Intercellular Interactions Mediated by HGF And TGF-Β Promote the 3D Spherical and Xenograft Growth of Liver Cancer Cells.

BACKGROUND: Recently, the importance of the interactions between liver cancer cells and fibroblasts has been increasingly recognized; however, many details remain to be explored. METHODS: In this work, we first studied their intercellular interactions using conditioned medium from mouse embryonic fibroblasts (MEFs), then through a previously established coculture model. RESULTS: Culturing in a conditioned medium from MEFs could significantly increase the growth, migration, and invasion of liver cancer cells. The coculture model further demonstrated that a positive feedback loop was formed between transforming growth factor-ß (TGF-ß) from HepG2 cells and mHGF (mouse hepatocyte growth factor) from MEFs during coculture. In this feedback loop, c-Met expression in HepG2 cells was significantly increased, and its downstream signaling pathways, such as Src/FAK, PI3K/AKT, and RAF/MEK/ERK, were activated. Moreover, the proportion of activated MEFs was also increased. More importantly, the growth-promoting effects caused by the interaction of these two cell types were validated in vitro by a 3D spheroid growth assay and in vivo by a xenograft mouse model. CONCLUSION: Collectively, these findings provide valuable insights into the interactions between fibroblasts and liver cancer cells, which may have therapeutic implications for the treatment of liver cancer.

The Effects of Ginkgo biloba Extract on Autophagy in Human Macrophages Stimulated by Cigarette Smoke Extract.

OBJECTIVE: To investigate the effects of Ginkgo biloba extract (GBE) on autophagy in human macrophages stimulated by cigarette smoke extract (CSE). METHODS: The human monocyte cell line U937 was cultured in vitro, and phorbol ester (PMA) was added to the cell culture medium to induce differentiation into human macrophages. CSE was prepared by traditional methods for experiments. The cells were divided into four groups: the blank group, the CSE model group, the GBE + CSE group, and the rapamycin + CSE group. Immunofluorescence was used to identify human macrophages, transmission electron microscopy was used to observe the ultrastructure of human macrophages in each group, ELISA was used to measure the amount of IL-6 and IL-10 in the supernatant from each group of cells, the mRNA levels of p62, ATG5, ATG7, and Rab7 were measured by real-time qPCR, and the protein expression levels of p62, ATG5, ATG7, and Rab7 were measured by Western blotting. RESULTS: U937 cells were successfully differentiated into human macrophages after induction with PMA. The CSE model group had many more autophagosomes than the blank group. Compared with the CSE model group, the GBE + CSE group and the rapamycin + CSE group had significantly more autophagolysosomal. Compared with the other groups, the CSE model group had a higher level of IL-6 but a lower level of IL-10 in the supernatant (p < 0.05). Compared with the blank group, the mRNA and protein expression levels of p62 in the CSE model group were significantly decreased, while the mRNA and protein expression levels of ATG5 and ATG7 were significantly increased in the CSE model group (p < 0.05). No difference was found in the mRNA and protein expression levels of Rab7 between the blank group and the CSE model group. Compared with the CSE model group, the IL-6 level in the GBE + CSE group and the rapamycin + CSE group cell culture supernatant decreased significantly, p62 mRNA and protein expression significantly decreased, while ATG5, ATG7, and Rab7 mRNA and protein expression levels were significantly increased (p < 0.05). Moreover, increased LC3-II/LC3-I ratio were also found in the GBE + CSE group and the rapamycin + CSE group compared with the CSE model group. CONCLUSIONS: GBE could promote the fusion of autophagosomes and lysosomes in human macrophages, enhance the autophagy function of human macrophages, and reduce the damaging effect of CSE on the autophagy function of macrophages.

Effects of high-activity radioactive iodine treatment on renal function in patients with differentiated thyroid carcinoma - retrospective study.

