Bioresponsive nanocomplex integrating cancer-associated fibroblast deactivation and immunogenic chemotherapy for rebuilding immune-excluded tumors.

Cancer-associated fibroblasts (CAFs) play a crucial role in creating an immunosuppressive environment and remodeling the extracellular matrix within tumors, leading to chemotherapy resistance and limited immune cell infiltration. To address these challenges, integrating CAFs deactivation into immunogenic chemotherapy may represent a promising approach to the reversal of immune-excluded tumor. We developed a tumor-targeted nanomedicine called the glutathione-responsive nanocomplex (GNC). The GNC co-loaded dasatinib, a CAF inhibitor, and paclitaxel, a chemotherapeutic agent, to deactivate CAFs and enhance the effects of immunogenic chemotherapy. Due to the modification with hyaluronic acid, the GNC preferentially accumulated in the tumor periphery and responsively released cargos, mitigating the tumor stroma as well as overcoming chemoresistance. Moreover, GNC treatment exhibited remarkable immunostimulatory efficacy, including CD8+ T cell expansion and PD-L1 downregulation, facilitating immune checkpoint blockade therapy. In summary, the integration of CAF deactivation and immunogenic chemotherapy using the GNC nanoplatform holds promise for rebuilding immune-excluded tumors.

Tuning Piezoelectricity via Thermal Annealing at a Freestanding Ferroelectric Membrane.

Tuning the ferroelectric domain structure by a combination of elastic and electrostatic engineering provides an effective route for enhanced piezoelectricity. However, for epitaxial thin films, the clamping effect imposed by the substrate does not allow aftergrowth tuning and also limits the electromechanical response. In contrast, freestanding membranes, which are free of substrate constraints, enable the tuning of a subtle balance between elastic and electrostatic energies, giving new platforms for enhanced and tunable functionalities. Here, highly tunable piezoelectricity is demonstrated in freestanding PbTiO3 membranes, by varying the ferroelectric domain structures from c-dominated to c/a and a domains via aftergrowth thermal treatment. Significantly, the piezoelectric coefficient of the c/a domain structure is enhanced by a factor of 2.5 compared with typical c domain PbTiO3. This work presents a new strategy to manipulate the piezoelectricity in ferroelectric membranes, highlighting their great potential for nano actuators, transducers, sensors and other NEMS device applications.

Exosome miR-552 Promotes Laryngocarcinoma Cells Malignant Progression via the PTEN/TOB1 Axis.

INTRODUCTION: Tumor exosome-derived miRNAs play important roles in the human laryngocarcinoma. However, it is still unknown if exosome miR-552 is involved in the laryngocarcinoma. The aim of the current study was to explore exosome miR-552's role in laryngocarcinoma and its underlying mechanisms. METHODS: Hep-2 exosome was characterized by transmission electron microscopy and nanoparticle tracking technology. CCK-8 was used to determine cell viability, and a xenograft animal model was used to determine the tumorigenicity. qPCR and Western blotting were used to measure the changes in target biomarkers. Luciferase reporter assay was used to evaluate the interactions between miR-552 and PTEN. miRNA sequencing was used to check the changes in miRNA profiles. RESULTS: miR-552 was upregulated in the laryngocarcinoma patients and was positively correlated to the cell proliferation and tumor growth. PTEN was identified as a direct target of miR-552. Hep-2 exosome is featured by high expression of miR-552 and treatment of Hep-2 exosome enhanced cell proliferation and tumorigenicity. The underlying mechanisms revealed that treatment of exosomes enhanced the malignant transformation of recipient cells in part by regulating epithelial-mesenchymal transition. CONCLUSION: Exosome miR-552 promotes laryngocarcinoma cells' malignant progression in part by the regulation of the PTEN/TOB1 axis.

Body mass index and death by cognitive impairment.

