Jet Electroforming of High-Aspect-Ratio Microcomponents by Periodically Lifting a Necked-Entrance Through-Mask.

High-aspect-ratio micro- and mesoscale metallic components (HAR-MMMCs) can play some unique roles in quite a few application fields, but their cost-efficient fabrication is significantly difficult to accomplish. To address this issue, this study proposes a necked-entrance through-mask (NTM) periodically lifting electroforming technology with an impinging jet electrolyte supply. The effects of the size of the necked entrance of the through-mask and the jet speed of the electrolyte on electrodeposition behaviors, including the thickness distribution of the growing top surface, deposition defect formation, geometrical accuracy, and electrodeposition rate, are investigated numerically and experimentally. Ensuring an appropriate size of the necked entrance can effectively improve the uniformity of deposition thickness, while higher electrolyte flow velocities help enhance the density of the components under higher current densities, reducing the formation of deposition defects. It was shown that several precision HAR-MMMCs with an AR of 3.65 and a surface roughness (Ra) of down to 36 nm can be achieved simultaneously with a relatively high deposition rate of 3.6 µm/min and thickness variation as low as 1.4%. Due to the high current density and excellent mass transfer effects in the electroforming conditions, the successful electroforming of components with a Vickers microhardness of up to 520.5 HV was achieved. Mesoscale precision columns with circular and Y-shaped cross-sections were fabricated by using this modified through-mask movable electroforming process. The proposed NTM periodic lifting electroforming method is promisingly advantageous in fabricating precision HAR-MMMCs cost-efficiently.

Breaking the Tumor Chronic Inflammation Balance with a Programmable Release and Multi-Stimulation Engineering Scaffold for Potent Immunotherapy.

Tumor-associated chronic inflammation severely restricts the efficacy of immunotherapy in cold tumors. Here, a programmable release hydrogel-based engineering scaffold with multi-stimulation and reactive oxygen species (ROS)-response (PHOENIX) is demonstrated to break the chronic inflammatory balance in cold tumors to induce potent immunity. PHOENIX can undergo programmable release of resiquimod and anti-OX40 under ROS. Resiquimod is first released, leading to antigen-presenting cell maturation and the transformation of myeloid-derived suppressor cells and M2 macrophages into an antitumor immune phenotype. Subsequently, anti-OX40 is transported into the tumor microenvironment, leading to effector T-cell activation and inhibition of Treg function. PHOENIX consequently breaks the chronic inflammation in the tumor microenvironment and leads to a potent immune response. In mice bearing subcutaneous triple-negative breast cancer and metastasis models, PHOENIX effectively inhibited 80% and 60% of tumor growth, respectively. Moreover, PHOENIX protected 100% of the mice against TNBC tumor rechallenge by electing a robust long-term antigen-specific immune response. An excellent inhibition and prolonged survival in PHOENIX-treated mice with colorectal cancer and melanoma is also observed. This work presents a potent therapeutic scaffold to improve immunotherapy efficiency, representing a generalizable and facile regimen for cold tumors.

Reversing cancer immunoediting phases with a tumor-activated and optically reinforced immunoscaffold.

In situ vaccine (ISV) is a promising immunotherapeutic tactic due to its complete tumoral antigenic repertoire. However, its efficiency is limited by extrinsic inevitable immunosuppression and intrinsic immunogenicity scarcity. To break this plight, a tumor-activated and optically reinforced immunoscaffold (TURN) is exploited to trigger cancer immunoediting phases regression, thus levering potent systemic antitumor immune responses. Upon response to tumoral reactive oxygen species, TURN will first release RGX-104 to attenuate excessive immunosuppressive cells and cytokines, and thus immunosuppression falls and immunogenicity rises. Subsequently, intermittent laser irradiation-activated photothermal agents (PL) trigger abundant tumor antigens exposure, which causes immunogenicity springs and preliminary infiltration of T cells. Finally, CD137 agonists from TURN further promotes the proliferation, function, and survival of T cells for durable antitumor effects. Therefore, cancer immunoediting phases reverse and systemic antitumor immune responses occur. TURN achieves over 90 % tumor growth inhibition in both primary and secondary tumor lesions, induces potent systemic immune responses, and triggers superior long-term immune memory in vivo. Taken together, TURN provides a prospective sight for ISV from the perspective of immunoediting phases.