INTRODUCTION: It is not clear whether high-activity radioactive iodine (¹³¹I) treatment will affect renal function. This study aimed to investigate the effects of high-activity ¹³¹I treatment on the clinical metrics of renal function in patients with differentiated thyroid carcinoma (DTC). MATERIAL AND METHODS: 262 DTC patients with abnormal baseline renal function (group A) and 262 DTC patients with normal baseline renal function (group B) who received 131I therapy were analysed. Each group was further divided into three subgroups based on the cumulative activity of 131I: subgroup 1 if the cumulative activity was less than 11.1 GBq; subgroup 2 if the cumulative activity was between 11.1 GBq and 18.5 GBq; and subgroup 3 if the cumulative activity was more than 18.5 GBq. The clinical metrics of renal function including serum creatinine (SCr), blood urea nitrogen (BUN) and estimated glomerular filtration rate (eGFR) were measured and compared before initial 131I treatment and 5 years later. RESULT: There was no significant difference of the demographics between the two groups. In group A, SCr and BUN levels were elevated in 186 and 113 patients, respectively, and eGFR was decreased in 108 patients before the initial ¹³¹I therapy. SCr and BUN levels were found to be increased in all subgroups 5 years after the initial ¹³¹I therapy; furthermore, eGFR was found to be decreased in all subgroups after ¹³¹I therapy, and the difference was statistically significant (p < 0.05). A gender bias was not observed in the changing trends of SCr and BUN levels and eGFR. In group B, no significant difference in the mean levels of SCr, BUN, and eGFR was observed in the 3 subgroups (p > 0.05), regardless of gender, before the initial ¹³¹I therapy and 5 years later. A total of 5, 2, and 2 patients presented with abnormal renal function after ¹³¹I treatment in subgroups 1, 2, and 3, respectively. No statistically significant difference was observed in the incidence of renal dysfunction among the 3 subgroups (p = 0.423). CONCLUSION: Our findings suggest that the nephrotoxicity of high-activity ¹³¹I therapy, regardless of gender, is very low in patients with DTC with normal renal function; however, high-activity ¹³¹I therapy may exacerbate the loss of renal function in those with renal dysfunction.

Recent Progress on the Role of Fibronectin in Tumor Stromal Immunity and Immunotherapy.

As a major component of the stromal microenvironment of various solid tumors, the extracellular matrix (ECM) has attracted increasing attention in cancer-related studies. ECM in the tumor stroma not only provides an external barrier and framework for tumor cell adhesion and movement, but also acts as an active regulator that modulates the tumor microenvironment, including stromal immunity. Fibronectin (Fn), as a core component of the ECM, plays a key role in the assembly and remodeling of the ECM. Hence, understanding the role of Fn in the modulation of tumor stromal immunity is of great importance for cancer immunotherapy. Hence, in-depth studies on the underlying mechanisms of Fn in tumors are urgently needed to clarify the current understanding and issues and to identify new and specific targets for effective diagnosis and treatment purposes. In this review, we summarize the structure and role of Fn, its potent derivatives in tumor stromal immunity, and their biological effects and mechanisms in tumor development. In addition, we discuss the novel applications of Fn in tumor treatment. Therefore, this review can provide prospective insight into Fn immunotherapeutic applications in tumor treatment.

Quantitative Scintigraphy Evaluated the Relationship between 131I Therapy and Salivary Glands Function in DTC Patients: A Retrospective Analysis.

Purpose: Quantitative scintigraphy to evaluate salivary gland function changes in patients with differentiated thyroid cancer (DTC) after iodine-131 (131I) treatment. Methods: A total of 458 patients with DTC grouped by sex and age were included. Salivary gland scintigraphy was performed to evaluate salivary gland function before and after 131I treatment. The uptake fraction (UF), uptake index (UI), and excretion fraction (EF) of two pairs of parotid glands and submandibular glands were measured and compared. The Chi-square test was conducted according to function impairment count. Results: Salivary gland function in different age groups and sexes were quite different, especially for women <55 years old, who had decreased UF, UI, and EF of all four glands without basal injury. The secretion or uptake function of some salivary glands with basic function impairment before 131I treatment was increased after iodine treatment. Only a small percentage of males showed reduced functional parameters after several treatments. The most significant difference in the count of impairment for the four salivary glands were the first and third examinations, which was more evident in women. The submandibular gland had the most significant reduction in uptake. Conclusion: Changes in salivary gland function are more common in young females being treated for DTC. Impairment of salivary gland function is correlated with the number of treatments and the cumulative dose of 131I. Some salivary gland functions impaired before 131I treatment were enhanced in the early treatment.

Umbilical Cord Mesenchymal Stem Cell Therapy for Regenerative Treatment of Rheumatoid Arthritis: Opportunities and Challenges.

