Anti-PD-L1 mediating tumor-targeted codelivery of liposomal irinotecan/JQ1 for chemo-immunotherapy.

Immune checkpoint blockade therapy has become a first-line treatment in various cancers. But there are only a small percent of colorectal patients responding to PD-1/PD-L1 blockage immunotherapy. How to increase their treatment efficacy is an urgent and clinically unmet need. It is acknowledged that immunogenic cell death (ICD) induced by some specific chemotherapy can enhance antitumor immunity. Chemo-based combination therapy can yield improved outcomes by activating the immune system to eliminate the tumor, compared with monotherapy. Here, we develop a PD-L1-targeting immune liposome (P-Lipo) for co-delivering irinotecan (IRI) and JQ1, and this system can successfully elicit antitumor immunity in colorectal cancer through inducing ICD by IRI and interfering in the immunosuppressive PD-1/PD-L1 pathway by JQ1. P-Lipo increases intratumoral drug accumulation and promotes DC maturation, and thereby facilitates adaptive immune responses against tumor growth. The remodeling tumor immune microenvironment was reflected by the increased amount of CD8+ T cells and the release of IFN-γ, and the reduced CD4+Foxp3+ regulatory T cells (Tregs). Collectively, the P-Lipo codelivery system provides a chemo-immunotherapy strategy that can effectively remodel the tumor immune microenvironment and activate the host immune system and arrest tumor growth.

Overview of recent advances in liposomal nanoparticle-based cancer immunotherapy.

The clinical performance of conventional cancer therapy approaches (surgery, radiotherapy, and chemotherapy) has been challenged by tumor metastasis and recurrence that is mainly responsible for cancer-caused mortalities. The cancer immunotherapy is being emerged nowadays as a promising therapeutic modality in order to achieve a highly efficient therapeutic performance while circumventing tumor metastasis and relapse. Liposomal nanoparticles (NPs) may serve as an ideal platform for systemic delivery of the immune modulators. In this review, we summarize the cutting-edge progresses in liposomal NPs for cancer immunotherapy, with focus on dendritic cells, T cells, tumor cells, natural killer cells, and macrophages. The review highlights the major challenges and provides a perspective regarding the clinical translation of liposomal nanoparticle-based immunotherapy.

Codelivery of dihydroartemisinin and doxorubicin in mannosylated liposomes for drug-resistant colon cancer therapy.

Multidrug resistance (MDR) is a major hurdle in cancer chemotherapy and makes the treatment benefits unsustainable. Combination therapy is a commonly used method for overcoming MDR. In this study we investigated the anti-MDR effect of dihydroartemisinin (DHA), a derivative of artemisinin, in combination with doxorubicin (Dox) in drug-resistant human colon tumor HCT8/ADR cells. We developed a tumor-targeting codelivery system, in which the two drugs were co-encapsulated into the mannosylated liposomes (Man-liposomes). The Man-liposomes had a mean diameter of 158.8 nm and zeta potential of -15.8 mV. In the HCT8/ADR cells that overexpress the mannose receptors, the Man-liposomes altered the intracellular distribution of Dox, resulting in a high accumulation of Dox in the nuclei and thus displaying the highest cytotoxicity (IC50=0.073 µg/mL) among all the groups. In a subcutaneous HCT8/ADR tumor xenograft model, administration of the Man-liposomes resulted in a tumor inhibition rate of 88.59%, compared to that of 47.46% or 70.54%, respectively, for the treatment with free Dox or free Dox+DHA. The mechanisms underlying the anti-MDR effect of the Man-liposomes involved preferential nuclear accumulation of the therapeutic agents, enhanced cancer cell apoptosis, downregulation of Bcl-xl, and the induction of autophagy.

Perspective on Water-Soluble Two-Photon Initiator for Two-Photon Polymerization.

Two-photon polymerization (TPP) as an unparalleled technology empowers the rapid prototyping of customized three-dimensional (3D) micro/nanostructures, garnering noticeable interest in tissue engineering, drug delivery, and regenerative medicine. These applications have a high requirement on the biocompatibility and integrity of 3D structures. Therefore, it is important to develop two-photon initiator with good water-solubility, initiation efficiency, and biocompatibility. Here, we share our insights into the development of a water-soluble two-photon initiator (WTPI) and applications from the material and manufacturing perspective. We highlight the nonlinear optical properties and the synthesis of WTPI through three pathways. Then we further demonstrate the applications of the TPP technique in the aqueous phase in the fields of tissue engineering, 4D printing, and ceramic manufacturing. Finally, a general conclusion and outlook are provided for the future development and application of WTPI.

