PTENε suppresses tumor metastasis through regulation of filopodia formation.

PTEN is one of the most frequently mutated genes in malignancies and acts as a powerful tumor suppressor. Tumorigenesis is involved in multiple and complex processes including initiation, invasion, and metastasis. The complexity of PTEN function is partially attributed to PTEN family members such as PTENα and PTENß. Here, we report the identification of PTENε (also named as PTEN5), a novel N-terminal-extended PTEN isoform that suppresses tumor invasion and metastasis. We show that the translation of PTENε/PTEN5 is initiated from the CUG816 codon within the 5'UTR region of PTEN mRNA. PTENε/PTEN5 mainly localizes in the cell membrane and physically associates with and dephosphorylates VASP and ACTR2, which govern filopodia formation and cell motility. We found that endogenous depletion of PTENε/PTEN5 promotes filopodia formation and enhances the metastasis capacity of tumor cells. Overall, we identify a new isoform of PTEN with distinct subcellular localization and molecular function compared to the known members of the PTEN family. These findings advance our current understanding of the importance and diversity of PTEN functions.

Structural and biochemical insights into the molecular mechanism of TRPT1 for nucleic acid ADP-ribosylation.

Nucleic acid ADP-ribosylation has been established as a novel modification found in a wide diversity of prokaryotic and eukaryotic organisms. tRNA 2'-phosphotransferase 1 (TRPT1/TPT1/KptA) possesses ADP-ribosyltransferase (ART) activity and is able to ADP-ribosylate nucleic acids. However, the underlying molecular mechanism remains elusive. Here, we determined crystal structures of TRPT1s in complex with NAD+ from Homo sapiens, Mus musculus and Saccharomyces cerevisiae. Our results revealed that the eukaryotic TRPT1s adopt common mechanisms for both NAD+ and nucleic acid substrate binding. The conserved SGR motif induces a significant conformational change in the donor loop upon NAD+ binding to facilitate the catalytic reaction of ART. Moreover, the nucleic acid-binding residue redundancy provides structural flexibility to accommodate different nucleic acid substrates. Mutational assays revealed that TRPT1s employ different catalytic and nucleic acid-binding residues to perform nucleic acid ADP-ribosylation and RNA 2'-phosphotransferase activities. Finally, cellular assays revealed that the mammalian TRPT1 is able to promote endocervical HeLa cell survival and proliferation. Together, our results provide structural and biochemical insights into the molecular mechanism of TRPT1 for nucleic acid ADP-ribosylation.

DEAR model in overweight endometrial cancer patients undergoing fertility-sparing treatment: A randomized controlled trial.

OBJECTIVE: To evaluate the effects of DEAR weight management in overweight patients undergoing fertility-sparing treatment for endometrial cancer or atypical hyperplasia. METHODS: Women with endometrial cancer or atypical hyperplasia who received fertility-sparing treatment and had a body mass index of >25 kg/m2 were randomly allocated to the DEAR (DEAR weight management) and control (self weight management) groups. Body morphology and composition, glycolipid metabolism, and tumor outcomes were assessed in both groups before and at 3 and 6 months after intervention. RESULTS: Overall, 72 subjects were included (36 in each group). Following intervention, the DEAR group showed significantly lower median body weight (69.45 vs. 78.05), body mass index (26.19 vs. 29.15), lipid accumulation index (29.21 vs. 57.86), body fat mass (24.00 vs. 29.30), visceral fat area (112.5 vs. 133.3), and glycolipid metabolic indices (except high density lipoprotein) than the control group (P < 0.05) and showed a decreasing trend. The test group achieved significantly higher complete remission (88.46% vs. 57.14%; P < 0.05); the time to complete remission did not differ significantly (P > 0.05). CONCLUSIONS: DEAR weight management can improve the studied parameters and complete remission rates in this population. REGISTRATION: NCT06169449.