BACKGROUND: Epidemiological studies have reported that among participants with impaired cognitive, overweight and mild obesity are associated with substantially improved survival, this finding has been termed the "obesity paradox" and has led to uncertainty about secondary prevention. AIMS: To explore whether the association of BMI with mortality differed in different MMSE score, and whether the obesity paradox in patient with cognitive impairment (CI) is real. METHODS: The study used data from CLHLS, a representative prospective population-based cohort study in China, which included 8348 participants aged ≥ 60 years between 2011 and 2018. The independent association between BMI and mortality in differed MMSE score by calculating hazard ratios (HRs) in multivariate Cox regression analysis. RESULTS: During a median (IQR) follow-up of 41.18 months, a total of 4216 participants died. In the total population, underweight increased the risk of all-cause mortality (HRs, 1.33; 95% CI 1.23-1.44), compared with normal weight, and overweight was associated with a decreased risk of all-cause mortality (HR 0.83; 95% CI 0.74-0.93). However, compared to normal weight, only underweight was associated with increased mortality risk among participants with MMSE scores of 0-23, 24-26, 27-29, and 30, and the fully-adjusted HRs (95% CIs) for mortality were 1.30 (1.18, 1.43), 1.31 (1.07, 1.59), 1.55 (1.34, 1.80) and 1.66 (1.26, 2.20), respectively. The obesity paradox was not found in individuals with CI. Sensitivity analyses carried out had hardly any impact on this result. CONCLUSION: We found no evidence of an obesity paradox in patients with CI, compared with patients of normal weight. But underweight individuals may have increased mortality risk whether in the population with CI or not. And overweight/obese people with CI should continue to aim for normal weight.

MiR-5189-3p Suppresses cell Proliferation, Invasion and Migration Through Targeting EIF5A2 in Laryngeal Squamous Cell Carcinoma.

A growing body of evidence suggests that miR-5189-3p plays a critical role in multiple diseases. This study aimed to investigate the function of miR-5189-3p in laryngeal squamous cell carcinoma (LSCC) and explore its underlying mechanisms. qRT-PCR was designed to determine the expression levels of miR-5189-3p and eukaryotic translation initiation factor 5A2 (EIF5A2), while CCK-8 assay was performed to measure the effects of miR-5189-3p on cell proliferation. Transwell assay was performed to evaluate cell invasion as well as migration, and wound healing assay was applied to demonstrate cell migratory ability. Target gene prediction and luciferase reporter assay were developed to screen the possible target gene of miR-5189-3p, and Western blot was designed to measure EIF5A2 protein expression. MiR-5189-3p was down-regulated in LSCC tissues and cell lines. Up-regulation of miR-5189-3p notably inhibited cell proliferation, invasion, and migration in HEP2 and FADU cells. EIF5A2 was the potential downstream gene of miR-5189-3p, and overexpression of miR-5189-3p apparently reduced EIF5A2 expression. Moreover, reintroduction of EIF5A2 rescued the tumor suppressive effects of miR-5189-3p. MiR-5189-3p functions as a tumor inhibitor in LSCC progression via directly regulating EIF5A2 and may be a potential therapeutic target for LSCC.

Association Between Children's Empathy and Depression: The Moderating Role of Social Preference.

Although empathy is typically an adaptive characteristic of children, extreme empathy alone or in combination with a negative environment may contribute to a risk of depression. The present study comprehensively investigated the associations between the three constructs of empathy and depression in children, as well as the potential moderating effect of peer relationships (i.e., social preference) on this association. A total of 1223 children (mean age = 10.50 ± .93 years) completed questionnaires on empathy and depression, and social preference was nominated by their peers. Cognitive empathy and positive empathy exerted a positive quadratic effect on depression, while negative empathy had a positive linear association with depression. For children with a low social preference, all three empathy constructs were positively quadratically correlated with depression, extremely high and low empathy were associated with increased depression, and moderate empathy was associated with the lowest level of depression. For children with a high social preference, higher positive empathy was associated with lower depression.

Measuring volatile emissions from biosolids: A critical review on sampling methods.

