Efficacy and Safety of Placebo During the Maintenance Therapy of Ovarian Cancer in Randomized Controlled Trials: A Systematic Review and Meta-analysis.

Introduction: This meta-analysis evaluated the efficacy and safety of placebo during the maintenance therapy of ovarian cancer (OC) patients in randomized controlled trials (RCTs). Methods: A comprehensive literature review was performed for RCTs published up to and including August 2020 from four electronic databases. We analyzed the efficacy and safety in the control arms of the maintenance therapy in advanced OC patients. Hazard ratios (HRs) and the corresponding 95% confidence intervals (CIs) of progression-free survival (PFS) and overall survival (OS) were estimated in the placebo arms and the observation arms, respectively, using the Frequency Framework method. We also calculated the incidences of common adverse effects (AEs) in the placebo arms. Results: In total, 41 articles with 20,099 (4,787 in the placebo arms, 3,420 in the observation arms, and 11,892 in the experiment arms) patients were included in this meta-analysis. Compared with observation, placebo did not improve or reduce PFS (HR, 1.02; 95% CI, 0.87-1.20; P = 0.81) and OS (HR, 1.02; 95% CI, 0.89-1.16; P = 0.76) of OC patients, while other treatments, except for radiotherapy, significantly improved PFS and OS (all P < 0.05). The incidences of AEs produced by placebo were 94.03% in all grades and 20.22% in grade ≥3. The incidences of AEs were 29.75% in fatigue, 26.38% in nausea, 24.34% in abdominal pain, 18.92% in constipation, 16.65% in diarrhea, 14.55% in vomiting, 13.89% in hypertension, and 13.14% in headache. Conclusions: Placebo did not improve or reduce the PFS and OS benefits of OC patients in RCTs but increased the incidences of AEs.

Selective estrogen receptor modulator with estrogen does not affect the proliferation and apoptosis of uterine leiomyoma cells.

BACKGROUND: The administration of menopausal hormone therapy (MHT) in women with uterine leiomyomas is still debated. The purpose of this article is to study the proliferation and apoptosis of uterine leiomyoma cells under the impact of selective estrogen receptor modulator (SERM) combined with estrogen. METHODS: Primary cultured uterine leiomyoma cells in the perimenopausal period were treated with estrogen (17-beta estradiol) + SERM (raloxifene) as the tissue selective estrogen complex (TSEC) group, while both estrogen + medroxyprogesterone acetate (E+P) and estrogen (E) alone as were used as control groups. The expression of proliferating cell nuclear antigen (PCNA) and B-cell lymphoma-2 (Bcl-2) proteins was assessed by methylthiazolyldiphenyl-tetrazolium bromide (MTT) assay and western-blot analysis, respectively. RESULTS: The proliferation in the TSEC group was weaker than the control groups (P<0.001). There was no statistical difference between the TSEC and blank control group on cell proliferation at 72 h (P=0.13). However, there was a significant difference between the other groups (P<0.001). PCNA expression of TSEC was lower than that of the E + P and E groups (P<0.05). There was no statistical difference in the expression of PCNA between the TSEC and blank control groups (P=0.63). Bcl-2 expression of TSEC was lower than that of the E + P and E groups (P<0.05). There was no statistical difference in the expression of Bcl-2 between the TSEC group and the blank control group (P=0.60). CONCLUSIONS: SERM combined with estrogen may have a better safety for perimenopausal women with uterine leiomyoma in MHT.

Improved antimelanogenesis and antioxidant effects of polysaccharide from Cuscuta chinensis Lam seeds after enzymatic hydrolysis.