A programmable releasing versatile hydrogel platform boosts systemic immune responses via sculpting tumor immunogenicity and reversing tolerogenic dendritic cells.

Immunogenicity improvement is a valuable strategy for tumor immunotherapy. However, immunosuppressive factors bestow tolerogenic phenotype on tumor-infiltrating DCs, which exhibit weak antigen presentation and strong anti-inflammatory cytokines secretion abilities, limiting the effectiveness of tumor immunotherapy even if the tumor has adequate immunogenicity. Herein, we designed a programmable releasing versatile hydrogel platform (PIVOT) to sculpt tumor immunogenicity, increase intratumoral DCs and cDC1s abundance, and reverse the tolerogenic phenotype of DCs, thus promoting their maturation for boosting innate and adaptive immune responses. Responsive to tumoral reactive oxygen species (ROS), the hydrogel splits and promotes the activation of DCs and macrophages. Then, oxaliplatin is first released from PIVOT to sculpt tumor immunogenicity by inducing immunogenic cell death (ICD) and causing tumoral DNA fragments exposure simultaneously. Subsequently, the impaired DNA fragments bind to high mobility group protein 1 (HMGB1) forming the DNA-HMGB1 complex. Moreover, exogenous FMS-like tyrosine kinase 3 ligand (Flt-3L) recruits masses of DCs, especially cDC1s, which will endocytose the complex benefiting from TIM-3 blockade (αTIM3) that can reverse tolerogenic DCs. Finally, the endocytosis activates the cGAS-STING pathway of cDC1s, which promotes the secretion of type I IFN that triggers innate immune responses, and CXCL9 which recruits CD8+ effector T cells to initiate the following adaptive immune response against tumor progress. PIVOT achieves nearly 90 % tumor growth inhibition and induces systemic antitumor immune responses. In conclusion, this study focuses on ICD-mediated tumor immunogenicity sculpture and nucleic acid endocytosis-involved tolerogenic DCs reversal, providing a novel paradigm for enhancing DCs-based antitumor immune responses.

Artificial Intelligence Aided Lipase Production and Engineering for Enzymatic Performance Improvement.

With the development of artificial intelligence (AI), tailoring methods for enzyme engineering have been widely expanded. Additional protocols based on optimized network models have been used to predict and optimize lipase production as well as properties, namely, catalytic activity, stability, and substrate specificity. Here, different network models and algorithms for the prediction and reforming of lipase, focusing on its modification methods and cases based on AI, are reviewed in terms of both their advantages and disadvantages. Different neural networks coupled with various algorithms are usually applied to predict the maximum yield of lipase by optimizing the external cultivations for lipase production, while one part is used to predict the molecule variations affecting the properties of lipase. However, few studies have directly utilized AI to engineer lipase by affecting the structure of the enzyme, and a set of research gaps needs to be explored. Additionally, future perspectives of AI application in enzymes, including lipase engineering, are deduced to help the redesign of enzymes and the reform of new functional biocatalysts. This review provides a new horizon for developing effective and innovative AI tools for lipase production and engineering and facilitating lipase applications in the food industry and biomass conversion.

Tumor Environment Regression Therapy Implemented by Switchable Prune-to-Essence Nanoplatform Unleashed Systemic Immune Responses.

Coevolution of tumor cells and surrounding stroma results in protective protumoral environment, in which abundant vessel, stiff structure and immunosuppression promote each other, cooperatively incurring deterioration and treatment compromise. Reversing suchenvironment may transform tumors from treatment-resistant to treatment-vulnerable. However, effective reversion requires synergistic comprehensive regression of such environment under precise control. Here, the first attempt to collaboratively retrograde coevolutionary tumor environment to pre-oncogenesis status, defined as tumor environment regression therapy, is made for vigorous immune response eruption by a switchable prune-to-essence nanoplatform (Pres) with simplified composition and fabrication process. Through magnetic targeting and multimodal imaging of Pres, tumor environment regression therapy is guided, optimized and accomplished in a trinity way: Antiangiogenesis is executed to rarefy vessels to impede tumor progression. By seizing the time, cancer associated fibroblasts are eliminated to diminish collagen and loosen the stiff structure for deep penetration of Pres, which alternately functioned in deeper tumors, forming a positive feedback loop. Through this loop, immune cell infiltration, immunosuppression mitigation and immunogenic cells death induction are all fulfilled and further escalated in the regressed environment. These transformations consequently unleashed systemic immune responses and generated immune memory against carcinoma. This study provides new insights intotreatment of solid tumors.