Heavy metal spatial distribution, source analysis, and ecological risks in the central hilly area of Hainan Island, China: results from a high-density soil survey.

The presence of heavy metals in soil has gained considerable attention due to their potential risks to ecosystems and human health. In this study, a thorough soil investigation was performed in the hilly region of central Hainan, which was formerly regarded as an area with the highest ecological environmental quality. A total of 7094 soil samples were systematically collected with high density over a large area. Simultaneously, a detailed investigation was conducted on the surrounding environment of each sampling point, including environmental factors such as soil, land use and crop types. The soil samples were analysed for heavy metals, pH, organic matter, and other parameters. The soil heavy metal pollution level, ecological risk and health risk were evaluated using the geo-accumulation index and the potential ecological risk index. The findings showed that the average contents of the heavy metals As, Cd, Cr, Cu, Hg, Ni, Pb and Zn in the soil were 1.68, 0.042, 24.2, 6.49, 0.0319, 7.06, 29.6 and 49.8 mg·kg-1 respectively. Except for Hg, the mean values of the other heavy metals were either lower than or similar to the background values of Hainan. Also, only a few localised areas showed contamination by heavy metals. The primary sources of heavy metals, identified by a positive matrix factorisation model, could be categorised into four types: natural sources related to the soil formation process from acidic intrusive rocks (such as granite); natural sources primarily influenced by atmospheric deposition; anthropogenic sources associated with agricultural activities; and natural sources related to the soil formation process from middle-mafic intrusive rocks and black shales. The correlation analysis and variance analysis findings suggested that the content of heavy metals in the soil was primarily associated with the parent rock. The study area generally had low heavy metal levels and was not significantly polluted. However, agricultural activities still affected the enrichment of heavy metals. Therefore, it is imperative to remain vigilant about the ecological risks linked to soil heavy metals while continuing land development and expanding agricultural activities in the future. These findings indicate that conducting high-density soil surveys can enhance our understanding of regional soil heavy metals and enable reliable recommendations for agricultural planning. Whether in areas with low pollution risk or potential pollution risk, it is recommended that high-density soil surveys be conducted provide scientific guidance for further agricultural development.

Discovery of a miniaturized PROTAC with potent activity and high selectivity.

The approved small-molecule inhibitors of anaplastic lymphoma kinase (ALK) have shown remarkable efficacy in some subset of cancer patients. However, the numerous ALK mutants or fusion partners are resistant to such drugs, greatly limiting their application in clinic. Despite the drug design strategy of proteolysis-targeting chimera (PROTAC) holds great potential to overcome drug resistance in theory, there are obvious disadvantages for the reported PROTACs that include high molecular weight, long linkers, difficult synthesis routes as well as insufficient evidence in activity for diverse ALK mutants. In this study, we designed and synthesized a miniaturized PROTAC of ALK named AP-1 following the principle of minimalist design. Two simple chemical units of ligands and a minimized linker with only two atoms were selected for synthesis of AP-1. At cellular level, AP-1 successfully degraded three types of ALK mutants including NPM-ALK, EML4-ALK and F1174L mutation ALK form with potent activity, high selectivity in ALK-positive cells. In xenograft mouse model, AP-1 showed the stronger antitumor efficacy than ceritinib as well as ALK degraders reported in literatures. AP-1 with an extremely simple PROTAC structure can be served as an effective candidate drug for therapy of various types of ALK-positive cancers. And the design principle of AP-1 has a good guiding significance for overcoming the disadvantages such as excessive molecular weight and poor solubility of PROTAC.

Effects of recorded maternal voice on anthropometric parameters and heart rate in premature infants: A pilot randomised controlled trial.