Cuscuta chinensis polysaccharide (CPS) was extracted using hot water and enzymatically hydrolyzed C. chinensis polysaccharide (ECPS) was produced by the mannase enzymatic hydrolysis process. The purpose of this research was to investigate the antimelanogenic activity of ECPS and CPS in B16F10 melanoma cells. The in vitro antioxidant activity was assessed by their ferric iron reducing power and DPPH free radical scavenging activities. The molecular mass distribution of polysaccharides was determined using SEC-MALLS-RI. CPS was successfully enzymatically degraded using mannase and the weighted average molecular weights of CPS and ECPS were 434.6 kDa and 211.7 kDa. The results of biological activity assays suggested that the enzymatically hydrolyzed polysaccharide had superior antimelanogenic activity and antioxidant effect than the original polysaccharide. ECPS exhibited antimelanogenic activity by down-regulating the expression of tyrosinase, MITF, and TRP-1 without cytotoxic effects in B16F10 melanoma cells. In conclusion, ECPS have the potential to become a skin whitening product.

Improved antimelanogenesis and antioxidant effects of polysaccharide from Cuscuta chinensis Lam seeds after enzymatic hydrolysis

Cuscuta chinensis polysaccharide (CPS) was extracted using hot water and enzymatically hydrolyzed C. chinensis polysaccharide (ECPS) was produced by the mannase enzymatic hydrolysis process. The purpose of this research was to investigate the antimelanogenic activity of ECPS and CPS in B16F10 melanoma cells. The in vitro antioxidant activity was assessed by their ferric iron reducing power and DPPH free radical scavenging activities. The molecular mass distribution of polysaccharides was determined using SEC-MALLS-RI. CPS was successfully enzymatically degraded using mannase and the weighted average molecular weights of CPS and ECPS were 434.6 kDa and 211.7 kDa. The results of biological activity assays suggested that the enzymatically hydrolyzed polysaccharide had superior antimelanogenic activity and antioxidant effect than the original polysaccharide. ECPS exhibited antimelanogenic activity by down-regulating the expression of tyrosinase, MITF, and TRP-1 without cytotoxic effects in B16F10 melanoma cells. In conclusion, ECPS have the potential to become a skin whitening product.

Koninginins R-S from the endophytic fungus Trichoderma koningiopsis.

Two new metabolites named koninginins R-S (1-2) were isolated from the culture of Trichoderma koningiopsis YIM PH30002. Their chemical structures were elucidated by the extensive spectroscopic analysis. These isolated compounds showed certain antifungal activities against phytopathogens, Fusarium flocciferum and Fusarium oxysporum.

Perineal leiomyoma in a postmenopausal woman: A case report.

Leiomyomas in the female reproductive system are commonly located in the uterus and typically regress following the menopause. Vulval leiomyomas are rare, and to the best of our knowledge, perineal leiomyomas in postmenopausal women have not been previously reported in the literature. The present case describes a 60-year-old Chinese woman who experienced perineal tenderness and lumbosacral radiating pain. The patient, who went through the menopause 12 years previously, had presented with a painful perineal mass for 1 year, which was subsequently diagnosed as a postmenopausal perineal leiomyoma. The mass was locally resected, and histopathological examination of the lesion resulted in a diagnosis of benign epithelioid leiomyoma. Immunohistochemical staining identified that the leiomyoma was positive for estrogen receptor and negative for progesterone receptor expression. The patient was followed up for 1 year and did not experience any pain or recurrence. The symptoms of local and lumbosacral radiating pain are extremely rare and may be induced by peripheral nerve stimulation. The etiology of postmenopausal perineal leiomyoma may be associated with infection, dietary, stress and environmental factors, and the role of estrogen cannot be overemphasized in cases of postmenopausal leiomyoma.

The influence of hydrogen peroxide initiator concentration on the structure of eucalyptus lignosulfonate.

