The G-protein-coupled estrogen receptor agonist G-1 suppresses proliferation of ovarian cancer cells by blocking tubulin polymerization.

The G-protein-coupled estrogen receptor 1 (GPER) has recently been reported to mediate the non-genomic action of estrogen in different types of cells and tissues. G-1 (1-[4-(6-bromobenzo[1,3] dioxol-5yl)-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinolin-8-yl]-ethanone) was developed as a potent and selective agonist for GPER. G-1 has been shown to induce the expression of genes and activate pathways that facilitate cancer cell proliferation by activating GPER. Here we demonstrate that G-1 has an anticancer potential with a mechanism similar to vinca alkaloids, the commonly used chemotherapy drugs. We found that G-1 blocks tubulin polymerization and thereby interrupts microtubule assembly in ovarian cancer cells leading to the arrest of cell cycle in the prophase of mitosis and the suppression of ovarian cancer cell proliferation. G-1 treatment also induces apoptosis of ovarian cancer cells. The ability of G-1 to target microtubules to suppress ovarian cancer cell proliferation makes it a promising candidate drug for treatment of ovarian cancer

Characterization of a Weak Allele of Zebrafish cloche Mutant

Hematopoiesis is a complicated and dynamic process about which the molecular mechanisms remain poorly understood. Danio rerio (zebrafish) is an excellent vertebrate system for studying hematopoiesis and developmental mechanisms. In the previous study, we isolated and identified a cloche172 (clo172) mutant, a novel allele compared to the original cloche (clo) mutant, through using complementation test and initial mapping. Here, according to whole mount in-situ hybridization, we report that the endothelial cells in clo172 mutant embryos, although initially developed, failed to form the functional vascular system eventually. In addition, further characterization indicates that the clo172 mutant exhibited weaker defects instead of completely lost in primitive erythroid cells and definitive hematopoietic cells compared with the clos5 mutant. In contrast, primitive myeloid cells were totally lost in clo172 mutant. Furthermore, these reappeared definitive myeloid cells were demonstrated to initiate from the remaining hematopoietic stem cells (HSCs) in clo172 mutant, confirmed by the dramatic decrease of lyc in clo172runx1w84x double mutant. Collectively, the clo172 mutant is a weak allele compared to the clos5 mutant, therefore providing a model for studying the early development of hematopoietic and vascular system, as well as an opportunity to further understand the function of the cloche gene

The Hippo/YAP pathway interacts with EGFR signaling and HPV oncoproteins to regulate cervical cancer progression

The Hippo signaling pathway controls organ size and tumorigenesis through a kinase cascade that inactivates Yes-associated protein (YAP). Here, we show that YAP plays a central role in controlling the progression of cervical cancer. Our results suggest that YAP expression is associated with a poor prognosis for cervical cancer. TGF-α and amphiregulin (AREG), via EGFR, inhibit the Hippo signaling pathway and activate YAP to induce cervical cancer cell proliferation and migration. Activated YAP allows for up-regulation of TGF-α, AREG, and EGFR, forming a positive signaling loop to drive cervical cancer cell proliferation. HPV E6 protein, a major etiological molecule of cervical cancer, maintains high YAP protein levels in cervical cancer cells by preventing proteasome-dependent YAP degradation to drive cervical cancer cell proliferation. Results from human cervical cancer genomic databases and an accepted transgenic mouse model strongly support the clinical relevance of the discovered feed-forward signaling loop. Our study indicates that combined targeting of the Hippo and the ERBB signaling pathways represents a novel therapeutic strategy for prevention and treatment of cervical cancer

Confinement of carbon dots localizing to the ultrathin layered double hydroxides toward simultaneous triple-mode bioimaging and photothermal therapy

It is a great challenge to develop multifunctional nanocarriers for cancer diagnosis and therapy. Herein, versatile CDs/ICG-uLDHs nanovehicles for triple-modal fluorescence/photoacoustic/two-photon bioimaging and effective photothermal therapy were prepared via a facile self-assembly of red emission carbon dots (CDs), indocyanine green (ICG) with the ultrathin layered double hydroxides (uLDHs). Due to the J-aggregates of ICG constructed in the self-assembly process, CDs/ICG-uLDHs was able to stabilize the photothermal agent ICG and enhanced its photothermal efficiency. Furthermore, the unique confinement effect of uLDHs has extended the fluorescence lifetime of CDs in favor of bioimaging. Considering the excellent in vitro and in vivo phototherapeutics and multimodal imaging effects, this work provides a promising platform for the construction of multifunctional theranostic nanocarrier system for the cancer treatment

Diagnostic significance of CK19, TG, Ki67 and galectin-3 expression for papillary thyroid carcinoma in the northeastern region of China