Effects of probiotics in patients with morbid obesity undergoing bariatric surgery: a systematic review and meta-analysis.

BACKGROUND: Probiotics are commonly used after bariatric surgery. However, uncertainty remains regarding their effects. The purpose of this systematic review was to assess the effect of probiotics in patients with morbid obesity undergoing bariatric surgery. METHODS: PubMed, Cochrane Library, Embase, Science Direct, and Web of Science were searched from inception to April 4, 2023. No language restrictions were applied. Relevant randomized controlled trials and controlled clinical trials were included. We used the aggregated data extracted from the trials and assessed the heterogeneity. When severe heterogeneity was detected, a random effect model was used. All stages of the review were done by independent authors. RESULTS: We screened 2024 references and included 11 randomized controlled trials and controlled clinical trials. Compared with the protocol groups, probiotics showed significant effects on regulating aspartate amino transferase level (MD = -4.32 U/L; 95% CI [-7.10, -1.53], p = 0.002), triglycerides (MD = -20.16 mg/dL; 95% CI [-34.51, -5.82], p = 0.006), weight (MD = -1.99 kg; 95% CI [-3.97, -0.01], p = 0.05), vitamin B12 (MD = 2.24 pg/dL; 95% CI [-0.02, 4.51], p = 0.05), dietary energy (MD = -151.03 kcal; 95% CI [-215.68, -86.37], p < 0.00001), dietary protein (MD = -4.48 g/day, 95% CI [-8.76, -0.20], p = 0.04), dietary carbohydrate (MD = -34.25 g/day, 95% CI [-44.87, -23.62], p < 0.00001), and dietary fiber (MD = -2.17 g/day, 95% CI [-3.21, -1.14], p < 0.0001). There were no severe side effects related to probiotics. CONCLUSIONS: Our meta-analysis suggested that probiotics may delay the progression of liver function injury, improve lipid metabolism, reduce weight, and reduce food intake, although the effects on other indicators were insignificant. Probiotics may be helpful for patients undergoing bariatric surgery. The review was registered on PROSPERO (International prospective register of systematic reviews): CRD42023407970. No primary source of funding.

Antigenicity and adjuvanticity co-reinforced personalized cell vaccines based on self-adjuvanted hydrogel for post-surgical cancer vaccination.

Cancer vaccine-based postsurgical immunotherapy is emerging as a promising approach in patients following surgical resection for inhibition of tumor recurrence. However, low immunogenicity and insufficient cancer antigens limit the widespread application of postoperative cancer vaccines. Here, we propose a "trash to treasure" cancer vaccine strategy to enhance postsurgical personalized immunotherapy, in which antigenicity and adjuvanticity of purified surgically exfoliated autologous tumors (with whole antigen repertoire) were co-reinforced. In the antigenicity and adjuvanticity co-reinforced personalized vaccine (Angel-Vax), polyriboinosinic: polyribocytidylic acid (pIC) and tumor cells that have undergone immunogenic death are encapsulated in a self-adjuvanted hydrogel formed by cross-linking of mannan and polyethyleneimine. Angel-Vax exhibits an enhanced capacity on antigen-presenting cells stimulation and maturation compared to its individual components in vitro. Immunization with Angel-Vax provokes an efficient systemic cytotoxic T-cell immune response, contributing to the satisfied prophylactic and therapeutic efficacy in mice. Furthermore, when combined with immune checkpoint inhibitors (ICI), Angel-Vax effectively prevented postsurgical tumor recurrence, as evidenced by an increase in median survival of approximately 35% compared with ICI alone. Unlike the cumbersome preparation process of postoperative cancer vaccines, the simple and feasible approach herein may represent a general strategy for various kinds of tumor cell-based antigens in the inhibition of postsurgical tumor relapse by reinforced immunogenicity.

A Multivalent Personalized Vaccine Orchestrating Two-Signal Activation Rebuilds the Bridge Between Innate and Adaptive Antitumor Immunity.