PURPOSE: To explore the benefits of a recorded maternal voice intervention on weight, recumbent length, head circumference, and heart rate of preterm infants in the neonatal intensive care unit. METHODS: A pilot randomised controlled trial was conducted in this study. Preterm infants in the neonatal intensive care unit (N = 109) were recruited and randomly assigned to an intervention or control group. Both groups received routine nursing care, while preterm infants in the intervention group received a recorded maternal voice program of 20 min, twice daily for 21 days. Preterm infants' daily weight, recumbent length, head circumference, and heart rate were collected during the 21-day intervention. Participants' heart rate in the intervention group was also recorded once a day pre-during-after the recorded maternal voice program. RESULTS: Preterm infants in the intervention group showed a significant increase in weight (-75.94, 95% CI -108.04, -43.85, P < 0.001), recumbent length (-0.54, 95% CI -0.76, -0.32, P < 0.001), and head circumference (-0.37, 95%CI -0.56, -0.18, P < 0.001) compared with the control group. Preterm infants in the intervention group also showed significant changes in heart rate pre-during-after the recorded maternal voice program. However, no significant differences were found in the heart rate scores between the two groups. DISCUSSION: The changes in heart rate pre-during-after the intervention may help explain participants' more significant increase in weight, recumbent length, and head circumference. PRACTICE IMPLICATIONS: The recorded maternal voice intervention could be incorporated into clinical practice to promote growth and development in preterm infants in the neonatal intensive care unit. STUDY REGISTRATION: Australian New Zealand Clinical Trials Register, https://www.anzctr.org.au/; (registration number: ACTRN12622000019707).

Effects of monoacylglycerols with different saturation degrees on physical and whipping properties of milk fat-based whipping creams.

Milk fat-based whipping cream is primarily comprised of cream and whole milk. It has melt-in-the-mouth texture and unique milk flavor. However, milk fat-based whipping cream suffers from poor emulsion stability and foam firmness. The effects of monoacylglycerols (MAGs) with different saturation degrees (M1: 98% saturation, M2: 70% saturation and M3: 30% saturation) on emulsion properties (average particle size, viscosity, and emulsion stability) and whipping properties (overrun, firmness, shape retention ability, and foam stability) of milk fat-based whipping creams were investigated in this study. MAGs significantly decreased particle sizes (from 2.84 to 1.16 µm) and enhanced viscosity (from 350 to 490 cP) of the milk fat-based emulsions (emulsion without MAGs: M0, 5.01 µm, 298 cP) (P < 0.05). MAGs increased the stability of the milk fat-based emulsions with lesser phase separation during centrifugation tests and lower changes in particle sizes and viscosities during temperature cycling tests. Emulsion M1 with highest degree of saturation is less likely to destabilize and phase inverse. The decrease sharply in conductivity can be attributed to the entrapment of large amounts of air. Following that, the conductivity of M1 with low variation indicating high whipping resistance and less likely to coalescence and phase separation. Adding MAGs can significantly enhance overrun (M1: 205.3%, M2: 198.5%, M3: 141.4%) as compared to the control sample (M0: 97.9%) (P < 0.05). In emulsions containing MAGs with high degree of saturation (M1 and M2), firmness (M1: 95 g, M2: 109 g) and shape retention ability of the whipped creams were reduced as compared to control emulsion without MAG (M0: 173 g), but the foam stability (M1: 89%, M2: 91%) was enhanced (M0: 81%); M3 (firmness: 507 g; foam stability: 66%) has the contrasted effects. Whipping cream M2 demonstrated the best whipping properties with high overrun (198.46%), good firmness (109 g), shape retention ability and foam stability (91%). Good quality whipping creams can be obtained by selecting suitable MAGs.

circPTEN1, a circular RNA generated from PTEN, suppresses cancer progression through inhibition of TGF-ß/Smad signaling.