<p>Abstract</p> <p>Background</p> <p>To evaluate the expression and differential diagnostic significance of CK19, TG, Ki67 and galectin-3 in papillary thyroid carcinoma (PTC) (metastatic and non metastatic), follicular adenoma and nodular goiter in patients from the northeastern part of China.</p> <p>Methods</p> <p>441 PTC specimens and 151 other benign thyroid specimens (97 cases of nodular goiter, 54 cases of nonmalignant follicular adenoma) were collected. Immunohistochemistry for CK19, TG, Ki67 and galectin-3 was performed.</p> <p>Results</p> <p>CK19, TG, Ki67 and galectin-3 expression was 96.37% (425/441), 82.77% (365/441), and 40.59% (179/441), 96.82% (427/441), respectively, for the PTC group and the expression of these markers in the benign thyroid lesions group was 25.83% (39/151), 79.47% (120/151), and 37.09% (56/151), 50.99% (77/151), respectively. The expression of CK19 and galectin-3 in PTC was much higher than that in the nonmalignant group (p < 0.05). However, the expression of TG, Ki67 did not differ among these two groups (p > 0.05). The diagnostic efficiency of CK19 and galectin-3 for PTC was 96.37% (537/592) and 84.63% (501/592). CK19 and galectin-3 expression rate in PTC was higher than that in benign disease cases.</p> <p>Conclusions</p> <p>The diagnostic efficiency of CK19 for PTC was slightly better than galectin-3. The utilization of these markers combined with morphologic evaluation may be helpful in the differential diagnosis of papillary thyroid carcinoma in the northeastern region of China.</p

Non‐BCMA targeted CAR‐T cell therapies for multiple myeloma

Abstract Despite the emergence of new strategies in recent years, multiple myeloma (MM) is still an incurable disease with poor outcome. As a new treatment, chimeric antigen receptor (CAR‐) T cell therapy brought exciting news to patients with relapsed or refractory MM. B‐cell maturation antigen (BCMA) is ubiquitously expressed on the surface of myeloma cells and is considered an “ideal” target of CAR‐T cell. BCMA‐targeted CAR‐T cell therapies achieved remarkable efficacy in relapsed or refractory MM patients in several clinical trials. However, some patients had no response or relapsed after BCMA targeted CAR‐T cell therapy. Myeloma cells also express other surface markers which might be used as targets for CAR‐T cell therapy. Encouragingly, CAR‐T cells targeting these non‐BCMA markers are being tested in clinical trials or under preclinical investigation, already showing some promising results. In this review, we summarized and provided an update of these advances

YAP1-LATS2 feedback loop dictates senescent or malignant cell fate to maintain tissue homeostasis

Dysfunction of the homeostasis-maintaining systems in specific cell types or tissues renders the organism susceptible to a range of diseases, including cancers. One of the emerging mechanisms for maintaining tissue homeostasis is cellular senescence. Here, we report that the Hippo pathway plays a critical role in controlling the fate of ovarian cells. Hyperactivation of Yes-associated protein 1 (YAP1), the major effector of the Hippo pathway, induces senescence in cultured primary human ovarian surface epithelial cells (hOSEs). Large tumor suppressor 2 (LATS2), the primary upstream negative regulator of YAP1, is elevated in both YAP1-induced and natural replicative-triggered senescence. Deletion of LATS2 in hOSEs prevents these cells from natural replicative and YAP1-induced senescence. Most importantly, loss of LATS2 switches ovarian cells from YAP-induced senescence to malignant transformation. Our results demonstrate that LATS2 and YAP1, two major components of the Hippo/YAP signaling pathway, form a negative feedback loop to control YAP1 activity and prevent ovarian cells from malignant transformation. Human cancer genomic data extracted from TCGA datasets further confirm the clinical relevance of our finding

Study Protocol of an App-Based Prevention Program for Perinatal Depression

The prevalence of perinatal depression (PND) in China is continuously rising, and the suicide rate among pregnant women is remarkably high. Preventing the occurrence of PND based on the management of primary health care is of great significance. Improving adherence to intervention programs is a key concern for PND prevention. Thus, a new intervention strategy based on mobile health could bring a new perspective to prevent the occurrence of PND and reduce the sample dropout rate. A single-blind, cluster randomized controlled trial will be performed to evaluate the effectiveness of a personalized, dynamic, and stratified intervention strategy based on an app. Four health centers will be randomly selected and randomly assigned to an intervention group (two centers) and a control group (two centers). Participants (n = 426) will be enrolled from the four selected health centers, with 213 in each group. The intervention group will receive the interventions personalized by the feature-matching algorithm of the user profile and be reassigned to the low-risk group (Edinburgh Postnatal Depression Scale [EPDS] &lt; 9) or moderate/high-risk group (9 &le; EPDS &lt; 13 and EPDS &ge; 13, but not meeting the criteria for PND) for intervention based on each EPDS score until 6 months after delivery. The control group will receive the same intervention components of the app but without the dynamic, personalized, and stratified function. Depression status, negative emotion symptoms, parental competence, and sample dropout rate will be measured at different weeks of pregnancy (12&ndash;16 [baseline], 24, 37) and at 42 days, 3 months, and 6 months after delivery. Follow-up evaluation (t6: 12 months after delivery) will also be conducted. If the intervention is effective, it will provide a personalized, time-friendly, and dynamic intervention for preventing PND. This phenomenon can effectively reduce the sample dropout rate and provide an empirical basis for promoting maternal mental health

Analysis on Influential Functions in the Weighted Software Network

Identifying influential nodes is important for software in terms of understanding the design patterns and controlling the development and the maintenance process. However, there are no efficient methods to discover them so far. Based on the invoking dependency relationships between the nodes, this paper proposes a novel approach to define the node importance for mining the influential software nodes. First, according to the multiple execution information, we construct a weighted software network (WSN) to denote the software execution dependency structure. Second, considering the invoking times and outdegree about software nodes, we improve the method PageRank and put forward the targeted algorithm FunctionRank to evaluate the node importance (NI) in weighted software network. It has higher influence when the node has lager value of NI. Finally, comparing the NI of nodes, we can obtain the most influential nodes in the software network. In addition, the experimental results show that the proposed approach has good performance in identifying the influential nodes