Rheumatoid arthritis (RA) is an autoimmune disease of unknown etiology with a high rate of disability. Traditional treatments for RA remain a challenging issue. For example, nonsteroidal anti-inflammatory drugs (NSAIDs) have no therapeutic effects on joint destruction, and the prominent side effects include gastrointestinal symptoms. RA is characterized by recurrence and bone attrition. Therefore, regenerative medicine and the use of umbilical cord mesenchymal stem cell (UC-MSC) therapies have recently emerged as potential options. UC-MSCs are multifunctional stem cells that are present in neonatal umbilical cord tissue and can differentiate into many kinds of cells, which have broad clinical application prospects in the tissue engineering of bone, cartilage, muscle, tendon, ligament, nerve, liver, endothelium, and myocardium. Moreover, UC-MSCs have advantages, such as convenient collection of materials and no ethical disputes; thus, these cells have attracted increasing attention from researchers. However, there are few clinical studies regarding UC-MSC therapy for RA. In this paper, we will review traditional drugs for RA treatment and then focus on UC-MSC therapy for RA, including preclinical and clinical UC-MSC applications for RA patients in the context of regenerative medicine. Finally, we will summarize the challenges and perspectives of UC-MSCs as a potential therapeutic strategy for RA. This review will help to design and discover more potent and efficacious treatments for RA patients and aid in advancing this class of cell therapy.

Precise medicine of programmed cell death-1/programmed cell death 1 ligand 1 inhibitor immunotherapy combined radiotherapy for inoperable advanced lung cancer: A protocol for systematic review and meta-analysis.

BACKGROUND: Programmed cell death-1/programmed cell death 1 ligand 1 (PD-1/PD-L1) inhibitors are a group of immune checkpoint inhibitors immunotherapy for cancer treatment. These immune checkpoint inhibitors are becoming first-line treatments for several types of cancer. Radiotherapy for cancer is a traditional treatment and the therapeutic effect is not satisfactory due to the side effect of chemotherapeutic drugs. This study aims to evaluate the efficacy and safety of PD1/PD-L1 inhibitor immunotherapy combined chemotherapy for inoperable advanced lung cancer. METHODS: We will utilize PubMed, PubMed Central, EMbase, Medline, CNKI, WAN FANG Database, and Web of Science to screen eligible studies published from January 1, 2015 to December 30, 2020. Two reviewers will extract data and evaluate the risk of bias independently. The quality of the included studies will be evaluated using the RevMan 5.3 software for data analysis. RESULTS: This review will summarize high-quality evidence of trials to evaluate the precise medicine efficacy and safety of PD1/PD-L1 inhibitor combined radiotherapy for inoperable advanced lung cancer. CONCLUSIONS: The findings of the systematic review will provide scientific evidence of the efficacy and safety of PD1/PD-L1 inhibitor combined radiotherapy for inoperable advanced lung cancer to guide the clinician's drug use. ETHICS AND DISSEMINATION: Not applicable. INPLASY REGISTRATION NUMBER: INPLASY202140123.

Optical coherence tomography versus intravascular ultrasound in patients with myocardial infarction: a diagnostic performance study of pre-percutaneous coronary interventions

Accurate coronary measurements are important in guiding percutaneous coronary intervention. Intravascular ultrasound is a widely accepted diagnostic modality for coronary measurement before percutaneous coronary intervention. The spatial resolution of optical coherence tomography is 10 times larger than that of intravascular ultrasound. The objective of the study was to compare quantitative and qualitative parameters of frequency domain optical coherence tomography (FDOCT) with those of intravascular ultrasound and coronary angiography in patients with acute myocardial infarction. Diagnostic parameters of coronary angiography, intravascular ultrasound, and FDOCT of 250 patients with coronary artery disease who required admission diagnosis were included in the analyses. Minimum lumen diameter detected by FDOCT was larger than that detected by quantitative coronary angiography (2.11±0.1 vs 1.89±0.09 mm, P<0.0001, q=34.67) but smaller than that detected by intravascular ultrasound (2.11±0.1 vs 2.19±0.11 mm, P<0.0001, q=12.61). Minimum lumen area detected by FDOCT was smaller than that detected by intravascular ultrasound (3.41±0.01 vs 3.69±0.01 mm2, P<0.0001). FDOCT detected higher numbers of thrombus, tissue protrusion, dissection, and incomplete stent apposition than those detected by intravascular ultrasound (P<0.0001 for all). More accurate and sensitive results of the coronary lumen can be detected by FDOCT than coronary angiography and intravascular ultrasound (level of evidence: III).

Correlation analysis between the parameters of contrast-enhanced ultrasonography in evaluating cervical cancer metastasis and expression of E-cadherin.