Personalized vaccines capable of circumventing tumor heterogeneity have exhibited compelling prospects. However, their therapeutic benefit is greatly hindered by the limited antigen repertoire and poor response of CD8+ T-cell immunity. Here, a double-signal coregulated cross-linking hydrogel-based vaccine (Bridge-Vax) is engineered to rebuild the bridge between innate and adaptive immunity for activating CD8+ T-cells against full repertoire of tumor antigens. Mechanistically, unlike prominent CD4+ T-cell responses in most cases, administration of Bridge-Vax encapsulated with granulocyte-macrophage colony-stimulating factor concentrates a wave of dendritic cells (DCs), which further promotes DCs activation with costimulatory signal by the self-adjuvanted nature of polysaccharide hydrogel. Simultaneously, synergy with the increased MHC-I epitopes by codelivered simvastatin for cross-presentation enhancement, Bridge-Vax endows DCs with necessary two signals for orchestrating CD8+ T-cell activation. Bridge-Vax elicits potent antigen-specific CD8+ T-cell responses in vivo, which not only shows efficacy in B16-OVA model but confers specific immunological memory to protect against tumor rechallenge. Moreover, personalized multivalent Bridge-Vax tailored by leveraging autologous tumor cell membranes as antigens inhibits postsurgical B16F10 tumor recurrence. Hence, this work provides a facile strategy to rebuild the bridge between innate and adaptive immunity for inducing potent CD8+ T-cell immunity and would be a powerful tool for personalized cancer immunotherapy.

A tactical nanomissile mobilizing antitumor immunity enables neoadjuvant chemo-immunotherapy to minimize postsurgical tumor metastasis and recurrence.

Neoadjuvant chemotherapy has become an indispensable weapon against high-risk resectable cancers, which benefits from tumor downstaging. However, the utility of chemotherapeutics alone as a neoadjuvant agent is incapable of generating durable therapeutic benefits to prevent postsurgical tumor metastasis and recurrence. Herein, a tactical nanomissile (TALE), equipped with a guidance system (PD-L1 monoclonal antibody), ammunition (mitoxantrone, Mit), and projectile bodies (tertiary amines modified azobenzene derivatives), is designed as a neoadjuvant chemo-immunotherapy setting, which aims at targeting tumor cells, and fast-releasing Mit owing to the intracellular azoreductase, thereby inducing immunogenic tumor cells death, and forming an in situ tumor vaccine containing damage-associated molecular patterns and multiple tumor antigen epitopes to mobilize the immune system. The formed in situ tumor vaccine can recruit and activate antigen-presenting cells, and ultimately increase the infiltration of CD8+ T cells while reversing the immunosuppression microenvironment. Moreover, this approach provokes a robust systemic immune response and immunological memory, as evidenced by preventing 83.3% of mice from postsurgical metastasis or recurrence in the B16-F10 tumor mouse model. Collectively, our results highlight the potential of TALE as a neoadjuvant chemo-immunotherapy paradigm that can not only debulk tumors but generate a long-term immunosurveillance to maximize the durable benefits of neoadjuvant chemotherapy.

The effect of students' online learning experience on their satisfaction during the COVID-19 pandemic: The mediating role of preference.

Introduction: During the peak of the COVID-19 pandemic, nearly all educational institutions globally had to eventually embrace the maneuver of transferring to nearly 100% online learning as a new routine for different curricula. Although many students in developing countries such as Kenya are only experiencing the exclusive online learning approach for the first time, research on students' experience and satisfaction with COVID-19-imposed online learning is largely lacking. Thus, this study examined the effect of online-learning experiences on satisfaction in the setting of the COVID-19 pandemic in Kenya. The mediating role of students' preference on the relationship between online-learning experience and satisfaction was also examined. Methods: A web-based survey involving 501 respondents was analyzed using IBM® SPSS® and AMOS software platforms. A structural equation model (SEM) was used to analyze the relationships. Results and Discussion: Results showed that 80% of participants indicated their preference for in-person learning as against 20% for online learning. Students' satisfaction-SS had a significant positive correlation with online classroom perceived quality-OCPQ, acquisition of self-confidence-ASC, teaching performance and engagement-TPE, and preference for online learning-POL but a negative correlation with internet access and cost-IAC. Moreover, while POL positively correlated with OCPQ, ASC, and TPE, it negatively correlated with IAC. Both the structural model for the main effect and the mediation model provided a good fit and confirmed these relationships. Student preference had a significant effect on satisfaction and played a significant mediating role in the relationship between online-learning experience and satisfaction. These findings shed light on the underlying factors that explain students' online learning satisfaction and provide guidelines for universities and policymakers to make better decisions that enhance students' online-learning experience and satisfaction.