As a by-product of wastewater treatment, biosolids are a source of volatile emissions which can lead to community complaints due to odours and other pollution risks. Sampling methods play a significant role in collecting gas emissions from biosolids-related sources (i.e., pure biosolids, landfilling, land application and composting of biosolids). Though a range of different sampling techniques (flux hood, wind tunnel, static chamber, headspace devices) have been explored in many published papers, the management and best practice for sampling emissions from biosolids is unclear. This paper presents a comprehensive review of sampling methods for collecting gaseous emissions from biosolids. To account for the inconsistent terminologies used to describe sampling devices, a standard nomenclature by grouping sampling devices into five categories was proposed. Literature investigating emission sampling from biosolids-related sources was reviewed. Subsequently a critical analysis of sampling methods in terms of design, advantages, and disadvantages were compiled based on literature findings and assumed mechanistic understanding of operation. Key operational factors such as the presence of fans, purge gas flow rates, insertion depth, and incubation conditions were identified and their level of influence on the measurement of emissions were evaluated. From the review, there are still knowledge gaps regarding sampling methods used to collect gases from biosolids-related sources. Therefore, a framework for the management of emission sampling methodologies based on common sampling purposes was proposed. This critical review is expected to improve the understanding of sampling methodologies used in biosolids-related sources, by demonstrating the potential implications and impacts due to different choices in sampling methods.

Spectral filtering effect-induced temporal rogue waves in a Tm-doped fiber laser.

We have experimentally and theoretically investigated optical rogue waves (ORWs) in a net negative dispersion Tm-doped fiber laser with a long cavity, adopting nonlinear polarization evolution as a mode-locker as well as a spectral filter. We obtained a state with numerous pulses bunched in a burst accompanied by perturbation within the burst, in which the spectrum was partially perturbed. After statistical analysis, we found that ORWs have existed in this bunching state. By adjusting the intra-cavity polarization controllers, the perturbed pulse bunching turned into a chaotic pulse bunching state, which gave rise to giant pulses with ultra-high amplitudes, and the giant pulses were a precursor of a broad-spectrum noise-like pulse. The probability of occurrence of ORWs was increased in the chaotic state, which is caused by multi-pulse instability induced by the spectral filtering effect. Simulation results confirm the experimental results and demonstrate that the spectral filter bandwidth (SFB) is directly related to the probability of the emergence of ORWs. When increasing the SFB across the range of multi-pulse instability at a fixed pump power, the frequency with which ORWs appear increases.

Survey of Clinical Translation of Cancer Nanomedicines-Lessons Learned from Successes and Failures.

In 1995, the year the first cancer nanomedicine, Doxil, was approved by the Food and Drug Administration (FDA), only 23 manuscripts appeared in a PubMed search for "nanoparticles for cancer" keywords. Now, over 25 000 manuscripts can be found using those same keywords, yet only 15 nanoparticle-based cancer nanomedicines are approved globally. Based on the clinicaltrials.gov database, a total of 75 cancer nanomedicines are under clinical investigation involving 190 clinical trials summarized here. In this Account, we focus on cancer nanomedicines that have been approved or reached clinical trials to understand this high attrition rate. We classify the various nanomedicines, summarize their clinical outcomes, and discuss possible reasons for product failures and discontinuation of product development efforts. Among ongoing and completed clinical trials, 91 (48 completed) are phase 1, 78 (59 completed) phase 2, and 21 (11 completed) phase 3. The success rate of phase 1 trials has been high-roughly 94%. Of those phase 1 trials with identified outcomes, 45 showed positive safety and efficacy results, with only one negative result (low efficacy) and two terminated due to adverse reactions. In some cases, findings from these trials have not only shown improved pharmacokinetics, but also avid drug accumulation within tumor tissues among active-targeting nanoparticles, including BIND-014, CALAA-01, and SGT-94. However, the success rate drops to ∼48% among completed phase 2 trials with identified outcomes (31 positive, 15 negative, and 4 terminated for toxicity or poor efficacy). A majority of failures in phase 2 trials were due to poor efficacy (15 of 19), rather than toxicity (4 of 19). Unfortunately, the success rate for phase 3 trials slumps to a mere ∼14%, with failures stemming from lack of efficacy. Although the chance of success for cancer nanomedicines starting from the proof-of-concept idea in the laboratory to valuable marketed product may seem daunting, we should not be discouraged. Despite low success rates, funding from the government, foundations, and research organizations are still strong-an estimated > $130 M spent by the National Institutes of Health (NIH) on R01s focused on nanomedicine in 2018 alone. In addition, the NIH created several special initiatives/programs, such as the National Cancer Institute (NCI) Alliance, to facilitate clinical translation of nanomedicines. Companies developing cancer nanomedicines raised diverse ranges of funds from venture capital, capital markets, and industry partnerships. In some cases, the development efforts resulted in regulatory approvals of cancer nanomedicines. In other cases, clinical failures and market pressure from improving standard of care products resulted in product terminations and business liquidation. Yet, recent approvals of nanomedicine products for orphan cancers and continuing development of nanoparticle based drugs for immune-oncology applications fuel continuing industrial and academic interest in cancer nanomedicines.