BACKGROUND: PTEN is one of the most frequently mutated genes in human cancer. Although the roles of canonical PTEN protein and PTEN isoforms have been extensively explored, the current understanding of PTEN family members cannot fully illustrate the diversity of their roles in biological processes and tumor development. Notably, the function of noncoding RNAs arising from PTEN has been less elucidated. METHODS: We searched circBase and circInteractome to analyze the potential of PTEN for generating circRNAs. Then, Sanger sequencing, RNase R and Actinomycin D assays were used to verify the ring structure of circPTEN1. In situ hybridization and qRT-PCR were used to determine the level of circPTEN1 in peritumor and tumor tissues of colorectal cancer (CRC). Furthermore, functional experiments, including Transwell assay, 3D multicellular tumor spheroid invasion assay and metastasis models, were performed using circPTEN1 knockdown and overexpression cell lines in vitro and in vivo to investigate the effects of circPTEN1 on tumor metastasis in CRC. Mechanistically, luciferase reporter assay, fluorescence in situ hybridization, electrophoretic mobility shift assay, RNA immunoprecipitation, RNA pull-down and mass spectrometry were executed. RESULTS: We identified a circular RNA generated from the PTEN gene, designated circPTEN1, that is frequently downregulated in colorectal cancer, and decreased expression of circPTEN1 predicts poor survival. Low expression of circPTEN1 promotes metastasis in PDX models in vivo and accelerates cancer cell invasion in vitro, whereas overexpression of circPTEN1 reveals opposite roles. Mechanically, we found that circPTEN1 is capable of binding the MH2 domain of Smad4 to disrupt its physical interaction with Smad2/3, which reduces the formation and subsequent nucleus translocation of Smad complexes and consequently suppresses the expression of its downstream genes associated with epithelial-mesenchymal transition upon TGF-ß stimulation. Furthermore, we found that eIF4A3 suppresses the cyclization of circPTEN1 by directly binding to the circPTEN1 flanking region. CONCLUSIONS: Our study uncovered a novel PTEN gene-generated circRNA with a tumor suppression function, and further revealed the mechanism of circPTEN1 in CRC metastasis mediated by TGF-ß. The identification of circPTEN1 provides a new direction for PTEN investigation, and elucidation of circPTEN1/TGF-ß/Smad signaling may pave the way for the development of a potential therapeutic strategy for the suppression of cancer progression.

Novel intragraft regulatory lymphoid structures in kidney allograft tolerance.

Intragraft events thought to be relevant to the development of tolerance are here subjected to a comprehensive mechanistic study during long-term spontaneous tolerance that occurs in C57BL/6 mice that receive life sustaining DBA/2 kidneys. These allografts rapidly develop periarterial Treg-rich organized lymphoid structures (TOLS) that form in response to class II but not to class I MHC disparity and form independently of lymphotoxin α and lymphotoxin ß receptor pathways. TOLS form in situ in the absence of lymph nodes, spleen, and thymus. Distinctive transcript patterns are maintained over time in TOLS including transcripts associated with Treg differentiation, T cell checkpoint signaling, and Th2 differentiation. Pathway transcripts related to inflammation are expressed in early stages of accepted grafts but diminish with time, while B cell transcripts increase. Intragraft transcript patterns at one week posttransplant distinguish those from kidneys destined to be rejected, that is, C57BL/6 allografts into DBA/2 recipients, from those that will be accepted. In contrast to inflammatory tertiary lymphoid organs (iTLOs) that form in response to chronic viral infection and transgenic Lta expression, TOLS lack high endothelial venules and germinal centers. TOLS represent a novel, pathogenetically important type of TLO that are in situ markers of regulatory tolerance.

Synthesis and Propulsion of Magnetic Dimers under Orthogonally Applied Electric and Magnetic Fields.