Tumor Microenvironment-Activated Hydrogel Platform with Programmed Release Property Evokes a Cascade-Amplified Immune Response against Tumor Growth, Metastasis and Recurrence.

In situ tumor vaccines (ITV) have been recognized as a promising antitumor strategy since they contain the entire tumor-specific antigens, avoiding tumor cells from evading immune surveillance due to antigen loss. However, the therapeutic benefits of ITV are limited by obstacles such as insufficient antigen loading, inadequate immune system activation, and immunosuppressive tumor microenvironments (TME). Herein, a tumor microenvironment-activated hydrogel platform (TED-Gel) with programmed drug release property is constructed for cascaded amplification of the anti-tumor immune response elicited by ITV. Both doxorubicin (Dox) and cytosine-phosphate-guanosine oligodeoxynucleotides (CpG) are released first, in which Dox induces immunogenic tumor cell death causing additional tumor antigen release and leading the dying primary tumor cells into autologous tumor vaccine, and the released CpG promotes antigen presenting cell activation. Subsequently, the decomposed scaffold materials in conjunction with CpG, turn the anti-inflammatory M2-like macrophages into the M1 type, reversing the immunosuppressive TME. With decomposition of the TED-Gel, large amounts of macromolecule anti-PD-L1 antibodies are liberated, reinvigorating the exhausted effector T cells. In vivo studies demonstrate that TED-Gel significantly inhibits the primary, distant and rechallenged tumor growth. Overall, the simple and powerful TED-Gel provides an alternative strategy for the future development of tumor vaccines with broad application.

New insights into the characteristics of DRAK2 and its role in apoptosis: From molecular mechanisms to clinically applied potential.

As a member of the death-associated protein kinase (DAPK) family, DAP kinase-associated apoptosis-inducing kinase 2 (DRAK2) performs apoptosis-related functions. Compelling evidence suggests that DRAK2 is involved in regulating the activation of T lymphocytes as well as pancreatic ß-cell apoptosis in type I diabetes. In addition, DRAK2 has been shown to be involved in the development of related tumor and non-tumor diseases through a variety of mechanisms, including exacerbation of alcoholic fatty liver disease (NAFLD) through SRSF6-associated RNA selective splicing mechanism, regulation of chronic lymphocytic leukemia and acute myeloid leukemia, and progression of colorectal cancer. This review focuses on the structure, function, and upstream pathways of DRAK2 and discusses the potential and challenges associated with the clinical application of DRAK2-based small-molecule inhibitors, with the aim of advancing DRAK2 research.

Multifunctional light-activatable nanocomplex conducting temperate-heat photothermal therapy to avert excessive inflammation and trigger augmented immunotherapy.

Photothermal therapy (PTT) has been known as an effective weapon against cancer. However, the necrosis induced by hyperthermia post PTT can trigger excessive inflammation response and arouse tumor self-protection resulting in tumor immunosuppression, metastasis and recurrence. To settle this issue, we here reported a multifunctional light-activatable nanocomplex (MILAN) to avoid hyperthermia and achieve temperate-heat PTT for extensive apoptosis, but not necrosis, and further antitumor immune response augmentation to inhibit metastasis and recurrence. Upon NIR irradiation, MILAN would controllably maintain around 43 °C, thus evoking the temperature-triggered phase transformation for the controllable drug release. Then, the released gambogic acid broke the thermoresistance of tumor cells, realizing enhanced apoptosis. Thereafter, the generated tumor-associated antigen accompanied with MILAN could facilitate dendritic cells (DCs) maturation for improved antigen presentation. Furthermore, MILAN promoted the tumor perfusion of DCs and T lymphocytes in triple-negative breast cancer (TNBC) models. Simultaneously, the immunosuppressive microenvironment was relieved and a strong systemic immune response was elicited against tumor progress through MILAN. Consequently, systemic immunity and persistent immune memory effect were fortified for pronounced cancer metastasis and recurrence inhibition. This work tactfully avoids the side effects of hyperthermia and brought a novel insight into cancer immunotherapy against TNBC.