In order to improve lignin-based materials' utilization, the grafting mechanism of lignin was studied by investigating hydrogen peroxide (H2O2) initiator's effect on the structure of eucalyptus lignosulfonate calcium (HLS). HLS was treated by low content of H2O2 (H2O2/HLS(wt)=1%, 2%, 4%) under various reaction temperature and time. Changes in HLS structure were investigated by difference UV, UV, FTIR, (1)H NMR, GPC and intrinsic viscosity. The results showed that though phenolic hydroxyl group (Ph-OH) of HLS was not oxidated to the quinoid structure, its content still decreased after treated by H2O2 initiator. Meanwhile, the new aryl-alkyl ether structures and increased average molecular weight were observed. A radical coupling mechanism for the decreasing Ph-OH group's content was proposed, which radicals may terminate between phenoxy and benzyl radicals. In addition, the cleavage of methoxyl-aryl ether made a decline in the content of syringyl units, while that of guaiacyl, p-hydroxyphenyl units and free aromatic C-5 hydrogen increased when HLS reacted with H2O2.

In vitro-activated tumor-bearing host T cells and the effectiveness of tumor vaccine immunotherapy.

BACKGROUND AND OBJECTIVE: Vaccination during periods of lymphopenia may facilitate immune responses to weak self-antigens and enhance antitumor immunity. The objective of this study was to determine the effectiveness of tumor vaccine immunotherapy combined with immune reconstruction using tumor-bearing host immune cells in lymphopenia, and to investigate the role of tumor-bearing host T cells activated in vitro during immunotherapy. DESIGN AND SETTING: Animal study conducted in the First Affiliated Hospital of Xi'an Jiaotong University from January 2009 to January 2010. PATIENTS AND METHODS: Lymphopenia was induced by cyclophosphamide. A reconstituted immune system with different syngeneic lymphocytes was employed, including lymphocytes from naïve rats (unsensitized group), tumor-bearing rats (tumor-bearing group), and tumor-bearing rats activated in vitro (activated group). All rats were immunized with granulocyte-macrophage colony-stimulating factor (GM-CSF)-modified NuTu-19 ovarian cancer (GM-CSF/NuTu-19) cells. Tumor vaccine-draining lymph nodes (TVDLNs) were harvested, and then stimulated to induce effector T cells (T(E)). T(E) were then adoptively transferred to rats bearing a 3-day pre-established abdominal tumor (NuTu-19), and the survival rate was calculated. RESULTS: Compared with the unsensitized group, the levels of interleukin-2 (IL-2) were significantly lower in the tumor-bearing group, whereas that of IL-4 were significantly higher (P<.05). The number of CD4+ T cells secreting interferon-γ and the specific cytotoxicity of CD8+ cytotoxic T lymphocytes were significantly lower (P<.05). The survival was significantly higher in the activated group compared with the other groups. CONCLUSIONS: Lymphocytes from tumor-bearing rats activated in vitro can effectively reverse the immunosuppressive effects of tumor-bearing hosts.

[Evaluation of immune reconstitution with in vitro-activated T cells from a tumor-bearing host].

AIM: To evaluate the reconstituted immune system with in vitro-activated T cells from tumor-bearing rats coupled with ovarian cancer vaccination. METHODS: Fischer 344 female rats were injected with cyclophosphamide (CY) as a lymphopenia (LP) model. The immune systems of the rats were reconstituted with in vitro-activated T cells from the same individuals. GM-CSF-modified ovarian cancer cells lines (NuTu-19) were injected within 24 h after immune reconstitution. The tumor vaccine draining lymph nodes (TVDLN) were harvested 8-10 days after vaccination and analyzed by FACS. The proliferative capacity of dendritic cells (DCs) was measured by the levels of MHC-II and CD86 molecules. The activation of T cells was monitored by the percentage of FITC-CD4 and PE-CD8 cells. The biological function of DCs such as processing and presenting antigens was assayed by immature DCs' phagocytosis of FITC-Dextran. RESULTS: Immune reconstitution with in vitro-activated T cells produced significantly more DCs, T cells and functionally enhanced immature DCs out of TVDLN. CONCLUSION: Reconstituting immune system with in vitro-activated T cells from a tumor-bearing host coupled with ovarian cancer vaccination during lymphocytopenia may selectively expand and activate particular T cells and DCs, leading to augmentation of anti-tumor immunity.