Anisotropic particles have been widely used to make micro/nanomotors that convert chemical, ultrasonic, electrical, or magnetic energy into mechanical energy. The moving directions of most colloidal motors are, however, difficult to control. For example, asymmetric dimers with two lobes of different sizes, ζ-potential, or chemical composition have shown rich propulsion behaviors under alternating current (AC) electric fields due to unbalanced electrohydrodynamic flow. While they always propel in a direction perpendicular to the applied electric field, their moving directions along the substrate are hard to control, limiting their applications for cargo delivery. Inspired by two separate engine and steering wheel systems in automobiles, we use orthogonally applied AC electric field and direct current (DC) magnetic field to control the dimer's speed and direction independently. To this end, we first synthesize magnetic dimers by coating dopamine-functionalized nanoparticles on geometrically asymmetric polystyrene dimers. We further characterize their static and dynamic susceptibilities by measuring the hysteresis diagram and rotation speed experimentally and comparing them with theoretical predictions. The synthesized dimers align their long axes quickly with a planar DC magnetic field, allowing us to control the particles' orientation accurately. The propulsion speed of the dimers, on the other hand, is tunable by an AC electric field applied perpendicularly to the substrate. As a result, we can direct the particle's motion with predesigned trajectories of complex shapes. Our bulk-synthesis approach has the potential to make other types of magnetically anisotropic particles. And the combination of electric and magnetic fields will help pave the way for the assembly of magnetically anisotropic particles into complex structures.

Evidence for 2-Methoxyestradiol-Mediated Inhibition of Receptor Tyrosine Kinase RON in the Management of Prostate Cancer.

2-Methoxyestradiol (2-ME2) possesses anti-tumorigenic activities in multiple tumor models with acceptable tolerability profile in humans. Incomplete understanding of the mechanism has hindered its development as an anti-tumorigenic compound. We have identified for the first-time macrophage stimulatory protein 1 receptor (MST1R) as a potential target of 2-ME2 in prostate cancer cells. Human tissue validation studies show that MST1R (a.k.a RON) protein levels are significantly elevated in prostate cancer tissues compared to adjacent normal/benign glands. Serum levels of macrophage stimulatory protein (MSP), a ligand for RON, is not only associated with the risk of disease recurrence, but also significantly elevated in samples from African American patients. 2-ME2 treatment inhibited mechanical properties such as adhesion and elasticity that are associated with epithelial mesenchymal transition by downregulating mRNA expression and protein levels of MST1R in prostate cancer cell lines. Intervention with 2-ME2 significantly reduced tumor burden in mice. Notably, global metabolomic profiling studies identified significantly higher circulating levels of bile acids in castrated animals that were decreased with 2-ME2 intervention. In summary, findings presented in this manuscript identified MSP as a potential marker for predicting biochemical recurrence and suggest repurposing 2-ME2 to target RON signaling may be a potential therapeutic modality for prostate cancer.

Interleukin-37 Attenuates Lipopolysaccharide (LPS)-Induced Neonatal Acute Respiratory Distress Syndrome in Young Mice via Inhibition of Inflammation and Cell Apoptosis.

BACKGROUND Neonatal acute respiratory distress syndrome (ARDS) is a common clinical syndrome caused by lung immaturity and the abnormal synthesis of pulmonary surfactant in preterm newborns, and it has high morbidity and mortality rates. The present study investigated the roles of interleukin-37 (IL-37) in the pathogenesis of neonatal ARDS and the underlying biochemical mechanism. MATERIAL AND METHODS We used 6-day-old neonatal C57BL/6 mice to establish the ARDS model. Inflammatory cytokines levels were measured with enzyme-linked immunosorbent assay (ELISA) Kits. The pathological morphology of lung tissues was observed by hematoxylin-eosin (HE) staining. The expression levels of proteins were assessed by Western blotting and apoptotic cells were detected via TUNEL assay. Further, the expression of nucleotide-bound oligomerization domain (Nod)-like receptor P3 (NLRP3) was detected with immunohistochemistry and Western blotting. RESULTS IL-37 attenuated lipopolysaccharide (LPS)-induced cell apoptosis and excessive inflammatory cytokines levels, including IL-1ß, IL-8, TNF-alpha, and MCP-1, and ameliorated lung pathological manifestations in an LPS-induced neonatal ARDS model. Moreover, IL-37 suppressed the abnormal expression of proteins related to the CXCR4/SDF-1 chemokine axis and NLRP3 inflammasome pathway. CONCLUSIONS The present results suggest that IL-37 protect against LPS-induced lung injury through inhibition of inflammation and apoptosis in lung tissue in an LPS-induced neonatal ARDS model. Hence, IL-37 may be considered as a potential therapeutic agent for neonatal ARDS.