The study aims to investigate the correlation between the parameters of contrast-enhanced ultrasonography in evaluating cervical cancer metastasis and expression of E-cadherin. All 120 patients with cervical cancer underwent contrast-enhanced ultrasonography. According to the results of postoperative pathological examination, patients were divided into distant metastasis group (group A), lymph node metastasis without distant metastasis group (group B) and no metastasis group (group C). Expression of E-cadherin in cervical cancer tissues was detected by enzyme-linked immunosorbent assay (ELISA). Correlations between the parameters of contrast-enhanced ultrasonography in evaluating cervical cancer metastasis and expression of E-cadherin were analyzed by Pearsons correlation analysis. Comparison of parameters of contrast-enhanced ultrasonography showed that, the baseline intensity of group A was 11.9±2.2 dB, which was significantly lower than that of group B and C. Baseline intensity of group B was significantly lower than that of group C (13.0±2.4 vs. 15.3±3.6 dB), significant differences were found among three groups (P<0.05). The sensitivity and specificity of the use of enhanced intensity ~83.7 dB in evaluating tumor metastasis of patients with cervical cancer were 82.42 and 79.32%, respectively. Expression level of E-cadherin protein in group A was 0.030±0.003 ng/ml, which was significantly lower than that in group B and C (P<0.05), expression level of E-cadherin protein in group A was significantly lower than that in group C (0.037±0.007 vs. 0.045±0.012 ng/ml), significant differences in the expression level of E-cadherin protein were found among the three groups of cervical cancer patients (P<0.05). Pearsons correlation analysis showed that there was a positive correlation between the baseline intensity of contrast-enhanced ultrasonography and the expression level of E-cadherin (P<0.05), while there was a negative correlation between the enhanced intensity of contrast-enhanced ultrasonography and the expression level of E-cadherin (P<0.05). Contrast-enhanced ultrasonography can be used to determine the tumor metastasis of cervical cancer patients, in addition, the combined use of contrast-enhanced ultrasonography and E-cadherin protein expression can significantly improve the diagnosis and treatment of cervical cancer.

Effectiveness of acupuncture for breast cancer related lymphedema: protocol for a single-blind, sham-controlled, randomized, multicenter trial.

BACKGROUND: Although various treatments for breast cancer related lymphedema exist, there is still a need for a more effective and convenient approach. Pilot studies and our clinical observations suggested that acupuncture may be a potential option. This study aims to verify the effectiveness of acupuncture on BCRL and evaluate its safety using a rigorously designed trial. METHODS/DESIGN: Women who are clinically diagnosed as unilateral BCRL, with a 10% to 40% increase in volume compared to the unaffected arm, will be recruited. Following baseline assessment, participants will be randomized to either the real acupuncture group or sham-acupuncture group at a ratio of 1:1, and given a standard real acupuncture or sham-acupuncture treatment accordingly on both arms followed by the same usual care of decongestive therapy. Volume measurements of both arms will be performed for every participant after each treatment. Data collected at baseline and the last session will be used to calculate the primary outcome and secondary outcomes. Other data will be exploited for interim analyses and trial monitoring. The primary outcome is the absolute reduced limb volume ratio. Secondary outcomes are incidence of adverse events and change in quality of life. A t test or non-parameter test will be used to compare the difference between two groups, and assess the overall effectiveness of acupuncture using the SPSS software (version 12). DISCUSSION: This study will help expand our knowledge about the effectiveness of acupuncture on BCRL, and how acupuncture might be used in the management of this condition. Acupuncture may be a promising complement or alternative to conventional lymphedema treatment methods, if its effectiveness is confirmed. TRIAL REGISTRATION: ClinicalTrials.gov NCT02803736 (Registered on October 31, 2016).

Efficacy and safety of Wuling San for treatment of breast-cancer-related upper extremity lymphoedema: study protocol for a pilot trial.

