-free survival, overall adverse events, serious adverse events, hematuria, allergy, and general discomfort. Subgroup analysis revealed that neither chemohyperthermia (CHT) nor electromotive drug administration (EMDA) showed statistically significant differences in oncological outcomes compared to BCG. Regarding adverse events, both CHT and EMDA groups showed lower rates of fever compared to the BCG group (OR: 0.26, 95% CI: 0.10-0.67, p = 0.005, and OR: 0.14, 95% CI: 0.05-0.37, p < 0.0001, respectively). No significant differences were observed in the remaining adverse events between either the CHT or EMDA group and the BCG group. CONCLUSION: Device-assisted intravesical chemotherapy appears to be a safe and viable alternative to BCG for patients with intermediate and high-risk NMIBC, showing comparable oncological outcomes and adverse events.

miR-638 suppresses cervical cancer progression by inhibiting NCAPG2 under the treatment of Tetrandrine.

BACKGROUND: The interaction of microRNA with Chinese herbal medicines is a promising therapeutic approach for prevention of cervical cancer. METHODS: Western blotting or qRT-PCR were carried out to identify the expression of NCAPG2 and miR-638. A tetrandrine (TET) cell model was used to explore the effects of miR-638 and its target gene NCAPG2 using CCK-8, transwell, wound healing, and western blot assays. Furthermore, luciferase activity assay was conducted to measure the interaction among TET, NCAPG2 and miR-638. RESULTS: Under TET treatment, Hela and SiHa cells exhibited repressed cell viability, migration, invasion, and epithelial-mesenchymal transition (EMT), and these effects were further enhanced by high expression of miR-638. In contrast, NCAPG2 expression was low in TET-treated cells and had an opposite effect to that of miR-638. CONCLUSION: We highlighted that miR-638 suppresses cervical cancer progression by inhibiting NCAPG2 under tetrandrine treatment.

Combination of hyperthermia and intravesical chemotherapy for the treatment of pT1 stage bladder cancer: A retrospectively clinical study.

PURPOSE: To evaluate the efficiency and safety of combined local bladder hyperthermia and intravesical chemotherapy (IVC) for the treatment of patients with pT1 stage bladder cancer. METHOD: A total of 189 patients with pT1 who underwent transurethral resection of bladder cancer (TURBT) were retrospectively reviewed. After TURBT, the patients with low-grade urothelial carcinoma (UC) were treated with either an IVC with pirarubicin (THP) protocol or chemo-thermotherapy (CHT) with THP protocol, whereas patients with high-grade UC were treated with either an intravesical immunotherapy (IVI) with bacillus Calmette-Guerin (BCG) protocol or CHT protocol, patients' characteristics, tumor biological features, and follow-up data were analyzed and compared between CHT and IVC group in low-grade UC, CHT, and IVI group in high-grade UC, respectively. RESULTS: The median follow-up time was 24 months. In patients with low-grade UC, the median recurrence free survival (RFS) interval and costs of treatment in CHT group were significantly higher than those in IVC group (p = .01, p < .001, respectively), CHT was associated with higher RFS compared with IVC by Kaplan-Meier analysis, and three patients in IVC group upgraded to high grade when tumor recurred, whereas no cases were found upgraded in CHT group, p = .38. In patients with high-grade UC, tumor recurrence rates at 12 (p = .004) and 24 months (p = .004) after TURBT, rate of complications (p = .04)-especially for hematuresis (p = .03) and irritation symptoms (p = .04)-the median costs of treatment (p < .001) in CHT group were significantly lower than those in IVI group, RFS interval, health-related quality of life) at 12 and 24 months after TURBT in CHT group was significantly higher than those in IVI group (p < .001, p = .002, and p < .001, respectively), and CHT was associated with higher RFS compared with IVI by Kaplan-Meier analysis. The rate of patients upstaged to pT2 in CHT group seemed lower than that in IVI group, but there was no significantly statistical difference (14.3% vs. 24%, p = .58). CONCLUSION: CHT has a beneficial prophylactic effect in patients with pT1 bladder cancer, especially in patients with high-grade UC, which is much more effective and safer than BCG, meanwhile it costs less compared with BCG.