Pigment Epithelium-derived Factor (PEDF) Blocks Wnt3a Protein-induced Autophagy in Pancreatic Intraepithelial Neoplasms.

An increase in autophagy characterizes pancreatic carcinogenesis, but the signals that regulate this process are incompletely understood. Because canonical Wnt/ß-catenin signaling is necessary for the transition from early to advanced pancreatic intraepithelial neoplasia (PanIN) lesions, we assessed whether Wnt ligands and endogenous inhibitors of Wnt signaling modulate autophagy. In this study, canonical Wnt3a ligand induced autophagy markers and vacuoles in murine PanIN cells. Furthermore, pigment epithelium-derived factor (PEDF), a secreted glycoprotein known for its anti-tumor properties, blocked Wnt3a-directed induction of autophagy proteins. Autophagy inhibition was complemented by reciprocal regulation of the oxidative stress enzymes, superoxide dismutase 2 (SOD2) and catalase. Transcriptional control of Sod2 expression was mediated by PEDF-induced NFκB nuclear translocation. PEDF-dependent SOD2 expression in PanIN lesions was recapitulated in a murine model of PanIN formation where PEDF was deleted. In human PanIN lesions, co-expression of PEDF and SOD2 was observed in the majority of early PanIN lesions (47/50, 94%), whereas PEDF and SOD2 immunolocalization in high-grade human PanIN-2/3 was uncommon (7/50, 14%). These results indicate that PEDF regulates autophagy through coordinate Wnt signaling blockade and NFκB activation.

Downregulation of STAT3/NF-κB potentiates gemcitabine activity in pancreatic cancer cells.

There is an unmet need to develop new agents or strategies against therapy resistant pancreatic cancer (PanCA). Recent studies from our laboratory showed that STAT3 negatively regulates NF-κB and that inhibition of this crosstalk using Nexrutine® (Nx) reduces transcriptional activity of COX-2. Inhibition of these molecular interactions impedes pancreatic cancer cell growth as well as reduces fibrosis in a preclinical animal model. Nx is an extract derived from the bark of Phellodendron amurense and has been utilized in traditional Chinese medicine as antidiarrheal, astringent, and anti-inflammatory agent for centuries. We hypothesized that "Nx-mediated inhibition of survival molecules like STAT3 and NF-κB in pancreatic cancer cells will improve the efficacy of the conventional chemotherapeutic agent, gemcitabine (GEM)." Therefore, we explored the utility of Nx, one of its active constituents berberine and its derivatives, to enhance the effects of GEM. Using multiple human pancreatic cancer cells we found that combination treatment with Nx and GEM resulted in significant alterations of proteins in the STAT3/NF-κB signaling axis culminating in growth inhibition in a synergistic manner. Furthermore, GEM resistant cells were more sensitive to Nx treatment than their parental GEM-sensitive cells. Interestingly, although berberine, the Nx active component used, and its derivatives were biologically active in GEM sensitive cells they did not potentiate GEM activity when used in combination. Taken together, these results suggest that the natural extract, Nx, but not its active component, berberine, has the potential to improve GEM sensitivity, perhaps by down regulating STAT3/NF-κB signaling. © 2016 Wiley Periodicals, Inc.

Combination of Nexrutine and docetaxel suppresses NFκB-mediated activation of c-FLIP.

