Self-assembly nanoplatform of platinum (â £) prodrug for enhanced ovarian cancer therapy.

Cisplatin is a metal platinum complex commonly used in the field of anti-tumor and one of the most commonly used drugs in combination chemotherapy. However, chemotherapy with Cisplatin induced overexpression of cyclooxygenase-2 (COX-2) protein in tumor cells, which could impair the therapeutic effect of chemotherapy on tumor progression. Here, we presented a novel method for the treatment of ovarian cancer with a self-assembly based nano-system. Cisplatin and tolfenamic acid were each linked to linoleic acid to give them the ability to self-assemble into nanoparticles in water. TPNPs had flexible drug ratio adjustability, homogeneous stability, and high drug loading capacity. Compared with Cisplatin, TPNPs could promote cellular uptake and tumor aggregation, co-induce enhanced apoptosis and tumor growth inhibition by inhibiting COX-2 in the mice xenograft model of human ovarian cancer, and reduce systemic toxicity. Therefore, TPNPs is a promising antitumor drug as a kind of self-assembly nano-prodrug with high drug load.

Glutamine metabolism targeting liposomes for synergistic chemosensitization and starvation therapy in ovarian cancer.

Platinum-based chemotherapy is a first-line therapeutic regimen against ovarian cancer (OC); however, the therapeutic potential is always reduced by glutamine metabolism. Herein, a valid strategy of inhibiting glutamine metabolism was proposed to cause tumor starvation and chemosensitization. Specifically, reactive oxygen species-responsive liposomes were developed to co-deliver cisplatin (CDDP) and bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl) ethyl sulfide (BPTES) [C@B LPs]. The C@B LPs induced effective tumor cell starvation and significantly sensitized OC cells to CDDP by reducing glutathione generation to prevent CDDP detoxification, suppressing ATP production to avoid CDDP efflux, hindering nucleotide synthesis to aggravate DNA damage induced by CDDP, and blocking mammalian target of rapamycin (mTOR) signaling to promote cell apoptosis. More importantly, C@B LPs remarkably inhibited tumor growth in vivo and reduced the side effects. Taken together, this study provided a successful strategy of synergistic chemosensitization and starvation therapy escalating the rate of therapeutic success in OCs. STATEMENT OF SIGNIFICANCE: This work proposed a valid strategy of inhibiting glutamine metabolism to cause tumor starvation and chemosensitization. Specifically, ROS-responsive liposomes were developed to co-deliver cisplatin CDDP and BPTES [C@B LPs]. The C@B LPs induced effective tumor cell starvation and significantly sensitized OC cells to cisplatin by reducing glutathione generation to prevent cisplatin detoxification, suppressing ATP production to avoid cisplatin efflux, hindering nucleotide synthesis to aggravate DNA damage induced by cisplatin, and blocking mTOR signaling to promote cell apoptosis. More importantly, C@B LPs remarkably inhibited tumor growth in vivo and reduced the side effects. Taken together, this study provided a successful strategy of synergistic chemosensitization and starvation therapy escalating the rate of therapeutic success in OCs.

A nanocomposite competent to overcome cascade drug resistance in ovarian cancer via mitochondria dysfunction and NO gas synergistic therapy.

Ovarian cancer (OC) is one of the most common and recurring malignancies in gynecology. Patients with relapsed OC always develop "cascade drug resistance" (CDR) under repeated chemotherapy, leading to subsequent failure of chemotherapy. To overcome this challenge, amphiphiles (P1) carrying a nitric oxide (NO) donor (Isosorbide 5-mononitrate, ISMN) and high-density disulfide are synthesized for encapsulating mitochondria-targeted tetravalent platinum prodrug (TPt) to construct a nanocomposite (INP@TPt). Mechanism studies indicated that INP@TPt significantly inhibited drug-resistant cells by increasing cellular uptake and mitochondrial accumulation of platinum, depleting glutathione, and preventing apoptosis escape through generating highly toxic peroxynitrite anion (ONOO-). To better replicate the microenvironmental and histological characteristics of the drug resistant primary tumor, an OC patient-derived tumor xenograft (PDXOC) model in BALB/c nude mice was established. INP@TPt showed the best therapeutic effects in the PDXOC model. The corresponding tumor tissues contained high ONOO- levels, which were attributed to the simultaneous release of O2•- and NO in tumor tissues. Taken together, INP@TPt-based systematic strategy showed considerable potential and satisfactory biocompatibility in overcoming platinum CDR, providing practical applications for ovarian therapy.

Heterologous biosynthesis of taraxerol by engineered Saccharomyces cerevisiae.