Lanthanide-Nucleotide Coordination Nanoparticles for STING Activation.

Activation of the stimulator of interferon genes (STING) is essential for blocking viral infections and eliciting antitumor immune responses. Local injection of synthetic STING agonists, such as 2'3'-cGAMP [cGAMP = cyclic 5'-guanosine monophosphate (cGMP)-adenosine monophosphate (AMP)], is a promising approach to enhance antiviral functions and cancer immunotherapy. However, the application of such agonists has been hindered by complicated synthetic procedures, high doses, and unsatisfactory systemic immune responses. Herein, we report the design and synthesis of a series of 2'3'-cGAMP surrogates in nanoparticle formulations formed by reactions of AMP, GMP, and coordinating lanthanides. These nanoparticles can stimulate the type-I interferon (IFN) response in both mouse macrophages and human monocytes. We further demonstrate that the use of europium-based nanoparticles as STING-targeted adjuvants significantly promotes the maturation of mouse bone-marrow-derived dendritic cells and major histocompatibility complex class I antigen presentation. Dynamic molecular docking analysis revealed that these nanoparticles bind with high affinity to mouse STING and human STING. Compared with soluble ovalbumin (OVA), subcutaneously immunized europium-based nanovaccines exhibit significantly increased production of primary and secondary anti-OVA antibodies (∼180-fold) in serum, as well as IL-5 (∼28-fold), IFN-γ (∼27-fold), and IFN-α/ß (∼4-fold) in splenocytes ex vivo. Compared with the 2'3'-cGAMP/OVA formulation, subcutaneous administration of nanovaccines significantly inhibits B16F10-OVA tumor growth and prolongs the survival of tumor-bearing mice in both therapeutic and protective models. Given the rich supramolecular chemistry with lanthanides, this work will enable a readily accessible platform for potent humoral and cellular immunity while opening new avenues for cost-effective, highly efficient therapeutic delivery of STING agonists.

An in situ spontaneously forming micelle-hydrogel system with programmable release for the sequential therapy of anaplastic thyroid cancer.

Anaplastic thyroid carcinoma (ATC) is a lethal malignancy with a 1 year survival rate of less than 20%. Combination chemotherapy with cisplatin and paclitaxel is recommended as a critical therapeutic approach toward ATC. However, harsh side-effects on patients and unsatisfactory intratumoral concentrations hamper the effectiveness of systemic chemotherapy. In this work, an in situ spontaneously forming micelle-hydrogel system (iMHS) with programmable-release characteristics was developed for sequential chemotherapy. Taking advantage of the diffusion rate of the hydrophobic drug in the micellar network and the degradation of the hydrogel matrix, iMHS supported sequential chemotherapy via programmatic release. Moreover, in vitro and in vivo studies demonstrated the superiority of sequential release from iMHS over other approaches, regardless of the genetic profile (e.g., different BRAF, TP53, and TERT promoter mutations, etc.). Additionally, iMHS presented the significant ability to prevent local tumor recurrence in a post-surgical model. Overall, iMHS may serve as a promising strategy for the enhanced localized treatment of ATC via the programmable release of chemotherapy drugs with implied translational value.

An Acidity-Initiated Self-Assembly/Disassembly Nanoprobe to Switch on Fluorescence for Tumor-Targeted Near-Infrared Imaging.

The deep penetration, real-time monitoring ability, and high resolution of near-infrared (NIR) fluorescence imaging make it suitable for tumor diagnosis. However, the lack of specificity and selectivity restricts its further application. Here, for the first time, we applied a CBT-Cys click condensation reaction to synthesize an acidity-initiated molecular probe (AIM-Probe, Cys(StBu)-Lys(Cy 5.5)-EDA-PMA-CBT), which could self-assemble into nanoparticles (AIM-NP) with self-quenched fluorescence under glutathione (GSH) reduction. AIM-NP could accumulate in tumors after intravenous injection. Subsequently, the EDA-PMA part of AIM-Probe in AIM-NP is fractured by the unique subacid condition in the tumor microenvironment, and AIM-NP disassembles into a small AIM-cleaved molecule (PMA-CBT-Cys-Lys(Cy5.5)-EDA) along with fluorescence switching on. As a result, AIM-NP could switch on fluorescence at the tumor site, thereby achieving tumor-targeted imaging. To our knowledge, utilizing tumor acidity to initiate the disassembly of self-assembled nanoparticles through a CBT-Cys click condensation reaction has not been reported.