Femtosecond Laser Maskless Optical Projection Lithography of Cartilage PCM Inspired 3D Protein Matrix to Chondrocyte Phenotype.

Hydrogels containing chondrocytes have exhibited excellent potential in regenerating hyaline cartilage. However, chondrocytes are vulnerable to dedifferentiation during in vitro culture, leading to fibrosis and mechanical degradation of newly formed cartilage. It is proposed to modulate cartilage formation via the developed chondrocyte pericellular matrix (PCM) -like scaffolds for the first time, in which the S, M, and L-sized scaffolds are fabricated by femtosecond laser maskless optical projection lithography (FL-MOPL) of bovine serum albumin-glyceryl methacrylate hydrogel. Chondrocytes on the M PCM-like scaffold can maintain round morphology and synthesize extracellular matrix (ECM) to induce regeneration of hyaline cartilage microtissues by geometrical restriction. A series of M PCM-like scaffolds is fabricated with different stiffness and those with a high Young's modulus are more effective in maintaining the chondrocyte phenotype. The proposed PCM-like scaffolds are effective in modulating cartilage formation influenced by pore size, depth, and stiffness, which will pave the way for a better understanding of the geometric cues of mechanotransduction interactions in regulating cell fate and open up new avenues for tissue engineering.

Multipatterned Chondrocytes' Scaffolds by FL-MOPL with a BSA-GMA Hydrogel to Regulate Chondrocytes' Morphology.

Repairing articular cartilage damage is challenging due to its low regenerative capacity. In vitro, cartilage regeneration is a potential strategy for the functional reconstruction of cartilage defects. A hydrogel is an advanced material for mimicking the extracellular matrix (ECM) due to its hydrophilicity and biocompatibility, which is known as an ideal scaffold for cartilage regeneration. However, chondrocyte culture in vitro tends to dedifferentiate, leading to fibrosis and reduced mechanical properties of the newly formed cartilage tissue. Therefore, it is necessary to understand the mechanism of modulating the chondrocytes' morphology. In this study, we synthesize photo-cross-linkable bovine serum albumin-glycidyl methacrylate (BSA-GMA) with 65% methacrylation. The scaffolds are found to be suitable for chondrocyte growth, which are fabricated by homemade femtosecond laser maskless optical projection lithography (FL-MOPL). The large-area chondrocyte scaffolds have holes with interior angles of triangle (T), quadrilateral (Q), pentagon (P), hexagonal (H), and round (R). The FL-MOPL polymerization mechanism, swelling, degradation, and biocompatibility of the BSA-GMA hydrogel have been investigated. Furthermore, cytoskeleton and nucleus staining reveals that the R-scaffold with larger interior angle is more effective in maintaining chondrocyte morphology and preventing dedifferentiation. The scaffold's ability to maintain the chondrocytes' morphology improves as its shape matches that of the chondrocytes. These results suggest that the BSA-GMA scaffold is a suitable candidate for preventing chondrocyte differentiation and supporting cartilage tissue repair and regeneration. The proposed method for chondrocyte in vitro culture by developing biocompatible materials and flexible fabrication techniques would broaden the potential application of chondrocyte transplants as a viable treatment for cartilage-related diseases.

Study on active lap tool influence function in grinding 1.8 m primary mirror.

We present a theoretical modeling method to predict the ring tool influence function (TIF) based on the computer-controlled active lap process. The gap on the lap-grinding layer is considered, and its influence on the ring TIF is analyzed too. The relationship between the shape of the ring TIF and the lap-workpiece rotation speed ratio is discussed in this paper. The recipe for calculating dwell time for axisymmetric fabrication is discussed. The grinding process of a 1.8 m primary mirror is improved based on these results. The grinding process is accomplished after 30 circles of grinding, and the surface shape error is from PV 82 µm RMS 16.4 µm reduced to PV 13.5 µm RMS 2.5 µm.

Synthesis of biocompatible BSA-GMA and two-photon polymerization of 3D hydrogels with free radical type I photoinitiator.