Positive influence of peers' interpersonal character on children's interpersonal character: The moderating role of children's and peers' social status.

INTRODUCTION: Peers are an important source of influence on children's social development. This study investigated the positive association between peers' and children's interpersonal character (i.e., humanity and justice) and the moderating role of children's and peers' social status including wealth (family SES), power (class leadership), and prestige (social preference and social visibility). METHODS: The participants were 1555 fourth-to ninth-graders (Mage = 12.76; 46.9% boys) and their reciprocal playmates in China. Questionnaires and peer nomination methods were used to measure interpersonal character and social status. Children's reciprocal playmates were used as the source of peer influence. RESULTS: The playmates' humanity and justice were positively associated with the children's humanity and justice regardless of the child's grade, gender, or sibling status. Children's level of social visibility moderated the associations between the playmates' and the children's humanity and justice, with children of low social visibility being more strongly influenced by their playmates. The moderating role of playmates' social status was displayed in two modes and appeared in the secondary school and singleton samples. First, playmates with a higher social preference were more closely related to secondary school children's justice; second, playmates with lower social visibility were more closely related to secondary school children's and singletons' justice. CONCLUSIONS: The findings confirm the positive relationships between peers' and children's interpersonal character and reveal an important moderating role of prestige status, especially social visibility, among the relationships. This study extends the research on positive peer influence and contributes to knowledge of peer influence mechanisms.

Group bias in children's merit-based resource allocation.

From early in life, children show sensitivity to both merit and group membership. However, little research has examined how children react to the conflicting demands of allocating meritoriously and favoring in-groups during resource allocation over the course of their development. We compared how children aged 3-5 years and children aged 6-8 years allocated and reasoned about allocations to in-group and out-group members in a merit-based context. In Study 1, in four distribution tasks, children needed to allocate resources to high- and low-merit persons who were either in-group or out-group members and then indicate the reasons for their decisions. In Study 2, we chose the condition where the conflict between merit and group bias was strongest and further tested the effect of merit and group bias. We found that children prioritized merit across conditions, whereas in a context where the conflict was sufficiently intense they also took group membership into consideration. In addition, with age, children incorporated the conflicting demands of merit and group bias during resource allocation. The findings suggest that, with age, children weighed the moral concerns of merit and the social concerns of group bias when determining the allocation of resources.

Macrophage-Membrane-Coated Nanoparticles for Tumor-Targeted Chemotherapy.

Various delivery vectors have been integrated within biologically derived membrane systems to extend their residential time and reduce their reticuloendothelial system (RES) clearance during systemic circulation. However, rational design is still needed to further improve the in situ penetration efficiency of chemo-drug-loaded membrane delivery-system formulations and their release profiles at the tumor site. Here, a macrophage-membrane-coated nanoparticle is developed for tumor-targeted chemotherapy delivery with a controlled release profile in response to tumor microenvironment stimuli. Upon fulfilling its mission of tumor homing and RES evasion, the macrophage-membrane coating can be shed via morphological changes driven by extracellular microenvironment stimuli. The nanoparticles discharged from the outer membrane coating show penetration efficiency enhanced by their size advantage and surface modifications. After internalization by the tumor cells, the loaded drug is quickly released from the nanoparticles in response to the endosome pH. The designed macrophage-membrane-coated nanoparticle (cskc-PPiP/PTX@Ma) exhibits an enhanced therapeutic effect inherited from both membrane-derived tumor homing and step-by-step controlled drug release. Thus, the combination of a biomimetic cell membrane and a cascade-responsive polymeric nanoparticle embodies an effective drug delivery system tailored to the tumor microenvironment.