The relationship between BCG immunotherapy and oxidative stress parameters in patients with nonmuscle invasive bladder cancer.

INTRODUCTION: Environmental chemicals have been associated with the regulation of oxidative stress markers, which have the potential for the development of bladder cancer. However, limited studies on the function of oxidative stress parameters and nonmuscle invasive bladder cancer (NMIBC) in therapy response are available. Here we studied the oxidative stress parameters in response to BCG immunotherapy in NMIBC patients. MATERIAL AND METHODS: A total of 120 patients with NMIBC and treatment with BCG were enrolled and categorized into 2 groups on BCG response, 50 patients were BCG-responsive (BCG-R) and 70 were BCG-nonresponsive (BCG-N). BCG-R have no evidence of tumor recurrence or advancement after 1 year of BCG immunotherapy, but BCG-N has a recurrence of tumor after 3 to 6 months cycles of BCG instillation, as determined by cystoscopy. In all groups, we measured the levels of oxidative stress markers- malondialdehyde (MDA), nitric oxide (NO), superoxide dismutase (SOD), and catalase (CAT). RESULTS: The levels of oxidative stress markers viz. MDA, NO, and SOD in the BCG-N group were significantly higher (P < 0.001) than in the BCG-R group. Furthermore, the data demonstrated a significant correlation between oxidative stress marker and NMIBC T1 high grade and tumor size >2.5 cm. However, no statistically significant difference was found between studied groups with CAT. CONCLUSION: The findings suggest that the carcinogenesis of NMIBC is associated with oxidative damage of biomolecules and indicates the involvement of oxidative stress markers in the development and recurrence of NMIBC.; Therefore, it is critical to ensure the management for T1 high grade and tumor size of >2.5 cm for antioxidant protection.

Surgery for Hepatocellular Carcinoma With Macroscopic Vascular Invasion in the Era of Modern Molecular Therapy.

It has been reported that patients with macroscopic vascular invasion accompanying hepatocellular carcinoma have a poor prognosis. Modern molecular therapy with multitargeted tyrosine kinase inhibitors and immune checkpoint inhibitors has shown promising results in patients with metastatic hepatocellular carcinoma; however, molecular therapy is limited to patients with Child-Pugh class A disease. This review summarizes the present status of surgical therapies, including conversion hepatectomy, for patients with MVI in the developing era of novel molecular therapy. Phase III studies showed patients with macroscopic vascular invasion had significant survival benefits from sorafenib [hazard ratio (HR)=0.68] and regorafenib (HR=0.67) versus placebo, and nivolumab (HR=0.74) versus sorafenib. Lenvatinib and atezolizumab plus bevacizumab showed marginal effects. It is currently widely assumed that molecular therapy alone will not cure the disease but that additional conversion hepatectomy will be required. A response other than progressive disease is essential but a pathological complete response is not always required. A significant randomized controlled trial has already started in China to assess the necessity for conversion hepatectomy after effective atezolizumab plus bevacizumab treatment, and the results are still awaited. According to Japanese national data, upfront hepatectomy can be recommended for patients with initially resectable disease and macroscopic vascular invasion other than for those with tumors in the main portal vein and the inferior vena cava. In addition, adequate adjuvant therapies with hepatic arterial chemotherapy and transarterial chemoembolization may be beneficial but an effective adjuvant molecular therapy is currently unavailable. In conclusion, novel molecular therapies with higher response rates customized to the oncologic characteristics of each hepatocellular carcinoma with macroscopic vascular invasion are needed to increase the likelihood of conversion surgery and improve long-term outcomes.

The efficacy of hyperthermic intravesical chemotherapy in high-risk non-muscle-invasive bladder cancer patients with BCG intolerance.