Although the development of three-dimensional (3D) printing technology is growing rapidly in the biomedical field, it remains a challenge to achieve arbitrary 3D structures with high resolution and high efficiency. Protein hydrogels fabricated by two- photon polymerization (TPP) have excellent mechanical properties, high precision, and 3D architecture. However, a large number of the amino acid group in bovine serum albumin (BSA) would be consumed when the protein-based hydrogels use dyes of free radical type II photoinitiators. In this study, we use glycidyl methacrylate (GMA) to modify BSA molecules to obtain a series of BSA-GMA materials, allowing the protein material to be two-photon polymerized with a water-soluble free radical type I photoinitiator. The precisely controllable 3D structure of the BSA-GMA hydrogel was fabricated by adjusting the concentration of the precursor solution, the degree of methacrylation, and the processing parameters of the TPP technique. Importantly, BSA-GMA materials are free of acidic hazardous substances. Meanwhile, the water-soluble initiator lithium phenyl (2,4,6-trimethylbenzoyl) phosphite (LAP) allows TPP on the vinyl group of the GMA chain and thus without consuming its amino acid group. The as-prepared BSA-GMA hydrogel structure exhibits excellent autofluorescence imaging, pH responsiveness, and biocompatibility, which would provide new avenues for potential applications in tissue engineering and biomedical fields to meet specific biological requirements.

22 nm Resolution Achieved by Femtosecond Laser Two-Photon Polymerization of a Hyaluronic Acid Vinyl Ester Hydrogel.

Three-dimensional (3D) bioinspired hydrogels have played an important role in tissue engineering, owing to their advantage of excellent biocompatibility. Here, the two-photon polymerization (TPP) of a 3D hydrogel with high precision has been investigated, using the precursor with hyaluronic acid vinyl ester (HAVE) as the biocompatibility hydrogel monomer, 3,3'-((((1E,1'E)-(2-oxocyclopentane-1,3-diylidene) bis(methanylylidene)) bis(4,1-phenylene)) bis(methylazanediyl))dipropanoate as the water-soluble initiator, and dl-dithiothreitol (DTT) as the click-chemistry cross-linker. The TPP properties of the HAVE precursors have been comprehensively investigated by adjusting the solubility and the formulation of the photoresist. The feature line width of 22 nm has been obtained at a processing laser threshold of 3.67 mW, and the 3D hydrogel scaffold structures have been fabricated. Furthermore, the average value of Young's modulus is 94 kPa for the 3D hydrogel, and cell biocompatibility has been demonstrated. This study would provide high potential for achieving a 3D hydrogel scaffold with highly precise configuration in tissue engineering and biomedicine.

Comparison of the effects of carbamyl-beta-methylcholine chloride administered by intravenous, intramuscular and intra-acupuncture point injections.

OBJECTIVE: To compare the effects of carbamyl-beta-methylcholine chloride (CMCC) administered by intra-acupuncture point injection (IAI), intramuscular injection (IMI), and intravenous injection (IVI), and to analyze the mechanisms. METHODS: In the IAI group, CMCC was injected into the Zusanli acupoint (ST 36) immediately after 30-min stimulation by electro-acupuncture (EA) at the acupoints, and into the femoral vein and skeletal muscle in IVI and IMI groups, respectively. Intra-gastric pressure was detected. The plasma concentration of CMCC was measured at various times. RESULTS: The gastric effect of CMCC in the IVI group was enhanced and attenuated more rapidly than in the other groups. In the IAI group, this effect was significantly stronger than that in the IMI group at 2 min and 15 min, but not significantly different between the two groups at 5 min and 30 min. Plasma concentration of CMCC in the IAI group was similar to that in the IVI group at 2 min, but higher than that in the IMI group. The concentration in the IAI group was higher than that in the IV group and similar to that in the IMI group at 5, 15 and 30 min, indicating rapid increase and slower reduction of the plasma concentration of the drug in the IAI group. There was a positive correlation between the plasma concentration of CMCC and intragastric pressure in all groups. CONCLUSION: The effect of IAI with CMCC was stronger than that of IMI and longer-lasting than that of IVI, which correlated with the blood concentration of CMCC.

Factor structure of the Youth Coping In Traumatic Times (YCITT) scale.