Taraxerol is an oleanane-type pentacyclic triterpenoid compound distributed in many plant species that has good effects on the treatment of inflammation and tumors. However, the taraxerol content in medicinal plants is low, and chemical extraction requires considerable energy and time, so taraxerol production is a problem. It is a promising strategy to produce taraxerol by applying recombinant microorganisms. In this study, a Saccharomyces cerevisiae strain WKde2 was constructed to produce taraxerol with a titer of 1.85 mg·l-1, and the taraxerol titer was further increased to 12.51 mg·l-1 through multiple metabolic engineering strategies. The endoplasmic reticulum (ER) size regulatory factor INO2, which was reported to increase squalene and cytochrome P450-mediated 2,3-oxidosqualene production, was overexpressed in this study, and the resultant strain WTK11 showed a taraxerol titer of 17.35 mg·l-1. Eventually, the highest reported titer of 59.55 mg·l-1 taraxerol was achieved in a 5 l bioreactor. These results will serve as a general strategy for the production of other triterpenoids in yeast.

[Systematic continuous sequence approach in diagnosing fetal deformity].

OBJECTIVE: To explore the value of ultrasonographic evaluation in fetal deformity in prenatal diagnosis by a systematic continuous sequence approach (SCSA). METHODS: Successive prenatal ultrasonographic evaluation was performed to monitor the whole anatomic structure,form, posture and movement of 16,685 fetuses during gestation aging 14 approximately 40(+3) weeks. RESULTS: Satisfactory ultrasonic images were obtained in 16,627 fetuses using the SCSA (99.65%). Of them, 514 abnormal fetuses were confirmed after subsequent labor or induced labor and 498 abnormal fetuses were correctly diagnosed using SCSA during prenatal stage (96.89%). Whereas 16 fetuses missed recognition (3.11%). Its sensitivity, specificity, positive and negative predictive value of diagnosis on fetal deformity were 96.98%, 99.96%, 98.66%, and 99.90 %, respectively. CONCLUSION: SCSA in prenatal ultrasonographic evaluation of the fetal structure and malformation is reliable and accurate.

[Fetal posterior cranial fossa in the second and third trimester].

OBJECTIVE: To examine the normal range of the width of posterior cranial fossa (WPCF) in the second and third trimester by ultrasonography, and to investigate its relationship with fetal congenital and chromosome abnormality. METHODS: WPCF of 2484 fetus (gestational age from 14 to 41 weeks) was measured by ultrasonograph routinely, and the infants were followed up. RESULTS: In 2848 fetus, 2772 were normal and 76 were abnormal. WPCF increased before 32 weeks, decreased after 33 weeks, the largest value of WPCF was 13.4 mm. The occurrence rate of WPCF> or =8 mm in normal fetus was 8.84%, and that in abnormal fetus was 17.46%. Most fetuses with chromosome abnormality had normal WPCF in the second trimester, but some fetuses with remarkable broadening in the late stage. Some abnormal fetuses (such as water head, Dandy-Walker's syndrome etc) showed significant extension of WPCF. CONCLUSION: WPCF increases before 32 weeks, decreases after 33 weeks;and can be easily measured during 29 - 32 weeks. WPCF of some fetus with chromosome abnormality or with congenital abnormality is remarkably broadened in the late stage. The fetus of WPCF> or =10 mm should be followed up closely, and antenatal diagnosis should be done if WPCF is more than 14 mm.

[Diagnosis of ovarian teratomas with two-dimensional ultrasound].

OBJECTIVE: To investigate the value of two-dimensional ultrasound in the diagnosis of tertoma in the ovary. METHODS: The sonographic images of 278 cases of ovarian teratomas confirmed by surgical pathology were reviewed. RESULTS: According to the surgical pathological results of the 278 cases, 95.3% (265/278) were benign, and 4.7% (13/278) were malignant. Among those, 88.5% (246/278) cases were unilateral, and 11.5% (32/278) were bilateral. Compared with the surgical pathological results, the rate of accurate diagnosis with ultrasound was 95.0% (264/278), the rate of misdiagnosis was 3.6% (10/278), and the rate of missed diagnosis was 1.4% (4/278). Among the benign cases, the rate of accurate dingnosis was 95.1% (252/265); the rate of misdiagnosis was 3.4% (9/265); and the rate of missed diagnosis was 1.5% (4/265). Among the 13 malignant cases, the rate of accurate diagnosis and misdiagnosis were 92.3% (12/13) and 7.7% (1/13), respectively. CONCLUSION: Two-dimensional ultrasound can be the first choice in diagnosing teratoma. Although the sonographic images of ovarian teratoma have specialities, they should be differentiated from other ovarian tumors, such as chocolate cyst of ovary, denaturation of subserous myoma, inflammatory mass, and etc.