BACKGROUND AND AIM: Some patients with high-risk non-muscle-invasive bladder cancer (NMIBC) are unable to receive adequate BCG instillations due to intolerance. In this study we aimed to investigate the efficacy and tolerability of hyperthermic intravesical chemotherapy (HIVEC®) treatment using Mitomycin C (MMC) in BCG-intolerant NMIBC patients. METHODS: Retrospectively collected data from a total of 22 high-risk papillary NMIBC patients who received adjuvant HIVEC therapy for BCG intolerance were analyzed. The primary outcomes of the study were recurrence-free survival (RFS), time to recurrence, progression-free survival (PFS), and time to progression following initial TURB. Detection of histologically confirmed urothelial carcinoma during follow-up was considered as recurrence, while detection of muscle-invasive disease was defined as progression. The secondary outcome was adverse events of HIVEC treatment. RESULTS: The median follow-up was 32.2 (IQR: 17.8-42.8) months. The RFS and PFS rates were 81.8% and 95.4%, respectively. The mean time to tumor recurrence and progression was 29.2 ± 14.3 and 16.7 months, respectively. Adverse events occurred in 50% of patients, and 95% of adverse events were mild to moderate. CONCLUSION: This study demonstrated that adjuvant HIVEC with MMC is an effective and safe alternative bladder sparing treatment in BCG intolerant high risk papillary NMIBC patients.

Non-muscle-invasive Bladder Cancer: Side-by-Side Guideline Comparison.

Clinical guidelines from the European Association of Urology, American Urological Association, Society of Urologic Oncology, and National Comprehensive Cancer Network are some of the most frequently accessed publications. These guidelines are published at varying frequency and use different methods to formulate their recommendations. Many guidelines still rely on expert opinion in areas where there is a lack of data. To be well executed guidelines they need to involve comprehensive panels who are content experts and multispecialty. This article reviews the strengths and weaknesses of current guidelines for non-muscle-invasive bladder cancer and possible opportunities for future improvements. PATIENT SUMMARY: Quality recommendations in guidelines are critical to provide the most effective care for patients with non-muscle-invasive bladder cancer.

Zhuidu Formula suppresses the migratory and invasive properties of triple-negative breast cancer cells via dual signaling pathways of RhoA/ROCK and CDC42/MRCK.

ETHNOPHARMACOLOGICAL RELEVANCE: Zhuidu Formula (ZDF) is composed of triptolide, cinobufagin and paclitaxel, which are the active ingredients of Tripterygium wilfordii Hook. F, dried toad skin and Taxus wallichiana var. chinensis (Pilg) Florin, respectively. Modern pharmacological studies show that triptolide, cinobufagin, and paclitaxel are well-known natural compounds that exert anti-tumor effects by interfering with DNA synthesis, inducing tumor cell apoptosis, and inhibiting the dynamic balance of the tubulin. However, the mechanism by which the three compounds inhibit triple-negative breast cancer (TNBC) metastasis is unknown. OBJECTIVE: The objective of this investigation was to examine the inhibitory essences of ZDF on the metastasis of TNBC and elucidate its potential mechanism. MATERIALS AND METHODS: Cell viability of triptolide (TPL), cinobufagin (CBF), and paclitaxel (PTX) on MDA-MB-231 cells was assessed employing a CCK-8 assay. The drug interactions of the three drugs on MDA-MB-231 cells were determined in vitro utilizing the Chou-Talalay method. MDA-MB-231 cells were identified for migration, invasion and adhesion in vitro through the implementation of the scratch assay, transwell assay and adhesion assay, respectively. The formation of cytoskeleton protein F-actin was detected by immunofluorescence assay. The expressions of MMP-2 and MMP-9 in the supernatant of the cells were determined by ELISA analysis. The Western blot and RT-qPCR were employed to explore the protein expressions associated with the dual signaling pathways of RhoA/ROCK and CDC42/MRCK. The anti-tumor efficacy of ZDF in vivo and its preliminary mechanism were investigated in the mouse 4T1 TNBC model. RESULTS: The results demonstrated that ZDF could significantly reduce the viability of the MDA-MB-231 cell, and the combination index (CI) values of actual compatibility experimental points were all less than 1, demonstrating a favorable synergistic compatibility relationship. It was found that ZDF reduces RhoA/ROCK and CDC42/MRCK dual signaling pathways, which are responsible for MDA-MB-231cell migration, invasion, and adhesion. Additionally, there has been a significant reduction in the manifestation of cytoskeleton-related proteins. Furthermore, the expression levels of RhoA, CDC42, ROCK2, and MRCKß mRNA and protein were down-regulated. ZDF significantly decreased the protein expressions of vimentin, cytokeratin-8, Arp2 and N-WASP, and inhibited actin polymerization and actomyosin contraction. Furthermore, MMP-2 and MMP-9 levels in the high-dose ZDF group were decreased by 30% and 26%, respectively. ZDF significantly reduced the tumor volume and protein expressions of ROCK2 and MRCKß in tumor tissues without eliciting any perceptible alterations in the physical mass of the mice, and the reduction was more pronounced than that of the BDP5290 treated group. CONCLUSION: The current investigation demonstrates that ZDF exhibits a proficient inhibitory impact on TNBC metastasis by regulating cytoskeletal proteins through the dual signaling pathways of RhoA/ROCK and CDC42/MRCK. Furthermore, the findings indicate that ZDF has significant anti-tumorigenic and anti-metastatic characteristics in breast cancer animal models.