The objective of the present study is to determine if a brief measure of coping strategies administered to children and adolescents after a mass traumatic event - Youth Coping In Traumatic Times (YCITT) - has a factor structure similar to that of a lengthier, widely used scale, the How I Coped Under Pressure Scale (HICUPS). The YCITT was developed for the New York City - Board of Education WTC Study, conducted 6 months after 9/11. Confirmatory Factor Analyses (CFA) and Exploratory Factor Analysis (EFA) were performed in two randomly selected sub-samples of youth in grades 6-12 (sub-sample 1, n=2249; sub-sample 2, n=2315). In sub-sample 1, CFA indicated acceptable fit of a four-factor solution based on the HICUPS (distraction, active coping, support seeking and avoidance) and EFA yielded a nearly identical solution. In sub-sample 2, CFA indicated that the fit of the HICUPS-based factor solution and the solution derived from the EFA in sub-sample 1 were very similar, with both indicating acceptable model fit. In conclusion, the brief YCITT has a factor structure, which is similar to that of the HICUPS. When used in large-scale assessments of future mass traumatic events, the measure can provide relevant information about youth coping strategies across four key coping domains.

Psychopathology among New York city public school children 6 months after September 11.

CONTEXT: Children exposed to a traumatic event may be at higher risk for developing mental disorders. The prevalence of child psychopathology, however, has not been assessed in a population-based sample exposed to different levels of mass trauma or across a range of disorders. OBJECTIVE: To determine prevalence and correlates of probable mental disorders among New York City, NY, public school students 6 months following the September 11, 2001, World Trade Center attack. DESIGN: Survey. SETTING: New York City public schools. PARTICIPANTS: A citywide, random, representative sample of 8236 students in grades 4 through 12, including oversampling in closest proximity to the World Trade Center site (ground zero) and other high-risk areas. MAIN OUTCOME MEASURE: Children were screened for probable mental disorders with the Diagnostic Interview Schedule for Children Predictive Scales. RESULTS: One or more of 6 probable anxiety/depressive disorders were identified in 28.6% of all children. The most prevalent were probable agoraphobia (14.8%), probable separation anxiety (12.3%), and probable posttraumatic stress disorder (10.6%). Higher levels of exposure correspond to higher prevalence for all probable anxiety/depressive disorders. Girls and children in grades 4 and 5 were the most affected. In logistic regression analyses, child's exposure (adjusted odds ratio, 1.62), exposure of a child's family member (adjusted odds ratio, 1.80), and the child's prior trauma (adjusted odds ratio, 2.01) were related to increased likelihood of probable anxiety/depressive disorders. Results were adjusted for different types of exposure, sociodemographic characteristics, and child mental health service use. CONCLUSIONS: A high proportion of New York City public school children had a probable mental disorder 6 months after September 11, 2001. The data suggest that there is a relationship between level of exposure to trauma and likelihood of child anxiety/depressive disorders in the community. The results support the need to apply wide-area epidemiological approaches to mental health assessment after any large-scale disaster.

[Effects of carbon sources, temperature and electron acceptors on biological phosphorus removal].

Effects of carbon sources, temperature and electron acceptors on phosphorus uptake and release were investigated in a pilot-scale oxidation ditch. Phosphorus uptake and release rates were measured with different carbon sources (domestic sewage, sodium acetate, glucose) at 25 degrees C. The results showed that the minimum phosphorus uptake and release rates of glucose were 5.12 mg x (g x h)(-1) and 6.43 mg x (g x h)(-1), respectively, and those of domestic sewage are similar to those of sodium acetate. Phosphorus uptake and release rates increased with the increase of temperature (12, 16, 20 and 25 degrees C) using sodium acetate as carbon sources. Anoxic phosphorus uptake rate decreased with added COD. Electron acceptors (oxygen, nitrate, nitrite) had significant effects on phosphorus uptake rate and their order was in accordance with oxygen > nitrate > nitrite. The mass ratio of anoxic P uptake and N consumption (P(uptake)/N (consumption)) of nitrate and nitrite were 0.96 and 0.65, respectively.

Use of mental health services by children and adolescents six months after the World Trade Center attack.

OBJECTIVE: The authors describe use of mental health services among children and adolescents after the September 11, 2001, attack on the World Trade Center. METHODS: Six months after the attack, sixth- through 12th-graders (N=6,986) who were representative of the student population were asked about their use of mental health services to talk about the attack as well as their exposure to the attack, symptoms of posttraumatic stress and major depressive disorders, and any conversations about the attack with a parent, teacher, or religious leader. RESULTS: Eighteen percent had used mental health services. Using in-school services was associated with conversation with a teacher about the attack. Using services outside school was associated with direct exposure to the attack, previous trauma exposure, probable psychiatric diagnosis, and conversation with a teacher or religious leader about the attack. CONCLUSIONS: Teachers and religious leaders can function as gatekeepers to identify children in need following a disaster.