INTRODUCTION: Breast-cancer-related upper extremity lymphoedema (BCUL), a common complication of mastectomy, can cause physical discomfort, psychological distress, cosmetic defects, functional disability and chronic recurrent erysipelas in the affected arm(s). It is a challenge to physicians involved in the management of these patients. Wuling San, a classic prescription in Traditional Chinese Medicine used in treating oedema for thousands of years, is reported by many Chinese journals to perform well in BCUL. Therefore, the aim of this study is to verify its efficacy and evaluate its safety using rigorous methodological designs in patients with BCUL. METHODS AND ANALYSIS: To verify the efficacy and assess the safety of Wuling San over a placebo, this double-blind, randomised, placebo-controlled, multicentre trial will be carried out in three hospitals. A total of 200 eligible patients with BCUL will be randomly allocated, in a ratio of 1:1, to either the experimental medicine group or the placebo group. The primary outcome measure will be the proportion of absolute reduced limb volume, as measured by perometry. The second outcome measure will be the number of participants with adverse events. The assessment will be carried out at the following time points: before enrolment (baseline) and 2, 4, 6 and 8 weeks after treatment. ETHICS AND DISSEMINATION: This trial will be conducted in accordance with the Declaration of Helsinki and supervised by the institutional review board of the Fourth Affiliated Hospital of Guangxi Medical University (approval number PJK2016088). All patients will receive information about the trial in verbal and written forms and will give informed consent before enrolment. This trial will help to demonstrate whether Wuling San is effective in the treatment of patients with BCUL. The results will be published in peer-reviewed journals or disseminated through conference presentations. TRIAL REGISTRATION NUMBER: NCT02726477; Pre-results.

No Association between TNF-α -308G/A Polymorphism and Idiopathic Recurrent Miscarriage: A Systematic Review with Meta-Analysis and Trial Sequential Analysis.

BACKGROUND: Conflicting results were reported on the association between the TNF-α -308G/A polymorphism and idiopathic recurrent miscarriage (IRM). Though three meta-analyses have been conducted on this topic, the conclusions were contradictory, and the results may be unreliable as certain crucial conditions were neglected. METHOD: A complete search was conducted in PubMed, Cochrane Library, and Embase, other sources like Google Scholar, ClinicalTrial.gov and reference lists of relevant articles were also retrieved. All candidate articles were accessed and screened using specific inclusion and exclusion criteria. Statistical analyses were performed on data extracted from eligible studies using the STATA 12.0 software and the TSA 0.9 beta software. RESULTS: Eventually, 12 case-control studies from 11 publications (with 1,807 cases and 2,012 controls) were included in this meta-analysis, and no evidence of any significant association was found in the overall analyses between the TNF-α -308G/A polymorphism and IRM risk. However, significant association was shown in Asian population (four studies from three publications) in the dominant model (AA + GA vs. GG), the allelic model (A vs. G), and the heterozygote model (GA vs. GG). CONCLUSIONS: TNF-α -308G/A polymorphism is not associated with IRM risk. Though significant association was found in Asian population, the result needs further confirmation from more studies.

Interleukin-6 Levels in Women with Polycystic Ovary Syndrome: A Systematic Review and Meta-Analysis.

BACKGROUND: The change of serum interleukin-6(IL-6) levels in women with polycystic ovary syndrome (PCOS), as well as the relations between IL-6 levels and body mass index (BMI), insulin resistance(IR) and androgen status of PCOS patients, are not fully understood. METHODS: A literature search was performed in October 2015 using PubMed, Embase and the Cochrane Library databases to identify studies. Random-effects model was used to estimate the standardized mean differences (SMDs) with 95% confidence intervals (CIs). RESULTS: Twenty articles with 25 case-control studies included 1618 women (922 PCOS patients and 696 controls) were included in this study. IL-6 levels in controls were significantly lower than that of PCOS patients (SMD = 0.78, 95%CI = 0.41-1.16, P<0.001), with significant heterogeneity across studies (I2 = 91% and P<0.001). Meta-regression analysis model indicated IR status was the main source of heterogeneity (P = 0.005). Results from group analysis suggested that high IL-6 levels in PCOS were significantly associated with Homeostasis Model Assessment of Insulin Resistance (HOMA2-IR) ratio and total testosterone ratio (T ratio), and was found in both lean and obese women with PCOS. Cumulative meta-analysis results indicated the total effect size (SMD) had tend to be stable since 2012(0.79 to 0.92). CONCLUSIONS: A high IL-6 level is not an intrinsic characteristic of PCOS, but may be a useful monitoring biomarker for the treatment of PCOS.

Synthesis, antitumor evaluation and crystal structure of hydroxyurea derivatives.

A series of hydroxyurea derivatives have been synthesized and elucidated by means of FT-IR, (1)H-, (13)C-NMR and MS. The exact stereostructures of representative compounds have been determined by X-ray crystal structure analysis. In the crystals, inversion dimers linked by pairs of N-H...O hydrogen bonds occurred, and further N-H...O links led to chains of molecules. In vitro antitumor activities against Tca8113 human tongue cancer cells and L1210 murine leukemia cells were evaluated. A total of 8 of the 12 compounds had higher inhibitory activities than hydroxyurea against L1210 cells. Among them, the most promising compounds were 3e, 3d, 3a and 2d.