Evaluation of thermal dose effect in radiofrequency-induced hyperthermia with intravesical chemotherapy for nonmuscle invasive bladder cancer.

PURPOSE: In nonmuscle invasive bladder cancer (NMIBC) patients who fail standard intravesical treatment and are unfit or unwilling to undergo a radical cystectomy, radiofrequency (RF)-induced hyperthermia combined with intravesical chemotherapy (RF-CHT) has shown promising results. We studied whether higher thermal dose improves clinical NMIBC outcome. METHODS AND MATERIALS: The cohort comprised 108 patients who started with RF-CHT between November 2013 and December 2019. Patients received intravesical mitomycin-C or epirubicin. Bladder hyperthermia was accomplished with an intravesical 915 MHz RF device guided by intravesical thermometry. We assessed the association between thermal dose parameters (including median temperature and Cumulative Equivalent Minutes of T50 at 43 °C [CEM43T50]) and complete response (CR) at six months for patients with (concomitant) carcinoma in situ (CIS), and recurrence-free survival (RFS) for patients with papillary disease. RESULTS: Median temperature and CEM43T50 per treatment were 40.9 (IQR 40.8-41.1) °C and 3.1 (IQR 0.9-2.4) minutes, respectively. Analyses showed no association between any thermal dose parameter and CR or RFS (p > 0.05). Less bladder spasms during treatment sessions was associated with increased median temperature and CEM43T50 (adjusted OR 0.01 and 0.34, both p < 0.001). CONCLUSIONS: No significant association between thermal dose and NMIBC outcome was found. Possibly thermal dose effect in patients of the current cohort exceeds a certain threshold value. On the other hand, occurrence of bladder spasms had a thermal dose limiting effect. We advise to treat patients with temperatures >40.5 °C for at least 45 min while respecting individual tolerability, including occurrence of bladder spasms.

A Phase 1/2 Study of Rapamycin and Cisplatin/Gemcitabine for Treatment of Patients With Muscle-Invasive Bladder Cancer.

INTRODUCTION: Cisplatin-based neoadjuvant chemotherapy (NAC) followed by cystectomy is the standard for muscle-invasive bladder cancer (MIBC), however, NAC confers only a small survival benefit and new strategies are needed to increase its efficacy. Pre-clinical data suggest that in response to DNA damage the tumor microenvironment (TME) adopts a paracrine secretory phenotype dependent on mTOR signaling which may provide an escape mechanism for tumor resistance, thus offering an opportunity to increase NAC effectiveness with mTOR blockade. PATIENTS & METHODS: We conducted a phase I/II clinical trial to assess the safety and efficacy of gemcitabine-cisplatin-rapamycin combination. Grapefruit juice was administered to enhance rapamycin pharmacokinetics by inhibiting intestinal enzymatic degradation. Phase I was a dose determination/safety study followed by a single arm Phase II study of NAC prior to radical cystectomy evaluating pathologic response with a 26% pCR rate target. RESULTS: In phase I, 6 patients enrolled, and the phase 2 dose of 35 mg rapamycin established. Fifteen patients enrolled in phase II; 13 were evaluable. Rapamycin was tolerated without serious adverse events. At the preplanned analysis, the complete response rate (23%) did not meet the prespecified level for continuing and the study was stopped due to futility. With immunohistochemistry, successful suppression of the mTOR signaling pathway in the tumor was achieved while limited mTOR activity was seen in the TME. CONCLUSION: Adding rapamycin to gemcitabine-cisplatin therapy for patients with MIBC was well tolerated but failed to improve therapeutic efficacy despite evidence of mTOR blockade in tumor cells. Further efforts to understand the role of the tumor microenvironment in chemotherapy resistance is needed.