Systematic screen with kinases inhibitors reveals kinases play distinct roles in growth of osteoprogenitor cells.

Cancer treatment-related bone loss has become growing problematic, especially in breast and prostate cancer treated with hormone/endocrine therapy, chemotherapy and radiotherapy. However, bone loss caused by targeted therapy in cancer patients is largely unknown yet. In present study, a kinase inhibitors screen was applied for MC3T3-E1, a murine osteoprogenitor cell line, and seven kinase inhibitors (GSK1838705A, PF-04691502, Dasatinib, Masitinib, GDC-0941, XL880 and Everolimus) were found to suppress the cell viability with dose- and time-dependent manner. The most interesting is that many kinase inhibitors (such as lapatinib, erlotinib and sunitinib) can promote MC3T3-E1 cell proliferation at 0.01 µM. 4 out of 7 inhibitors were selected to perform the functional study and found that they lead to cell cycle dysregulation, treatments of PF-04691502 (AKT inhibitor), Dasatinib (Src inhibitor) and Everolimus (mTOR inhibitor) lead to G1 arrest of MC3T3-E1 cells via downregulation of cyclin D1 and p-AKT, whereas XL880 (MET and VEGFR inhibitor) treatment results in increase of sub-G1 and G2/M phase by upregulation of p53 protein. Our work provides important indications for the comprehensive care of cancer patients treated with some targeted drugs.

Parental exposure to mass violence and child mental health: the First Responder and WTC Evacuee Study.

Children's reactions after being exposed to mass violence may be influenced by a spectrum of factors. Relatively unexplored is the extent to which family exposure to mass violence may affect child mental health, even when these children have not been directly exposed. In a representative sample of NYC public school children assessed 6 months after the September 11, 2001 attack on the World Trade Center (WTC), seemingly elevated rates of psychopathology were recorded among children of WTC evacuees. Children of NYC First Responders (police officers, EMTs, and fire fighters) displayed a complex pattern of response to the WTC attack. Overall, the findings from this previous study support putative transmission of trauma to children whose parents were exposed to the WTC attack. The "Children of First Responder and WTC Evacuee Study"-a two-site longitudinal study-is currently underway in the United States (New York City) and in Israel (Tel Aviv area) in an effort to understand the impact of different patterns of mass violence. The NYC sample permits us to examine the impact of a rare instance of mass violence (e.g., WTC attack), while the Israeli sample provides information about repeated and frequent exposure to mass violence brought about by acts of terrorism. In addition, children's exposure to mass violence is considered in the context of their exposure to other potentially traumatic events. This study aims to improve our general understanding of the impact of mass violence on children, especially the psychological effects on children whose parents' work experiences are by nature stressful. Knowledge generated by this study has implications for guiding efforts to meet the needs of children who have, directly or through a family member, been subjected to rare or infrequent mass violent event as well as to children whose exposure to mass violence is part of daily life.

Study of hypoxia-induced expression of HIF-1alpha in retina pigment epithelium.

It was shown that the expression of HIF-1alpha in retinal pigment epithelium increased under hypoxic conditions. Eight hours after the start of hypoxic exposure, the expression of HIF-1alpha reached the peak and sustained after 24-hour hypoxia. However, the morphology of PRE cells began to change and the expression of HIF-1alpha decreased after long-term (48-hour) hypoxia. Hypoxia-induced increase in the level of HIF-1alpha in RPE. It can be an important step in choriodal neovascularization.

Posttraumatic stress in children with first responders in their families.

High levels of exposure and occupational stress of first responders may have caused children in first-responder families to become traumatized following the September 11th, 2001 terrorist attacks. New York City public school children (N = 8,236) participated in a study examining mental health problems 6 months after the World Trade Center attack. Results revealed that children with emergency medical technician (EMT) family members had a high prevalence of probable posttraumatic stress disorder (PTSD; 18.9%). Differences in rates of probable PTSD among EMTs' and firefighters' children were explained by demographic characteristics. Where EMTs are drawn from disadvantaged groups, one implication of this study is to target EMT families in any mental health interventions for children of first responders.