[Animal experiments of immunotherapy with ovarian tumor vaccine during lymphopenia induced by chemotherapy.].

OBJECTIVE: To explore the mechanisms and effects of adoptive immunotherapy with ovarian cancer vaccine modified by GM-CSF gene which was used after immunologic reconstitution during lymphopenia induced by chemotherapy. METHODS: Lymphopenia was induced by chemotherapy with cyclophosphamide. The immune reconstituted model was built in rats. The tumor vaccine draining lymph nodes were harvested after the ovarian cancer cells NUTU-19 modified by GM-CSF gene were injected. The effector T cells (T(E)) were got after being stimulated and amplified. Enzyme-linked immunosorbent assay was used to detect the level of interleukin (IL)-2 and IL-4 secreted by T(E). Intracellular cytokine staining was used to determine frequency of tumor-specific T(E). Fluorescence-activated cell sorting (FACS) was used to detect the special cytotoxicity of T(E) killing target cells. The survival period of rats bearing pre-established abdominal ovariam carcinoma after being adoptively transferred by T(E) was observed. RESULTS: Compared with those in control group, the significant higher levels IL-2 [(65.7 +/- 4.0) pg/ml] and lower levels IL-4 [(277 +/- 49) pg/ml] were observed in chemotherapy-immune reconstitution-vaccine immunization group. The amount of CD(4)(+) T cells secreting interferon-gamma (13.0 +/- 2.1)% were also significantly increased. The rate of the special cytotoxicity of killing T cells (86.5 +/- 1.1)% was markedly improved. The survival period of rats (110 +/- 16) days was increased in chemotherapy-immune reconstitution-vaccine immunization group. CONCLUSIONS: The combined immunotherapy of chemotherapy-immune reconstitution-tumor vaccine immunotherapy may increase the frequency and function of specific tumor T(E). The specific cytotoxicity is increased and the weak reaction of T(E) to tumor is improved, which showed that this therapy can enhance immune reaction.

[Effect of integrative Chinese and Western medicine in treating pregnant women with intrahepatic cholestasis].

OBJECTIVE: To evaluate the therapeutic effect of compound salvia injection combined with ursodeoxycholic acid (UDCA) in treating pregnant women with intrahepatic cholestasis (ICP) and its influence on perinatal babies. METHODS: One hundred and twenty-eight patients of ICP were assigned to two groups. The 72 patients in the treatment group were treated with salvia injection (20 mL in 10% glucose 500 mL for intravenous dripping once a day) and UDCA (15 mg, thrice daily by oral taken), and the 56 patients in the control group were treated with UDCA alone, all were treated for 14 days. Changes of itching symptom (estimated by scoring) and serum levels of biochemical indexes, including alanine aminotransferase (ALT), aspartate aminotransferase (AST), bilirubin (TBil) and glycocholic acid (GCA), were determined before and after treatment, and conditions of the newborns were compared after delivery. RESULTS: Compared with before treatment, scores of itching were lowered from 3.6 scores to 1.4 scores in the treatment group, and from 3.4 scores to 1.6 scores in the control group, showing no significant difference between groups (P > 0.05), but the lowering was shown earlier in the former. Levels of biochemical indexes were improved significantly (P < 0.01) in both groups, but the improvements were more significant in the treatment group, the difference between groups was significant (P < 0.05). The difference between groups in the incidence of fetal distress, meconium-stained fluid and neonatal asphyxia were insignificant (P > 0.05). The birth weights of the newborns were higher in the treatment group than in the control group (3,108 +/- 236 g vs 2,681 +/- 269 g, P < 0.05). CONCLUSION: The combined therapy of compound salvia injection and UDCA shows better effect in treating ICP than that of UDCA alone.