A spontaneous multifunctional hydrogel vaccine amplifies the innate immune response to launch a powerful antitumor adaptive immune response.

Substantial progress has been made with cancer immunotherapeutic strategies in recent years, most of which mainly rely on enhancing the T cell response. However, sufficient tumor antigen information often cannot be presented to T cells, resulting in a failed effector T cell response. The innate immune system can effectively recognize tumor antigens and then initiate an adaptive immune response. Here, we developed a spontaneous multifunctional hydrogel (NOCC-CpG/OX-M, Ncom Gel) vaccine to amplify the innate immune response and harness innate immunity to launch and maintain a powerful adaptive immune response. Methods: Ncom Gel was formed by a Schiff base reaction between CpG-modified carboxymethyl chitosan (NOCC-CpG) and partially oxidized mannan (OX-M). The effects of the Ncom Gel vaccine on DCs and macrophages in vitro and antigen-specific humoral immunity and cellular immunity in vivo were studied. Furthermore, the antitumor immune response of the Ncom Gel vaccine and its effect on the tumor microenvironment were evaluated. Results: The Ncom Gel vaccine enhanced antigen presentation to T cells by facilitating DC uptake and maturation and inducing macrophages to a proinflammatory subtype, further leading to a T cell-mediated adaptive immune response. Moreover, the innate immune response could be amplified via the promotion of antigen-specific antibody production. The Ncom Gel vaccine reversed the tumor immune microenvironment to an inflamed phenotype and showed a significant antitumor response in a melanoma model. Conclusions: Our research implies the potential application of injectable hydrogels as a platform for tumor immunotherapy. The strategy also opens up a new avenue for multilayered cancer immunotherapy.

Numerical Analysis and Experimental Study on Fabrication of High Aspect Ratio Tapered Ultrafine Holes by Over-Growth Electroforming Process.

High aspect ratio (HAR) ultrafine tapered holes (diameter ≤5 µm; AR ≥5) are the most important elements for some high-tech perforated metallic products, but they are very difficult to manufacture. Therefore, this paper proposes a nontraditional over-growth electroforming process. The formation mechanism of the HAR ultrafine tapered holes is investigated, and the factors controlling the geometric shape evolution are analyzed numerically. It was found that the geometric shape and dimensions of the holes are highly dependent on the diameter and thickness of the photoresist film patterns, but are hardly affected by the spacing between two neighboring patterns; the achievable diameter for a given hole depth becomes small with the increasing pattern diameter, but it becomes big with the increasing pattern thickness. These correlations can be well interpreted by the established two empirical equations that characterize the relationship between the minimum orifice of the tapered hole and the structural parameters of the photoresist film patterns previously formed on the substrate. Application of the fabricated 1500 tapered holes with 3-µm diameter and 17-AR as the nozzles of the medical precision nebulizer is also examined. The studies show that the over-growth electroforming process is highly applicable in fabricating the perforated metallic plate with HAR ultrafine tapered holes.

The Effect of Electrolytic Jet Orientation on Machining Characteristics in Jet Electrochemical Machining.

Jet electrochemical machining (Jet-ECM) is a significant prospective electrochemical machining process for the fabrication of micro-sized features. Traditionally and normally, the Jet-ECM process is carried out with its electrolytic jet being vertically impinged downstream against the workpiece. Therefore, other jet orientations, including a vertically upstream orientation and a horizontal orientation, have rarely been adopted. In this study, three jet orientations were applied to electrolytic jet machining, and the effect of jet orientations on machining characteristics was systemically investigated. Horizontal jet orientation is of great benefit in achieving accurate micro-sized features with excellent surface quality with either a static jet or a scanning jet for the Jet-ECM. On the other hand, the Jet-ECM with a horizontal jet orientation has a smaller material removal rate (MMR) than the ones with vertical jet orientations, which have almost the same MMR. It was found that an enhancement of machining localization and a reduction of MMR for horizontal jet electrochemical machining primarily results from an improvement of the mass-transfer field. The horizontal orientation of the jet is beneficial for the Jet-ECM processes to improve machining accuracy.