Intergenerational transmission of interpersonal strengths: The role of parent gender, family processes, and child characteristics.

Interpersonal strengths are important positive traits of human beings. This study investigated the phenomenon and mechanisms of the intergenerational transmission of interpersonal strengths. A total of 992 fourth-to ninth-grade children (48.1% boys, Mage = 12.63) and both mothers and fathers in China were involved in the present study. The results showed that fathers' (but not mothers') interpersonal strengths were directly associated with children's interpersonal strengths. Different transmission mechanisms of mothers and fathers were found: mother-child relationships and fathers' parenting styles explained the association between parents' and children's interpersonal strengths and between marital relationships and children's interpersonal strengths. Consistent transmission effects and mechanisms were found across child grade, gender, and sibling status. The findings of the current study provide evidence of intergenerational correlations for both parents regarding interpersonal strengths. Parents (especially fathers) with interpersonal strengths can raise children with corresponding strengths through particular family processes regardless of child characteristics.

Tumor-Targeting Micelles Based on Linear-Dendritic PEG-PTX8 Conjugate for Triple Negative Breast Cancer Therapy.

Most small molecular chemotherapeutics have poor water solubility and unexpected pharmacokinetics and toxicity to normal tissues. A series of nano drug delivery systems have been developed to solve the problems, among which a micelle based on linear-dendritic polymer-drug conjugates (LDPDCs) is a promising strategy to deliver hydrophobic chemotherapeutics due to its small size, fine stability in blood circulation, and high drug loading capacity. In this work we synthesized a novel amphiphilic linear-dendritic PEG-PTX8 conjugate which can also encapsulate extra free PTX and self-assemble into uniform ultrasmall micelles with a hydrated diameter of 25.50 ± 0.27 nm. To realize efficient drug delivery to tumor sites, a cyclic tumor homing and penetrating peptide iNGR was linked to the PEG-PTX8 conjugate. The biological evaluation was performed on a human triple negative breast cancer model. PTX accumulation in tumor at 24 h of the TNBC-bearing mice treated with iNGR-PEG-PTX8/PTX micelles was significantly enhanced (P < 0.001, two-way ANOVA) compared to that of Taxol and untargeted MeO-PEG-PTX8/PTX micelles. Furthermore, iNGR-PEG-PTX8/PTX micelles showed an obvious strong antitumor effect, and the median survival time of TNBC bearing mice treated with iNGR-modified micelles was significantly extended compared to Taxol. Therefore, this smart micelle system may be a favorable platform for effective TNBC therapy.

Dual Functional Peptide-Driven Nanoparticles for Highly Efficient Glioma-Targeting and Drug Codelivery.

Compared with peripheral tumors, glioma is very difficult to treat, not only because it has general features of tumor but also because the therapy has been restricted by the brain-blood barrier (BBB). The two main features of tumor growth are angiogenesis and proliferation of tumor cells. RNA interference (RNAi) can downregulate VEGF overexpression to inhibit tumor neovascularization. Meanwhile, doxorubicin (DOX) has been used for cytotoxic chemotherapy to kill tumor cells. Thus, combining RNAi and chemotherapy has been regarded as a potential strategy for cancer treatment. However, the BBB limits the shVEGF-DOX codelivery system to direct into glioma. Here, a smart drug delivery system modified with a dual functional peptide was established, which could target to transferrin receptor (TfR) overexpressing on both the BBB and glioma. It showed that the dual-targeting delivery system had high tumor targeting efficiency in vitro and in vivo.