Exvivo experiments of human ovarian cancer ascites-derived exosomes presented by dendritic cells derived from umbilical cord blood for immunotherapy treatment.

OBJECTIVES: Exosomes, a type of membrane vesicles, released from tumor cells have been shown to be capable of transferring tumor antigens to dendritic cells and activating specific cytotoxic T-lymphocytes. Recent work has demonstrated the presence of high numbers of exosomes in malignant effusions. Umbilical cord blood (UCB) is a rich source of hematopoietic stem cells and from which a significant number of dendritic cells can be produced. We hypothesized that the exosomes released from metastatic ovarian carcinoma were able to present tumor specific antigen to dendritic cells derived from unrelated umbilical cord blood, then could stimulate resting T cells to differentiate and induce effective cytotoxicity. STUDY DESIGN: Exosomes were isolated by ultracentrifugation of malignant ascites from ovarian cancer patients (n = 10). Purified exosomes were further characterized by Western blot analyses and immunoelectronic microscopy. Dendritic cells were collected from unrelated umbilical cord blood and cultured in the presence of GM-CSF, IL-4 and TNF-α. Resting T cells were mixed with dentritic cells previously primed with exosomes and the cytotoxicity were measured by MTT method. T cells were activated by DCs presented with exosomes. RESULTS: 1) the exosomes isolated from the ascites were membrane vesicles of about 30-90nm in diameter; 2) the exosomes expressed MHC class I molecules, HSP70, HSP90, Her2/Neu, and Mart1; and 3)umbilical cord blood-derived DCs previously exosome-primed stimulated resting T cells to differentiate and produce effective cytotoxicity. CONCLUSIONS: These results suggested that tumor-specific antigens present on exosomes can be presented by DCs derived from unrelated umbilical cord blood to induce tumor specific cytotoxicity and this may represent as a novel immunotherapy for ovarian cancer.

Immune protection effect of exosomes against attack of L1210 tumor cells.

We investigated the anti-tumor immunity of L1210 cell-secreted exosomes. Exosomes were purified by ultrafiltration centrifugation and sucrose gradient ultracentrifugation. Expression of H-2D and interstitial cell adhesion molecule (ICAM(-1 was investigated by solid-phase immuno-electron microscopy and expression of Hsp70 was investigated by western blotting. DBA/2 mice were immunized with a given dose of exosomes (2.5 or 5 microg(. Transmission electron microscopy revealed that L1210-derived exosomes were membrane vesicles. They were labeled by colloidal gold H-2D and ICAM-1. Western blot analysis demonstrated the presence of Hsp70 antigens in L1210 exosomes. Exosome immunization partly inhibited the growth of implanted tumor in mice. There was a significant difference between exosome groups and the control group (P < 0.05(. In conclusion, exosomes can be considered as a candidate therapeutic vaccine for leukemia.

[Expression and its clinical significance of p27 protein in cervical carcinoma tissues].

AIM: To investigate the expression of p27 protein and its significance in cervical carcinoma tissues. METHODS: The p27 protein expression in 26 normal cervical tissues and 48 cervical carcinoma tissues was detected by streptavidin-peroxidase staining(SP method). RESULTS: The positive rate of p27 protein expression in 48 cervical carcinoma tissues was 39.5%, and that in 26 normal cervical tissues was 72.7%. The former was obviously lower than the latter(P<0.01). In addition, The positive rate of p27 protein in 48 cervical carcinoma tissue was correlated with the differentiation degree of the carcinoma, clinical phase of the patients and lymph node metastasis. In the poorly-differentiated cancer cells, advanced phase patients and the patients with lymph node metastasis, positive rate of p27 protein expression was the lowest. CONCLUSION: The expression of p27 protein is related to differentiation degree of cancer cells, clinical phase of the patients and lymph node metastasis. Detection of p27 protein expression may be valuable to assess prognosis of the patients with cervical carcinoma.