The Prognostic Impact of Extent of Vascular Invasion in Follicular Thyroid Carcinoma.

BACKGROUND: Encapsulated angioinvasive follicular thyroid carcinoma (EAFTC) is associated with an increased risk of distant metastasis and reduced survival compared to minimally invasive follicular thyroid carcinoma (MIFTC). There is controversy regarding the extent of surgery and adjuvant radioactive iodine therapy for angioinvasive follicular thyroid carcinoma when stratified by number of foci of angioinvasion. METHODS: All follicular thyroid carcinoma cases from 1990-2018 were identified from a thyroid cancer database. Primary outcomes were distant metastasis-free survival (DMFS) and disease-specific survival (DSS) with factors of interest being age, gender, tumour size, treatment, foci of angioinvasion and histological subtype. RESULTS: A total of 292 cases were identified; 139 MIFTC, 141 EAFTC and 12 widely invasive follicular thyroid carcinoma (WIFTC). Over a follow-up period of 6.25 years, DMFS was significantly reduced (p < 0.001) with 14.2% (EAFTC) and 50% of WIFTC developing metastasis. The risk of metastasis in EAFTC with ≥ 4 foci of angioinvasion was 31.7% (HR = 5.89, p = 0.004), 6.3% for EAFTC with < 4 foci of angioinvasion (HR = 1.74, p = 0.47), compared to 3.6% MIFTC. Age ≥ 50 years (HR = 4.24, p = 0.005) and tumour size (HR = 1.27, p = 0.014) were significantly associated with increased risk of distant metastasis. DSS was reduced significantly (p < 0.001), with 7.8% EAFTC patients dying of disease. For EAFTC patients, DSS was 96.8% for < 4 foci and 82.6% for ≥ 4 foci of angioinvasion (p = 0.003). CONCLUSION: EAFTC is at increased risk of distant metastasis related to the extent of angioinvasion. Tumours with < 4 foci of angioinvasion should be considered for a total thyroidectomy, particularly in older patients.

Development and investigation of a novel device with gemcitabine for hyperthermic intravesical chemotherapy.

PURPOSE: To evaluate the safety and efficacy of a novel hyperthermic intravesical chemotherapy (HIVEC) device in combination with gemcitabine. MATERIALS AND METHODS: A pilot clinical trial was performed on patients with high-risk non-muscle invasive bladder cancer (NMIBC), who received HIVEC via the novel device (BR-PRG). Treatment regimen included eight weekly instillations of intravesical GEM (3 g in 150 mL normal saline [NS]) at a temperature of 45 °C for 60 min. Assessment of adverse events (AEs) was the primary objective of the trial. Disease recurrence and the thermal stability of GEM were also analyzed. RESULTS: A total of 116 HIVEC treatments were delivered. Fifteen and eighteen patients were included in the effectiveness and safety analysis, respectively. Median follow-up was 12 months; five patients experienced a disease recurrence. One-year cumulative incidence of recurrence was 23.8% in EORTC intermediate risk group and 37.5% in high-risk group. Ten patients experienced at least one AE, with the most common being acute urinary tract infection, followed by urinary tract pain, and hematuria. Two patients experienced acute cystitis (grade 3 AE) and instillations were postponed until full recovery. Other AEs were minor, and no systemic toxicity was observed. The contents of GEM in solution of 0.9% NS or NS mixed with artificial urine were stable at 25 °C, 37 °C, 43 °C, 45 °C, 47 °C and 50 °C for 2 h. CONCLUSION: GEM can be an ideal drug for use in HIVEC due to its good thermal stability. BR-PRG, combined with GEM was safe and effective in administering HIVEC.