Lack of effective options following failure to conventional chemotherapeutic agent such as Docetaxel (DX) is a major clinical challenge in the management of prostate cancer. These observations underscore the need for deciphering the underlying mechanism of DX resistance to enable the development of effective therapeutic approaches. We observed up regulation of the anti-apoptotic protein c-FLIP and its up stream regulators including receptor tyrosine kinase RON and transcription factor NFκB (p65) in tumors obtained from metastatic prostate cancer patients. We also observed significant downregulation of these molecules in prostate tumors isolated from patients treated with DX as first line therapy. Further, we identified the over the counter anti-inflammatory agent, Nexrutine (NX) suppresses c-FLIP protein levels, and expression in androgen-independent prostate cancer cells (PC-3). Remarkably, the observed decreased levels of c-FLIP were further reduced in combination with DX. Transient expression assays coupled with electrophoretic mobility shift and DNA affinity protein assay revealed that NX and DX suppresses c-FLIP promoter activity by preventing p65 binding. Notably, NX in combination with DX abolished binding of p65 to the c-FLIP promoter sequence containing NFκB binding sites. Biologically, these alterations resulted in reduced growth of PC-3 cells. Taken together, these observations suggest the utility of RON, p65, and c-FLIP as potential markers to predict response to DX treatment. Furthermore, our results also identified NX as an agent to potentiate the therapeutic response of DX by suppressing activation of c-FLIP and its upstream regulators.

Pigment epithelium-derived factor restoration increases bone mass and improves bone plasticity in a model of osteogenesis imperfecta type VI via Wnt3a blockade.

Null mutations in for pigment epithelium-derived factor (PEDF), the protein product of the SERPINF1 gene, are the cause of osteogenesis imperfecta (OI) type VI. The PEDF-knockout (KO) mouse captures crucial elements of the human disease, including diminished bone mineralization and propensity to fracture. Our group and others have demonstrated that PEDF directs human mesenchymal stem cell (hMSC) commitment to the osteoblast lineage and modulates Wnt/ß-catenin signaling, a major regulator of bone development; however, the ability of PEDF to restore bone mass in a mouse model of OI type VI has not been determined. In this study, PEDF delivery increased trabecular bone volume/total volume by 52% in 6-mo-old PEDF-KO mice but not in wild-type mice. In young (19-d-old) PEDF-KO mice, PEDF restoration increased bone volume fraction by 35% and enhanced biomechanical parameters of bone plasticity. A Wnt-green fluorescent protein reporter demonstrated dynamic changes in Wnt/ß-catenin signaling characterized by early activation and marked suppression during terminal differentiation of hMSCs. Continuous Wnt3a exposure impeded mineralization of hMSCs, whereas the combination of Wnt3a and PEDF potentiated mineralization. Interrogation of the PEDF sequence identified a conserved motif found in other Wnt modulators, such as the dickkopf proteins. Mutation of a single amino acid on a 34-mer PEDF peptide increased mineralization of hMSC cultures compared with the native peptide sequence. These results indicate that PEDF counters Wnt signaling to allow for osteoblast differentiation and provides a mechanistic insight into how the PEDF null state results in OI type VI.-Belinsky, G. S., Sreekumar, B., Andrejecsk, J. W., Saltzman, W. M., Gong, J., Herzog, R. I., Lin, S., Horsley, V., Carpenter, T. O., Chung, C. Pigment epithelium-derived factor restoration increases bone mass and improves bone plasticity in a model of osteogenesis imperfecta type VI via Wnt3a blockade.

Electric-Field Assisted Assembly of Colloidal Particles into Ordered Nonclose-Packed Arrays.

Nonclose-packed colloidal arrays have many potential applications ranging from plasmonic sensors, light trapping for photovoltaics, to transparent electrodes. However, scalable fabrication of those structures remains a challenge. In this Article, we investigate the robustness of an electric-field assisted approach systematically. A monolayer of nonclose-packed crystalline array is first created under a low-frequency alternating-current electric field in solution. We then apply a sequence of direct-current pulses to fix the particle array onto the substrate so that it remains intact even after both field removal and solvent evaporation. Key process parameters such as the alternating-current field strength, direct-current magnitude, particle concentration, and solvent-evaporation rate that affect both ordering and fixing of colloidal particles have been studied systematically. We find that direct currents with an intermediate magnitude induce electrophoretic motion of particles toward the substrate and facilitate their permanent adhesion on the substrate due to strong van der Waals attraction. A higher current, however, causes lateral aggregation of particles arising from electroosmotic flow of solvent and destroys the periodic ordering between particles. This approach, in principle, can be conveniently adapted into the continuous convective assembly process, thus making the fabrication of nonclose-packed colloidal arrays scalable.

Paraneoplastic neurological syndromes (PNS) caused by occult breast cancer and metastatic carcinoma of the lymph node.

Paraneoplastic neurological syndromes (PNS) are immune-mediated, subacute, and progressive syndromes caused by remote effects of malignant tumours rather than the direct infiltration of tumours. The most common maladies related to PNS are small cell lung cancer, breast and ovarian cancer, and Hodgkin's lymphoma. Diagnoses of PNS frequently precede tumour diagnoses because the primary tumour is often occult. It is difficult for clinicians to recognise PNS, because there are various neurological symptoms and signs in the patient but few abnormal results of the examinations. The examination of paraneoplastic panels (cerebrospinal fluid (CSF) and serum) is useful in the diagnosis of PNS, but the false negatives should be considered. Due to the severe neurological morbidity and mortality caused by PNS, early diagnoses are important to allow for time to treat the underlying tumour and to obtain functional improvement. It is worth noting that regular re-examination and follow-up are crucial for reducing the rates of misdiagnosis and missed diagnosis of PNS.

Factors influencing risky decision-making in patients with cerebral infarction.

Numerous studies have found that the framing effect is common in medical scenarios, but few studies have examined the influence of the framing effect upon thrombolytic therapy for cerebral infarction. In this study, 1040 inpatients and outpatients in the department of neurology were recruited to explore whether there is a framing effect in decision-making within thrombolytic therapy, and if so, which factors influence that effect. The findings from Study 1 indicate that the framing effect occurred in patients both with and without cerebral infarction (χ(2) = 7.90, p = .005; χ(2) = 5.16, p = .023, respectively), with both groups displaying risk-seeking behavior (thrombolytic therapy) in the positive frame and no risk aversion or risk seeking in the negative frame. The results of Study 2 show that the patients preferred risk seeking in both collaborative and individual decision-making. In the collaborative decision-making group, the patients in the senior group showed the framing effect (χ(2) = 5.35, p < .05), with the patients in the positive frame (G) showing more significant risk seeking than both those in the negative frame (H) and those in the other positive frame (A, C, and E). In summary, decision-making about thrombolytic therapy in patients with cerebral infarction is influenced by the framing effect, and some influencing factors should be attended in clinical practice. Further research is necessary to guide the treatment of cerebral infarction.

FLIP: molecular switch between apoptosis and necroptosis.

Cancerous growth is one of the most difficult diseases to target as there is no one clear cause, and targeting only one pathway does not generally produce quantifiable improvement. For a truly effective cancer therapy, multiple pathways must be targeted at the same time. One way to do this is to find a gene that is associated with several pathways; this approach expands the possibilities for disease targeting and enables multiple points of attack rather than one fixed point, which does not allow treatment to evolve over time as cancer does. Inducing programmed cell death (PCD) is a promising method to prevent or inhibit the progression of tumor cells. Intricate cross talk among various programmed cell death pathways including cell death by apoptosis, necroptosis or autophagy plays a critical role in the regulation of PCD. In addition, the complex and overlapping patterns of signaling and lack of understanding of such networks between these pathways generate hurdles for developing effective therapeutic approaches. This review article focuses on targeting FLIP (Fas-associated death domain-like interleukin-1-converting enzyme-like inhibitory protein) signaling as a bridge between various PCD processes as an effective approach for cancer management.